Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
INTRODUCTION Mental Retardation (MR) is a clinically and etiologically heterogeneous group of conditions. It is lifelong burden that has a predominating impact on the life of the patients, his relatives & even on society as a whole. American Association on Mental Retardation (AAMR) now called the AAIDD (American Association of Intellectual Developmental Disability) and WHO (World Health Organisation) in 2002 defined mental disability as the expression of limitations in individual functioning in social and behavioural context (Luckasson et al. 2002). Mental retardation is one of the common disorders in human. It is the incomplete development of mental capacities & associated behavioural abnormalities (Kaur et al., 2006). Mental retardation is the manifestation of defect in the structure & function of neuronal synapses. It is defined as the failure to develop a sufficient cognitive and adaptive level. In the clinical practice it is measured by the IQ and grouped into four degrees of severity: mild, moderate, severe and profound with IQ levels respectively of 70-50-55, 50-55 to 35-40, 35-40 to 20-25 & below 20 (Battagia & Carey, 2003). In profound cases severe physical deformities, seizures, deafness and short life expectancy is present (Xu and Chen, 2003). Mental retardation is either the only consistent handicap called non syndromic mental retardation or is combined with physical/or behavioural abnormalities called syndromic mental retardation (Winnepenninckx et. al., 2003). It is diagnosed before age 18, and include below average general intellectual function, accompanied by impairment in person’s ability to acquire the skills necessary for daily living (Rauch, 2006). According to WHO mental retardation is “incomplete or insufficient development of mental capacities”. The diagnosis of MR requires an IQ score of at least 2 standard deviations (SD) below the means IQ of 100 (i.e. IQ>70). Equivalent deficits in at least two areas of functional life skills or adaptive skills also must be present to meet the diagnostic criteria for mental retardation. 1 According to estimates 1-3% of the human population has an IQ below 70 & suffers from learning & adaptive disabilities (Curry et al., 1997; Roeleveld et al., 1997; Crones et al., 2001; Aggarwal et al. 2012). Incidence of mental retardation is 2-3 times higher in developing countries as compared to the developed countries. In last 50 years, prevalence and incidence have changed. Mclaren and Bryson (1987) reported the prevalence of mental retardation as 1.25% based on total population survey. In U.K about 1.5 million people have an IQ<70 (Penrose, 1988). Barrof (1991) reported 0.9% of population had mental retardation. Severe mental retardation has a prevalence of 3.5 per 1000 individual. The prevalence of moderate to severe retardation (IQ<50) is 30 to 55 per 10,000 and mild handicap (IQ 50-70) is present in about 2% of the population (Roeleveld et al., 1997). The risk of mental retardation is found to be higher in children with congenital defects (Decoufle et al.,2001). Studies from California reported that small infants were at increased risk for mild and severe mental retardation (Lisa 2001). Mild individuals are educable, intermittent for intensity of support required & having prevalence 0.9-2.75% in total population. Individual of Moderate category are trainable with limited support requirement. Severe individuals are non-trainable, require extensive support and having prevalence 0.3-0.4% in total population (Harum, 2005), whereas those with IQ>20 have profound mental retardation are severely deficit in adaptive behavior & need lifetime support. In China however the reported prevalence was at 9.3 per 1000 of the population (Xie et al 2008). Pilot studies of severe mental retardation conducted in selected populations in Pakistan and India have reported extra ordinarily high prevalence estimates in the range of 12-24/1,000 (Hasan et al., 1981; Narayanan, 1981 and Belmont, 1986). The prevalence rates of mild and severe retardation in Karachi were significantly associated with low socioeconomic status and consanguinity. Sixty percent of children were from consanguineous unions (Shamis et al., 1989 and Darr et al., 1998). Profound mental retardation accounts for 1 to 2% of all mentally retarded people. With IQ scores of 20 to 25, these children have little muscle coordination during early childhood and do not reach developmental milestones such as walking and talking (Aicardi, 1998). 2 In India mild mental retardation was found in 22% children in 0-5 years age group, 19% children in 6-11 years age, and among 6% in children of 12-16 years age group among those attending the psychiatric clinics/child guidance clinics according to ICMR report (ICMR 2005). Among all the classes of mental retardation 85%, 10%, 4% and 2% showed mild, moderate, severe and profound mental retardation respectively (King et. al 2009). The cause of mental retardation is extremely heterogeneous. It may be caused by either genetic or environmental factors or a combination of both. The cause of mental retardation could be established in less than half of all cases (Flint et al., 1995; Curreyet al., 1997; Haper, 2002; Kaur et al., 2003; & Lewis, 2007). In about 30% of mild mental retardation; Genetic and environmental causes explain in roughly equal proportion whereas in the remaining 70% of cases the cause is not known (Bundey et al., 1989; Lamont & Dennis, 1988; Broman et al., 1987). The frequency of disorders reported as exogenous and genetic causes of mental retardation is remarkably variable: exogenous causes vary from 18.6% to 44.5%, genetic causes from 17.45 to 47.1% and the etiology remains unknown in 4.3% to 8.3 % (Van et al., 2005). These variations have been explained by differences in degree of MR, patient’s selection criteria, study protocol & definition of diagnosis. The etiology of mental retardation has been explored in a large number of studies & differences in age, gender, social class & ethnicity have been found (Leonard & Wen 2002; WHO 2007). Intercultural differences in terms of urban-rural differences within homogeneous cultures or geographical distributions have received relatively little attention internationally, however WHO indicates that the urban-rural setting is an important factor regarding access to services for people with mental retardation (Sondenaa et al 2010). The American association on mental retardation has subdivided the disorders that may be associated with mental retardation into three general areas, prenatal causes, neonatal causes and postnatal causes (AAMR, 1992). It has been estimated that half of all cases are due to environmental factors and half to genetic factors. 3 Environmental factors include prenatal exposure of the foetus to toxic substances (e.g., alcohol, drugs), environmental contaminants, radiation, infection, malnutrition, illness of the mother (e.g. exposure to rubella, cytomegalovirus) etc. In addition, multiple problems during or after birth may cause mental retardation. Although any unusual stress during birth may cause brain damage, especially premature birth and low birth weight may predict mental retardation. During childhood, factors such as disease (e.g. measles), a blow on the head, environmental toxins, etc. may cause irreparable damage to the brain and the nervous system (Winnepenninckx et al., 2003). Among genetic factors, chromosomal abnormalities have been shown to be frequently associated with mental retardation. The whole spectrum of chromosomal unbalanced alterations such as trisomies, translocations, duplications, deletions and extra structurally abnormal chromosomes (ESACs) may be a cause of mental retardation (Xu and Chen, 2003). Cytogenetic analysis at a 400-500-band resolution is the standard investigation for suspected chromosomal rearrangement. Chromosome abnormalities have been reported in up to 40% of individuals with severe MR (Connor and Ferguson-Smith 1985; Schaefer and Bodensteiner 1992; Raynham et al., 1996) but in only 5%–10% of patients with mild MR (Hagberg et al., 1981; Lamont et al., 1986). Approximately 1 of 500 phenotypically normal individuals has a visible balanced chromosomal rearrangement when analysed at the resolution level of 400 bands (Nora et al., 1994). Cytogenetically detectable rearrangements of some specific chromosome ends, such as deletions of 4p (Estabrooks et al. 1999), 5p (Overhauser et al. 1994) and 17p (Ledbetter et al. 1989) are associated with welldefined MR syndromes. The genetic etiology for mental retardation has been recognized for many years & since the first identification of Down syndrome as a chromosomal abnormality, the focus of mental retardation research has been to identify smaller & smaller chromosomal abnormalities associated with diseases. Chromosomal & genetic disorders account for 30-40% of cases of moderate to severe mental retardation, environmental factors explain a further 10-30% & the cause is unknown in about 40% of cases (Gustavson et al.,1977). Other reports have 4 suggested that cryptic telomeric rearrangements resulting in gene-dosage imbalance might represent a significant cause of idiopathic MR (IMR; Knight and Flint 2000). Abnormalities in these regions are thought to be particularly difficult to detect by using conventional cytogenetic methods because the ends of most human chromosomes are morphologically similar. Chromosomal abnormalities are responsible for up to 28% of all mental retardation cases (Curry et al., 1997). Monosomies and trisomies are reportedly the frequent cause of mental retardation. Chromosomal abnormalities include numerical chromosome abnormalities trisomy 13 (Patau’s syndrome), 18 (Edwards’ syndrome) and 21 (Down syndrome), Turner syndrome (females possessing only one X chromosome) and Klinefelter patients (XXY males), partial chromosome abnormalities Deletions, insertions, inversions, translocations example is the Robertsonian translocation, which results from the breakage of two acrocentric chromosomes (13, 14, 15, 21 or 22) at or close to their centromeres followed by a fusion of the long arms. Cri-du-chat syndrome, characterized by mental retardation and cat-like crying in childhood results from a deletion of varying size of the short arm of chromosome 5 and microdeletions. Williams-Beuren syndrome7q11.23, Smith-Magenis syndrome, 17p11.2, Velocardiofacial syndrome, 22q11, Miller – Dieker syndrome (deletion of the 17p telomere) & the thalassemia/ mental retardation syndrome (deletion of 16p telomere). Chromosomal rearrangements result in segmental aneuploidy and alter the dosage of developmental genes (Joyce et al., 2001). The sex chromosome shows a much wider ranges of aneuploids than do autosomes due to several reasons (Miler & Therman, 2001). A common example is Klinefelter syndrome whose prevalence is 1 per 500 live male births characterized by tiny testes devoid of sperm cells, sterility, gynecomastia (a tendency to breast development & sometimes enunchoid habitus.) Deletions are usually lethal even as heterozygote, resulting in zygotic loss, stillbirths or infant deaths. Sometimes infants with chromosomal deficiencies survive long enough to permit observation of the abnormal phenotype they express eg. Cri-du-chat syndrome (Gardner et al., 2002). 5 Down syndrome is estimated to affect 1 in 750 live births. It is caused by a gene dosage-imbalance resulting from human chromosome-21 trisomy, and is the most commonly diagnosed congenital malformation/mental retardation syndrome (Jones 2006). Approximately 95% of diagnosed Down syndrome cases have a complete trisomy 21 and the remaining 5% either have somatic mosaicism (∼1%) or chromosome-21 translocations (∼4%) (Sherman et al. 2007). The clinical features of Down syndrome are comprised of severe cognitive impairment, characteristic facial profile, short stature, speech and developmental delay, chronic ear infections and hearing loss, and hypotonia. The diagnostic facial profile consists of epicanthal folds, flat nasal bridge, upslanting palpebral fissures, and protruding tongue (Girirajan, 2009). Monogenetic causes of mental retardation include those cases in which mutation in a single gene occur leading to mental retardation. The inheritance pattern subdivides the singe gene MR disorders as: autosomal dominant, autosomal recessive & X-linked. Patients with an autosomal dominant form of mental retardation may arise due to novel mutation as is for the case for patients with Rubinstein-Taybi syndrome (Petrij et al.1995). This disorder is caused by CREB gene located on chromosome 16p13.3, characterized by developmental delay, stature, characteristic facial features, broad thumbs & big toes. Autosomal recessive form of mental retardation is often 6 observed in metabolic disorders like phenylketoneuria (PKU). Another example is Smith-Lemli-Opitz syndrome. The disease is caused by mutation in both copies of the sterol delta-7-reductase (DHCR 7) gene. A four base pair deletion within the PRSS12 neurotrypsin gene was shown to be associated with mental retardation in a large pedigree with non-syndromic autosomal recessive mental retardation (Molinari et al., 2002). The fragile X patients show a gap or break on the X chromosome, the so called fragile site FRAXA. At the molecular level, the disorder is due to a mutation caused by the expansion of a CGG repeat located in the promoter region at the 5’ end of the FMR1 gene (Verkerk et al., 1991). Twenty five percent of total mental retardation cases fall under the category of X-linked mental retardation (XLMR) disease, comprising over 100 varied types of retardations that can be associated with fragile X chromosome, biochemical defects, neurological aberrations, bony dysplasia and a range of other disorders (Gracia 1998). The fragile X syndrome is the most frequent and best-studied X-linked syndrome, which has a prevalence of 1 in 4000-6000 (Kooy et al., 2003) and typical physical and behavioural abnormalities in the mentally retarded patients. X-linked forms of mental retardation occur as frequently as 1 in 600 males (Chelly and Mandel, 2001). In this syndrome the patients suffer from mild to severe mental retardation with very specific phenotypic features including a long face, prominent ears, a high-arched palate, flat feet and macro-orchidism. The relatively high frequency of X-linked mental retardation explains the excess of males over females observed among the mentally retarded (Leonard and Wen, 2002). The male to female ratio ranges from 1.3:1 to 1.9:1 because of X-linked syndrome (Kabra & Gulati, 2003).The relative chromosomal distribution of mental retardation genes has also been thoroughly analyzed, out of 282 human mental retardation genes, 16% reside on the X chromosome, whereas its content represent only 3.37– 4% of all known and predicted genes (Inlow 2004). In 2004, Online Mendelian Inheritance in Man recorded 1237 entries for ‘mental retardation’ of these 333 (27%) were mapped on the X-chromosome. At first sight, the apparent excess of X-linked genes involved in mental retardation disorders supports the hypothesis suggesting that the human X chromosome contains a disproportionately high density of genes influencing cognitive abilities and playing 7 an important role in the development of human intelligence (Skuse 2005). In order to identify novel genes involved with X linked mental retardation, the coding exons on the X chromosome from 208 families with X linked mental retardation had been subjected to a large-scale systematic resequencing. They found 250 XLMR conditions. It is a new beginning towards finding the cause behind X linked mental retardation (Tarpey et al. 2009). The number of associated disorders increases with the level of severity of mental retardation (Baird & Sadovnick 1985). A variety of disorders are associated with mental retardation such as epilepsy, cerebral palsy, vision & hearing impairment, speech/language problems and behavior problems (McLaren & Bryson, 1987). Some neurological disorders like microcephaly also leads to mental retardation in which there is reduction in brain cortex volume (McCeary et al 1996). Metabolic disorders like galactosemia, mucopolysaccharides, phenylketoneuria, etc. also lead to mental retardation. Galactosemia occurs due to deficiency of enzyme galactose-1-phosphate uridinyl transferase present in liver, skin & RBCs. (Kahler & Fahey, 2003). Mucopolysaccharidosis is an X-linked recessive disease occurs due to mutation of 1DS gene present in Xq28, which codes for iduronate 2-sulphatase (Wraith et al 2008). Phenylketoneuria (PKU) is a rare metabolic disorder in which baby appears normal but lacks enzyme Phenylalanine hydroxylase needed to breakdown phenylalanine. Hence phenylalanine accumulated in the blood leading to brain damage (Centerwall & Centerwall, 2000). Screening individuals with IMR for telomeric imbalances was first proposed by Ledbetter in 1992. This publication was followed by several others confirming the value of such a screen and outlining practical approaches to performing the investigation (Flint et al. 1995). FISH with multiple subtelomeric probes has been proved to be useful in the study of IMR cases. The first screen was carried out by Flint et al. (1995) and, although only 28 chromosome ends were examined in 99 IMR patients, their results indicated that at least 6% of IMR cases could be caused by cryptic telomeric imbalances. This frequency was later refined as 7.4% after including a marker for the telomeric region of 1p (Giraudeau et al. 1997). Highresolution G-banded analysis, together with fluorescence in situ hybridization (FISH) 8 and molecular techniques, has resulted in the delineation of further syndromes caused by terminal rearrangements, e.g. deletions of 1p (Slavotinek et al. 1999b) and 22q (Praphanphoj et al. 2000). The presence of unusual dysmorphic features help in diagnostic analysis of mentally retarded cases. The presence of dysmorphic features & positive family history of mental retardation indicates that 30-50% undiagnosed cases may fall to moderate to severe category (Fryns 1990). Necessary components of evaluation of child with idiopathic mental retardation are a comprehensive dysmorphic examination (Schaefer & Bodensteiner, 1992). Along with morphogenetic variation, cytogenetic & FISH analysis, dermatoglyphics may also serve as a diagnostic tool in mental retardation. Dermatoglyphics is a scientific method for anthropological, medicolegal & genetic studies. Its genetic bases are used to study familial inheritance & in diagnosis of genetic diseases. The word “Dermatoglyphics” is derived from the Greek word “Derma” meaning skin & “glyphic” meaning carvings (Schauman & Alter 1976). The science of finger prints is reputed particularly in forensic investigations (Penrose 1968; Igbigbi & Msamati 1999; Adebisi 2009). A marked increase of the loops on the fingerprints was found among the intellectually disabled children (Holt 1964; Shiono et al 1969). The study of ridged skin is considered as a window of congenital abnormalities. The dermal patterns are as typical of the Down syndrome condition as the facial features used in diagnosis (Bargankaur et al 1973). Plato & coworkers reported increased frequency of Sydney Lines in Down syndrome (Plato et al 1973). There were reports with definite correlation between the dermatoglyphics pattern & cleft deformity thereby suggesting the significance of this diagnostic tool in early detection of clinical condition with a genetic etiology. It may serve as a highly cost- effective tool of diagnostic evaluation. (Mathew et al 2005). The regularity of digital & dermatoglyphics deviations in Down syndrome allowed introduction of several highly reliable dermatoglyphic discriminate indices that can account for the most of the total dermatoglyphic variations between mental retardation & control groups. 9 The Indian subcontinent has relatively higher incidence & prevalence of genetic diseases. There are a number of factors that significantly increases the prevalence of genetic disorders in this subcontinent. The factors may be malnutrition, poverty, low socioeconomic status & deprivation syndrome. Consanguineous marriages and high birth rates are also major factors behind this (Verma and Bijarnia, 2002). In India, the incidence of mental retardation is reported to be 2-3%. Of these, 30% cases of severe mental retardation are genetically determined. (Kaur et al., 2003). To qualify as a risk factor a variable must be associated with an increased probability of disorder and must help in the onset of disorder. Variables that may be risk factors at one life stage may or may not be risk factors at a later stage of development. Embryological timetables are helpful in studying the etiology of human malformations. Risk factors can reside with the individual or within the family, community or institutions that surround the individual. They can be biological or psychosocial in nature. These factors are hard to isolate for two reasons. First, they are very closely related and complex in nature. Secondly they do not individually result in impairment. For example, risks among people of low socioeconomic class can run through generations because the cycle of poverty creates conditions which contribute to the incidence of disabilities. But at the same time it should be realized that heredity and prenatal environment work together to produce the infant. Identifying such factors in idiopathic cases can be a first step toward determining a cause behind mental retardation and then developing preventive interventions. The etiology of mental retardation is still unexplained in at least 50% of cases. Etiology of MR should be conceptualized as a specific diagnosis that can be translated into useful clinical information for the family including prognosis, recurrence risks & preferred modes of available therapy. The diagnostic process is aided considerably if the timing of a developmental insult can be determined: prenatal, perinatal, and postnatal (not mutually exclusive). So, the term etiology has a broad interpretation in mental retardation that can be caused by genetic, environmental & ecogenetic factors. Specific diagnosis for the patients provides a 10 better understanding of the possible reasons of pathogenesis and possible treatment options. The scientific field of genetics can help families affected by MR to have better understanding about heredity, what causes mental retardation to occur and what possible prevention strategies can be used to decrease its incidence. Some genetic disorders are associated with mental retardation, chronic health problems and developmental delay. Because of the complexity of human body, there are no easy answers to the question of what causes mental retardation. Keeping in view of the limited study on mental retardation from state of Haryana and complete lack of study from rural areas, the present study has been planned with the following objectives; 11 OBJECTIVES 1. To find the exact incidence of moderate mental retardation (MMR) in Haryana. 2. Characterization of morphogenetic variations of MMR and to find out the role of prenatal, postnatal and perinatal risk factor in the etiology of MMR 3. Dermatoglyphic study of affected persons of MMR and its correlation with level of mental retardation. 4. Identification of chromosomal abnormalities of moderate mental retardation. 5. Molecular cytogenetic analysis of patients of MMR with the help of PCR and FISH 12 REVIEW 2.1. MENTAL RETARDATION Mental retardation is attributable to any condition that impairs development of the brain before birth, during birth or in the childhood years (The Arc, 1993). The field of genetics has important implications for people with mental retardation. Since the brain is such a complex organ there are a number of genes involved in its development. Consequently, there are a number of genetic causes of mental retardation. Mental retardation (MR) is one of the most commonly observed neuropsychiatric disorders among children and adolescents. When affected children visit the general pediatrician, they often present with speech delay, behavioral disorders, or low school performance. A number of specific disorders have been identified as being genetically caused. The scientific field of genetics can help families affected by genetic disorders to have better understanding about heredity, what causes various genetic disorders to occur and what possible prevention strategies can be used to decrease the incidence of genetic disorder. Some genetic disorders are associated with mental retardation, chronic health problems and developmental delay. Because of the complexity of human body, there are no easy answers to the question of what causes mental retardation. Mental retardation (MR) also referred as ‘Intellectual Disability’, ‘Mental Deficit’, ‘Mental Subnormality’ or ‘Mental Handicap’ means delay in mental development; it means an impairment of the intellectual processes of the mind, making it difficult for the person to cope with environment in which they find themselves. Mental retardation is a particular state of functioning that begins in childhood and is characterized by decreased intelligence and adaptive skills and also is the most common developmental disorder (Bregman 1991). It is the incomplete development of mental capacities with associated behavioural abnormalities. 13 2.1.1 HISTORY History has not been kind to those with intellectual disability. Throughout history, people with mental disabilities have been viewed as incapable, insufficient and incompetent in their capacity for social adaptive skills, decision making and development. Individuals with developmental disabilities have been dependent on the culture, customs and beliefs of the era. In ancient Greece and Rome, infanticide was a common practice. By the second century A.D. individuals with disabilities, including children who lived in the Roman Empire were frequently sold to be used for entertainment or amusement. (Sheerenberger, 1983). There was no education or training, but they were primarily dedicated to physical care. Intellectual disability and mental illness were considered synonymous, and persons so afflicted were not believed to suffer from hunger, cold or pain. Changes occurred during the late 17th and 18th centuries as philosophers and scientists initiated ideas aimed at educating individuals (Scheerenberger 1986). In the agrarian, labour-intensive and largely illiterate medieval society, individuals who would in our times be labelled as intellectually disabled were not considered as being particularly disabled (Stainton 2001). American Association on Mental Retardation (AAMR) now called the AAIDD (American Association of Intellectual Developmental Disability) and WHO (World Health Organisation) in 2002 defined mental disability as the expression of limitations in individual functioning in social and behavioural context (Luckasson et al. 2002). A cornerstone event in the evolution of the care and treatment of the mentally retarded was the work of physician Jean-Marc-Gaspard Itard, who was hired in 1800 by the Director of the National Institutes for Deaf-Mutes in France to work with a boy named Victor (Sheerenberger, 1983). Itard developed a broad educational program for Victor to develop his senses, intellect and emotions. After 5 years of training, Victor continued to have significant difficulties in language and social interaction though he acquired more skills and knowledge than many of Itard's contemporaries believed possible. Itard's educational approach became widely accepted and used in the education of the deaf. Near the end of his life, Itard had the opportunity to educate a group of children who were mentally retarded. He did not 14 personally direct the education of these children, but supervised the work of Seguin. Seguin developed a comprehensive approach to the education of children with mental retardation, known as the Physiological method (Sheerenberger, 1983). Assuming a direct relationship between the senses and cognition, his approach began with sensory training including vision, hearing, taste and smell, eye-hand coordination. The curriculum extended from developing basic self-care skills to vocational education with an emphasis on perception, coordination, imitation, positive reinforcement, memory and generalization. A French psychiatrist was the first to differentiate between mental illness and intellectual disability as well as to establish levels of Intellectual disability. He believed that rather than being a single phenomenon, mental retardation existed in various degrees and so he differentiated between disabled people, whose IQ was severe, comparatively less severe and those whose intellectual disability was not as significant at all (Taylor et al. 2005).There is much of discussion in the field even today as for the use of the term intellectual disability and about how intellectual disability fits within the general construct of disability (Jacobson 2005, Greenspan et al. 2006). 2.1.2 DEFINITION & CLASSIFICATION An early classification scheme was proposed by the American Association on Mental Deficiency Retardation (AAMR). Individuals with mental retardation were considered as feeble-minded, meaning that their development was halted at an early age, it was difficult to keep pace with peers and manage their daily lives independently (Committee on Classification, 1910). The American Association on Mental Deficiency Retardation (AAMR) proposed and adopted a three part definition: "Mental retardation refers to subaverage general intellectual functioning which originates in the developmental period and is associated with impairment in adaptive behavior" (Heber, 1961). This definition included the three components low IQ (<85), impaired adaptive behavior and origination before the age of 16. Only IQ and age of onset were measurable with the existing psychometric techniques. Deficits in adaptive behavior were generally based on subjective interpretations by individual evaluators even though the ‘Vineland Social Maturity Scale’ was available (Sheerenberger, 1983). A five level classification scheme was introduced 15 replacing the previous three level systems, which had acquired a very negative connotation. The generic terms for mental retardation were adopted i.e. borderline (IQ 67-83), mild (IQ 50-66), moderate (IQ 33-49), severe (16-32), and profound (IQ <16). The most recent change in the definition of mental retardation was adopted in 1992 by the American Association on Mental Retardation "Mental retardation refers to substantial limitations in present functioning. It is characterized by significantly subaverage intellectual functioning, existing concurrently with related limitations in two or more of the following applicable adaptive skill areas: communication, selfcare, home living, social skills, community use, self-direction, health and safety, functional academics, leisure and work (AAMR, 1992). According to association’s definition, the diagnosis of mental retardation in a person displays the following three characteristics. 1.) The person’s intellectual functioning level is appox. 70 to 75 or below. 2.) There are related limitations in two or more applicable adaptive skill areas. 3.) The age of onset in 18 years or below. The adaptive behavior is quality of every day’s performance in coping with environmental demands. Diagnostic and Statistical Manual of Mental Disorders - IV (DSM-IV) defines mental retardation as significantly sub average intellectual functioning (i.e. IQ no higher than approximately two standard deviations below the mean), which is accompanied by significant limitations in adaptive functioning in at least two of the following areas: communication, functional academic skills, health, home living, leisure, safety, self-care, self-direction, social/interpersonal skills, use of community resources, and work (Ropers 2008). 2.2. INTELLIGENCE QUOTIENT (IQ) It is a score derived from one of the several different standardized test diagnosed to assess intelligence. The term “IQ” comes from the German IntelligenzQuotient. IQ scores have been shown to be associated with such factors as morbidity and mortality, parental social status (Neisser et al. 1997) and, to substantial degree, parental IQ. English man Francis Galton created the terms psychometrics and 16 eugenics and a method for measuring intelligence based on nonverbal, sensorymotor tests. It was initially popular but was abandoned after the discovery that it had no relationship to outcomes such as college grader (Gilham and Nicholas 2001). While the heritability of IQ has been investigated for nearly a century, controversy remains regarding the significance of heritability estimates (Johnson et al, 2009) and mechanism of inheritance is still a matter of some debate. During nineteenth century IQ contributed to separating mental retardation from mental retardation from mental illness and reducing the neglect, torture and ridicule heaped on both groups (Kaufman 2009). French psychologist Alfred Binet, together with Henri & Simon, after about 15 years of development, published the Binet-Simon test for the practical use of determining educational placement; the score on the Binet-Simon scale would reveal the child’s mental age. Binet stressed remarkably diversity of intelligence & the subsequent need to study it using qualitative, opposed to quantitative measures. Binet also stressed that intellectual development progressed at variable rates & could be influenced by the environment; therefore, intelligence was not based solely on Genetics, was malleable rather than fixed, and could only be found in children with comparable background. In 1904 From Binet’s work the IQ scale called the “Binet Scale” (and later the “Simon-Binet Scale”) was developed IQ scores with mentally retarded is below 70, intelligence quotient ranges between 50-70 in mild mental retardation, 35-50 in moderate mental retardation, 20-35 in severe mental retardation less than 20 in profound mental retardation. American psychologist Lewis Terman at Stanford University revised the Binet-Simon scale which resulted in the Stanford-Binet Intelligence Scales (1916). It became the most popular test in the United States for decades (Richardson and John, 2003). IQ scores of children are relative to children of a similar age. That, is a child of a certain age does not do as well on the tests as an older child or an adult with the same IQ. But relative to persons of a similar age, or other adults in the case of adults, they do equally well if the IQ scores are the same (Neisser, 1997). IQ can change to some degree over the course of childhood. Environmental and genetic factors play a role in determining IQ. Their relative importance have 17 been the subject of much research and debate. Various studies have found the heritability of IQ to be between 0.7 and 0.8 in adults and 0.45 in childhood in the United States (Kaufman, 2009). One proposed explanation is that people with different genes tend to seek out different environments that reinforce the effects of those genes (Neisser, 1997). However, heritability measures in infancy are as low as 0.2, around 0.4 in middle childhood, and as high as 0.8 in adulthood (Bouchard et al. 1990). Proper childhood nutrition appears critical for cognitive development; malnutrition can lower IQ. For example, iodine deficiency causes a fall, in average, of 12 IQ points (Qian et al, 2005). People with a higher IQ have generally lower adult morbidity and mortality. Post traumatic stress disorder (Breslau et al, 2006) and schizophrenics are less prevalent in higher IQ bands (Woodberry, 2008). People in the midst of a major depressive episode have been shown to have a lower IQ than when without symptoms and lower cognitive ability than people without depression of equivalent verbal intelligence (Mandelli et al, 2006). A decrease in IQ has also been shown as an early predictor of Alzheimer’s disease and other forms of dementia. Patients with multiple congenital abnormalities and mental retardation are the most frequent patient group who are referred to a genetic clinic. Specific diagnosis for the patients provide a better understanding of the possible reason of pathogenesis, therapy providing more information to families on recurrence risk, prognosis, possible treatment options and prenatal diagnosis. The genetic basis of mental retardation is now a huge field having started with modest beginnings with an initial survey of patients confined to long stay hospital institutions in 1930 (Penrose,1938). Diagnosis is highly dependent on a comprehensive personal and family medical history, a complete physical examination and a careful developmental assessment of the child. These will guide appropriate evaluations and referrals to provide genetic counseling, resources for the family and early intervention programs for the child (Rutter 2006). 18 2.3. EPIDEMIOLOGY Epidemiological and clinical studies of mental retardation in developed countries found that as compared to mild mental retardation, severe retardation is much more commonly associated with genetic, environmental, nutritional, infection toxicity, traumatic and other factors including brain disorders (cerebral palsy, seizures, vision impairments and hearing impairments) (Drillien et al., 1966 and Stein et al., 1984). Following a review of the most recent epidemiological studies, the prevalence of mental retardation was approximately 1.25% (McLaren and Bryson, 1987). It is estimated that approximately 89% of these children have mild mental retardation, 7% have moderate mental retardation and 4% have severe to profound mental retardation. It is generally accepted that MR occurs in 2-3% of the general population. Most authorities discuss MR in two categories – Milder MR (IQ 50-70) and more severe MR (IQ<50) (Schaefer & Bodonsteiner 1992). According to reports from developing countries the prevalence of mental retardation is 19.0/1000 for serious retardation and 65.3/1000 children for mild retardation (Durkin et al., 1998). Approximately 40% of cases with severe idiopathic mental retardation have chromosome abnormality, while the frequency is about 10% for mild idiopathic mental retardation (Joyce et al., 2001). The prevalence of MR is difficult to assess because of regional differences, variation in diagnostic criteria and study methodology. Epidemiological studies in India also indicate that 2-3 % of children in India suffer from MR (Kuppuswamy 1968). In India mild mental retardation was present in 22% children in 0-5 years age group, 19% children in 6-11 years age, and among 6% in children of 12-16 years age group among those attending the psychiatric clinics/child guidance clinics (ICMR 2005). Among all the classes diagnosed as mental retardation 85%, 10%, 4% and 2% showed mild, moderate, severe and profound mental retardation respectively (King et. al 2009). The most common cause of MR in industrialized nations is fetal alcohol syndrome with an incidence rate of 1 in 100 births. The second leading known cause 19 of MR is Down syndrome, or trisomy 21, with an incidence rate of 1 in 800-1000 births (Campbell et al. 2004). Malnutrition is a common cause of reduced intelligence in parts of the world affected by famine, such as Ethiopia (Durkin et al. 2000; Wines 2006). At least 7.6 million children are born globally every year with severe congenital malformations. Ninety percent of mentally retarded people are born in countries with low incomes (Kaur and Singh2010). Prevalence of mental disability in Karnataka was reported as 2.3% which was higher in elderly than young groups. It was also found that the prevalence of mental retardation increased with age, ranging from 2.0/1,000 cases for children younger than 6, to 14.7/1,000 cases for children ages 6 to 12, and 15.7/1,000 cases for youth ages 12 to 17 (Kumar 2008). Although mental onset of mental disabilities peaks at early ages and younger working age population. Severe disability is broadly concentrated at later ages (Patel et al. 2007). The Metropolitan Atlanta Developmental Disabilities Surveillance Program (MADDSP) monitors the prevalence of developmental disabilities and mental retardation in USA. In 1996 it was reported by MADDSP that an estimate of 16 per 1,000 children of 8- 10year age in metro Atlanta had intellectual disability (Bhasin et al. 2006). In an Indian study individuals with mental retardation, aged over 15 years prevalence rate of 14 per 1000 was reported (Noorbala et al. 2004). Predominantly from western Industrialized countries and Australia showed that the prevalence rates for severe mental retardation ranged between 2.8 to 7.3 per 1000, and mild mental retardation, between 3.2 and 79.3 per 1000 (Roeleveld 1997). Many studies have consistently found that the prevalence of intellectual disabilities was strongly associated with socioeconomic status. Allgar reported a lifetime prevalence rate of mental retardation to be 6.4 per 1000 (Allgar et al. 2008). In Australia 14.3 per 1000 children were found intellectually disable among normal population (Leonard et al. 2003). In Western countries the intellectual disabilities affected about 1.5-2% of the total population and 0.3-0.5% were severely impaired (IQ<50) (Leonard and Wen 2002). In contrast, the U.S. surgeon general has estimated that some 7.5 million persons living in the United States have a diagnosis of mental retardation, representing almost 3 percent 20 of the population (U.S. Department of Health and Human Services 2000). Halfon and Newacheck in 1999 reported prevalence rates for mental retardation at 10.5/1,000 for children younger than 18 in USA (Halfon and Newacheck 1999). Prevalence rate of mental retardation in Limburg in the Netherlands was reported as 6.4-7.0 per 1000 and in a study with similar methodology conducted in the UK. The prevalence rates of mild and serious retardation in Karachi were significantly associated with low socioeconomic status and consanguinity. Sixty percent of mentally retarded children were from consanguineous unions (Shamis et al., 1989 and Darr et al., 1988). Excess of both mild and serious retardation in the poorest segment of the population were attributed to undeveloped level of prenatal and perinatal services and high prevalence of brain infections and nutritional deficiencies. These factors may be due to socioeconomic disadvantage for major mental retardation. 2.4. SEX RATIO In general sex ratio was toward an excess of male in majority of studied populations, either in population with high level of cases of epidemiological studies or in selected groups. No significant correlation involving the age of either patients or mother age with sex was found. There were comparable male to female ratio for mild mental retardation (40% excess in Netherlands to 80% excess in Sweden (Hagberg et al., 1983). The male to female ratio ranges from 1.3:1 to 1.9:1 because of X-linked syndromes especially Fragile-X. (McLaren & Bryson 1987). For severe mental retardation 20% excess of males were reported. A number of other studies revealed that mental retardation of unknown etiology is more common in males and the male to female ratio is 3:1. This reflects a difference in registration and identification procedure and indicates a greater susceptibility of male central nervous system. There was no significant difference in mean IQ scores between boys and girls (p≥0.05) (Young et al., 2002). 2.5. ETIOLOGY Despite recent improvements in investigation methods, the etiology of MR remains unclear in 30 to 50% of cases.( Croen et al. 2001; Xu & Chen 2003). The 21 cause of MR may be genetic or environmental, and congenital (e.g.: fetal exposure to teratogenic agents, chromosome disorders), or acquired (e.g.: central nervous system infection, head trauma) (Ramakers 2002). A study assessed the epidemiological characteristics of MR in California between 1987 and 1994. After excluding children diagnosed with cerebral palsy, autism, chromosome aberrations, infections, endocrine or metabolic disorders, traumas or intoxications, brain malformations, and central nervous system diseases or neoplasms, the authors found 11,114 children with unclassified MR. They found out that a birthweight < 2.500 g was the strongest predictive factor for MR, and observed other risk factors associated with MR, such as low educational level, advanced maternal age at time of delivery, and multiple births (Croen et al. 2001). MR may be also classified into syndromic, that is, the child has dysmorphic characteristics that lead to the diagnosis of a genetic syndrome, or non-syndromic. The most prevalent causes, in decreasing order of frequency, were the following: perinatal asphyxia, Downs syndrome , neonatal or postnatal CNS infection and fetal alcohol syndrome. In a more recent study (Shevell et al. 2000) including 99 children younger than five years with global developmental delay, 44 (44%) had a definite diagnosis. In 715 cases investigated from 1985 to 1987 (Yeargin-Allsopp et al. 2003) the etiology of MR could be identified in only 22% of children. Seventy seven percent of the cases with known etiology included only four diagnosis- cerebral dysgenesis, hypoxic-ischemic encephalopathy, intrauterine exposure to toxins, and chromosome aberrations. Inborn errors of metabolism were not included in the diagnoses because they had already been identified by universal neonatal screening. Using logistic regression, the authors detected clinical characteristics associated with a greater probability of determining the etiology of MR: prenatal exposure to toxins, microcephaly, focal motor symptoms, and absence of autistic behavior. Causes of mental retardation can be roughly divided in to following categories:- 22 1. Chromosomal abnormalities: errors of chromosome numbers (Down’s syndrome), defects in chromosome or chromosomal inheritance (fragile X syndrome), chromosomal translocation, deletion, (cri du chat syndrome). 2. Genetic abnormalities and inherited metabolic disorders: galactosemia, Taysachs dieases, phenylketonuria. 3. Metabolic: congenital hypothyroidism, very high bilirubin levels in babies’ hypoglycemia. 4. Toxic: intrauterine exposure to alcohol, cocaine, amphetamine and other drugs, methylmercury poisoning and lead poisoning. 5. Malnutrition 6. Infections: congential and postnatal 7. Environmental: poverty, low socioeconomic status, deprivation syndrome. 8. Trauma: prenatal and postnatal 9. Idiopathic (unexplained) Other risk factors responsible for mental retardation have also been reported. Maternal smoking during pregnancy was associated with slightly more than 50% increase in the prevalence of idiopathic mental retardation and children whose mother smoked at least one pack during pregnancy have more than 75% increase in the occurrence of idiopathic mental retardation (Drews et al., 1996). Maternal hypertension during pregnancy was associated with a relative risk of mental retardation in the offspring of 6.1 with 95% confidence interval (Salonen et al., 1984). To qualify as a risk factor a variable must be associated with an increased probability of disorder and must help in the onset of disorder. Variables that may be risk factors at one life stage may or may not be risk factors at a later stage of development. Embryological timetables are helpful in studying the etiology of human malformations. Risk factors can reside with the individual or within the 23 family, community or institutions that surround the individual. They can be biological or psychosocial in nature. These factors are hard to isolate for two reasons. First, they are very closely related and complex in nature. Secondly they do not individually result in impairment. For example, risks among people of low socioeconomic class can run through generations because the cycle of poverty creates conditions which contribute to the incidence of disabilities. But at the same time it should be realized that heredity and prenatal environment work together to produce the infant. Identifying such factors in idiopathic cases can be a first step toward determining a cause behind mental retardation and then developing preventive interventions. Etiology is a multifactorial construct composed of various categories of risk factors. It is sometimes assumed that genetic and environmental influences act additively. However, genes and environmental factors can be correlated or interdependent. Children not only inherit genes from their parents but are also exposed to environments that are influenced by their own and their parent’s genetic make-up. During the last decade behavioural geneticists have drawn attention to the various ways in which gene-environment interactions can arise. They have argued that to a great extent individuals shape and select their environments and that genetic factors play a part in this process. Some risk factors like age, sex and genetic susceptibility are non-modifiable. Whereas many of the risks associated can be controlled. Such risks including behavioural factors like diet, physical inactivity, tobacco use and alcohol consumption which can be monitored. Biological factors like dyslipidemia, hypertension, overweight and hyperinsulinaemia are controllable risk factors. Other sociodemographic factors include interaction of socioeconomic, cultural with environmental risk factors. Exposures during development may have effects that can be detected at any point in the future. Developmental toxicity has adverse effects on the developing organism that result from exposure prior to conception i.e. exposure during prenatal development or postnatal exposure. Exposure to infectious agents can result in a variety of problems in the fetus and neonate, including malformations, congenital infection, short and long-term disability and death. A diagnostic survey carried out in southern Brazil included 202 individuals with MR from the Association of Parents and Friends of the Mentally Handicapped 24 (APAE) (Felix et al. 1998). The authors conducted a careful clinical examination and laboratory investigation to define the diagnosis in 132 patients (65.3%). Downs syndrome was detected in 32.2% of cases, followed by Mendelian inheritance disorders in 12.4%, acquired conditions including infections in 10.4%, and CNS malformations in 4.0%. The high percentage of Downs syndrome probably shows a selection bias The strong association between prevalence of mental retardation and malnutrition, traumatic brain injury, postnatal brain infection results in disorders of brain. There are many associated disorders such as epilepsy, cerebral palsy, vision and hearing impairments, behavior problems and speech / language problems (McLaren and Bryson, 1987). The number of associated disorders increases with the level of severity of mental retardation (Baird and Sadovnick 1985). Children with mental retardation are generally at increased risk of mortality (Eyman et al., 1990). In general more severe is the retardation; the child has more physical problem, developmental delay and shorter life. Developmental delay might be a set of symptoms for which a variety of etiologies are known, whereas global developmental delay is a subset of developmental disabilities and significant delay in two or more developmental domains (gross/fine motor, recognition, speech/language, personal/ social or activities of daily living is the global developmental delay (Simeonsson, 1992 and Majnemar et al., 1995). The yield of etiological evaluation of children with developmental delay and mental retardation varies widely 10% to 81% (Curry et al., 1997; Van et al., 2002; Shevell et al., 2003; van et al., 2005). A clinical and family study was carried out in 169 children attending schools for the mildly mentally retarded in Southampton to assess the prevalence of recognized medical risk factors; 71 children (42%) had such risk factors. These were prenatal in 22, perinatal in 41, and postnatal in eight. Risk factors of possible, but less certain, significance were found in a further 63 children (37%). In 86 families (51%) there was a history of serious educational problems in both parents. The prevalence of both types of risk factor was higher in the children whose parents had no educational problems. There were, however, 25 children (15%) whose 25 parents had no history of educational problems and in whom medical risk factors were either absent or minimal. (Lamont and Dennis 1998). As many as 50% of people with mental retardation have been found to possess more than one causal factors (AAMR, 1992). The cause in 75% of children with mild mental retardation is unknown (Kozma & Stock, 1992). Yet, the possibility of being born with mental retardation or developing the condition later in life can be caused by multiple factors unrelated to our genetic makeup. It is not only caused by the genotype (genetic makeup) of the individual, but also by the possible influences of environmental factors. These factors can range from drug use or nutritional deficiencies to poverty & cultural deprivation (AAMR 1992). Over 7000 genetic disorders have been identified and cataloged, with up to five new disorders being discovered every year (Mckusick, 1994). Over 350 inborn errors of metabolism have been identified, most of which lead to mental retardation (Scriver, 1995). Most identifiable causes of severe mental retardation originate from genetic disorders up to 60% of severe mental retardation can be attributed to genetic causes making it the most common cause in cases of severe mental retardation (Moser, 1995). Curry et al. (1997) have given the overview of causes of mental retardation. People with mild mental retardation are not as likely to inherit mental retardation due to their genetic makeup as are people with severe mental retardation. People with mild mental retardation are more likely to have the condition due to environmental factors such as nutritional status, personal health habits, socioeconomic level, access to health care & exposure to pollutants and chemicals, rather than acquiring the condition genetically (AAMR 1992). 2.6. DERMATOGLYPHICS Along with morphogenetic variation, dermatoglyphics is another area, which can serve as an assessment tool for mentally retarded cases. Dermatoglyphics is literally descriptive of patterns formed by epidermal ridges on fingers, palm and soles. The configuration are formed in early foetal life and once formed except for change in size, they do not change in the remaining intrauterine period and after birth. The pattern of skin ridges observed on palm and fingers and soles has been a useful adjunct in the study of human genetics. The fingerprints patterns have been 26 utilized in medicological studies and are highly individualistic. Out of the three finger tip patterns, simplest pattern type is the arch, where no triradius is found. The next pattern is loop with one associated triradius. The loop that opens out to either the radial or ulnar side of hand is called a radial or ulnar loop. The most complex pattern is the whorl pattern with two triradii. The nomenclature changes for the feet, a loop opens either towards the tibial or fibial side of the foot. A radial loop on a finger is the counterpart of a tibial loop on toe and an ulnar loop on a finger would have as its counterpart a fibular loop on a toe. There is no distinction for whorls and arches. At the base of each finger there is triradius. These triradii are designated a to d from index to little finger and t for the thenar area of the thumb. The angle between the lines drawn from the triradius, present at the base of the index finger to the axial triradius and from the triradius on the base of the 5th finger to the axial triradius represents the atd angle (Mavalwala, 1963). The angle between a, t and d is usually below 57 in normal individuals (Schumann and Alter, 1974). The position of triradius is determined by its distance from the distal wrist crease, expressed as a percentage of the distance from that wrist crease to the crease on the base of the middle finger. The pattern of the ridges follow certain patterns; loop, whorls, arches and triradii. In the palm of normal individuals most marked lines are normal flexion crease. In normal population, 6% persons may have only one transverse or simian crease and 11% sydney lines (Polani and Polani, 1969). During the early years of human cytogenetic studies, dermatoglyphics had medical applications in screening for autosomal disorders such as patients with multiple malformation and mental retardation, before completely reliable chromosome identification become possible. Dermatoglyphic studies became very important in chromosomal abnormalities, limb formation, non-chromosomal syndromes, deformities and association in clinical genetics (Tamtamy and McKusick, 1969). Unusual patterns were found associated with congenital disorders in many cases like cri du chat syndrome and wolf hirchhorn syndrome at the time of diagnosis (Verbov, 1970). The two palms of one individual are never exactly same. Bimanual differences are found in such traits as ridge-breadth, pattern size and complexity. Ridges tend to be thicker and patterns larger on right hands. Differences between corresponding palms of identical twins 27 are also different. Similarly, there are dermatoglyphic differences between the sexes. Ridges are wider in males. Pattern frequencies in all areas differ in the two sexes. For example fingers of females have more arches and fewer whorls than males. Dermatoglyphic differences also exist between races and populations (Simpson 1986). Jalali studied cross sectional study of 900 patients of myocardial Infarction and 900 control group. It was noticed that in myocardial infarction patients, the distribution of dermatoglyphic pattern showed 7.2% arches, 46.8% loops and 46% whorls of fingertip patterns in contrast to 30.7%, 50.7% and 45.5% respectively in control group. The arch type was significantly increased in myocardial infarction as compared to the control (P<0.001) and particularly in left thumb, left index and left ring finger (P<0.0001) (Jalali et al. 2002). Ranganath carried out work on quantitative dermatoglyphics in hypertension. They found that there was increase in ridge count in 1st digit of right hand in male. The atd angle was increased in male and decreased in female hypertensive patients as compared to controls. Kumbnani showed the absence of finger and palm prints in one and the only case afflicted with Naggely Syndrome. Known as Dermatopathia pigmentosa reported by the Times of India (Kumbnani 2007). Oladipo studied dermatoglyphic analysis of 90 sickle cell anaemia cases and observed decrease frequency of ulnar loop and increase frequency of whorl fingertip patterns, but not statistically significant. The atd angle, ab ridge count and position of axial triradius were almost same in both groups, however 2.2% of the cases had Sidney creases (Oladipo et al. 2007). High frequency of arches is often associated with Cat-Cry-Syndrome. The ridges are not continuous, but consist of segments of various lengths; some show branchings and other irregularities. These differences in detailed structure are largely accidental in origin. High finger ridge count is commonly recorded with trisomy of X chromosome. However, there is now some evidence that the total number of minutiae in a particular area is influenced by heredity (Kumbnani 2007). Not only palm and hand prints but also feet contribute towards identification. The dermatoglyphics of the sole and toes are a neglected field of the discipline. The investigations of the toe prints is another component of dermatoglyphics. The 28 collection of the toe prints is one of the toughest exercise unlike the finger and palm. The prints of the toes can only be collected on the slips of papers. It is not possible to role the toes like the fingers. There are a score of the experts who were keenly involved in the study of sole prints. The genetics of sole patterns were studied by Malhotra in 1984 and 1987. They found out that the heretability of the distal pattern ridge count does not differ from control group. They also saw the effect of heritability of counts for individual areas within as well as between populations (Malhotra et al. 1987). With advances in technology, the future holds great promise for more sophisticated integration of this technique and its applications. In conclusion, with such series of new scientific and technological breakthroughs in the evaluation of fingerprint it would soon be possible to understand analytic techniques with several dermatoglyphics traits for predictive discrimination. It could be useful in finding markers for diagnosis of chromosomal defects. In a study on Spanish population it was reported that the highest number of ridge counts was shown by the thumb of each hand in males as well as in females. There was a difference in number of ridges corresponded to index finger in both right and left hands for males and females (Esteban and Moral 1992). The Southern Nigerians had a significantly higher value of total finger ridge counts in females than males contradictory to the earlier studies. In Malawian subjects a women had significantly higher total finger ridge counts than men (Igbigbi and Msamati 1999). Another study on sub Saharan Africans had also shown that the values of total finger ridge counts found among the Zimbabweans were higher in men than in women. This conclusion is in contrast to that reported in Kenyans and Tanzanians (Igbigbi and Msamati 2005). Different dermatoglyphic traits provided crucial information in diagnosis of chromosomal aberrations of cri-du-chat syndrome and wolf Hirsch horn syndrome at the time when chromosome analysis failed to distinguish between the two similar chromosomes (Loesch, 1983). Dermatoglyphic analysis is also used in chromosome aberration involving small and unidentifiable fragments. It has been recently observed in fragile -X-syndrome. Dermatoglyphic abnormalities have been documented in fragile X syndrome which led to the establishment of useful 29 discriminate indices (Rodewald et al., 1986). It suggested a subtle aneuploidy effect. Sex chromosome aberration has less influence on ridge formation than other autosomal anomalies. Several indices of dermatoglyphics with physical characteristics have been studied in Ullrich-Turner syndrome (Preus, 1976). Digital and dermatoglyphic abnormality in Down syndrome is highly reliable indices. It is also highly reliable in certain characteristics like camptodactyly with 10 low fingertip arches, 18 trisomy syndrome, syndactyly of 3rd and 4th fingers with camptodactyly in triploidy, polydactyly with fibular arch S patterns in hallucal area in the 13 trisomy syndrome, high ridge count patterns like 10 fingertip whorls in Ullrich turner syndrome, High number of 2nd, 3rd and 4th interdigital patterns, very distal axial triradii and thenar and hypothenar patterns. Aberration of dermatoglyphic and flexion creases is observed in aneuploides. It is associated with minor hand anomalies. Simian’s creases and Sydney crease are associated with two classes of disorders (a) Congenital movement disorders and hypotonia (b) shortness of palms in Down syndrome or shortness of metacarpals in Turner syndrome. There is strong correlation between shortness of 5th fingers, medial clinodactyly and single flexion crease (Preus and Fraser, 1972). A correlation has been observed between camptodactyly and the presence of low arches in 18 Trisomy. The emerging association between certain combinations of dermatoglyphic traits and specific chromosome aberrations quickly established a useful diagnostic and an integral part of the medical diagnostics. Dermatoglyphic aberrations do not suggest a specific disorder. It provides incentives to perform other test which are considered as normal. 2.7. DEVELOPMENTAL DELAY Global developmental delay describes a clinical presentation with a large number of underlying causal factors. Accurate diagnosis of etiology has specific implication regarding treatment, management of possible associated conditions, prognosis, and estimation of recurrence risk of the disease. The first signs of communication occur when an infant learns that a cry will bring food, comfort and companionship. Newborns also begin to recognize important sounds in their environment such as the voice of their mother or primary caretaker. As they grow babies begin to sort out the speech sounds that compose the words of their language. 30 By 6 months of age most babies recognize the basic sounds of their native language. There are certain critical periods for speech and language development in infants. Therefore milestones in speech development are normally grouped into time of babbling, speaking first word and speaking first sentence. Normally babbling is seen during the first 12 months of growth of the infant. First word in normal infant is heard between 14 to 15 months. Whereas first sentence in normal child is expected within 18 to 24 months. Mentally retarded children usually cannot perform the following language abilities: (a) put words together (b) speak in complete sentences (c) acquire a larger, more varied vocabulary (d) develop grammatically. Mental retardation accounts for more than 50 percent of language delays. Language and delayed milestones in infancy provide the best insight into intellectual potential and it is independent of motor skills. Right from the fifth year the child should be able to follow a triple order instruction. For example open the door, put the glass on table, sit down (Illingworth 1980). In language development last stage is attained when a child is able to use adult type language which can be between five to six years (Grove 1984). Speech and understanding of the words follow similar stages in children. Single word grows to two words phrases. In two year time these phrases increases upto four words. By third year the child is able to speak small sentences (Gregory 1986). At about 9 months the child is able to judge his name and responds to ‘no’ (Brant and Holt 1986). The child smiles for the first time in six weeks of age. The infant responses to the socio verbal interactions in about two week later ( Franzen and Berg 1998). Earlier, motor development was thought to have a direct relationship to physical maturation. The midbrain and cortical control changes a baby into an upright adult. The first step to walking is head control. On onset of two months as the muscles of the neck and back are strengthened the baby holds his head (Gallalum and Ozmun 1998).The baby can sit at between 6 to 7 months. At 8 months standing with help, crawling at the age of 10 months and walking at 12 months (Franzen and Berg 1998). Cerebral cortical malformations are a major cause of developmental delay and epilepsy (Whiting 1999). This variation in the evaluation is due to many factors such as prevalent population differences, extent of diagnostic evaluation and time period during which the study was completed (Hunter 2000). 31 The prevalence of developmental delay was observed to vary considerably among different populations of the World. Global developmental delay was noted to be at 8.1% reported from Jamaica (Taylor et al. 1985). Global developmental delay was noted 10.8% reported from rural South Africa (Paul et al.1992). ). Development disabilities affect 5% to 10% of all children in USA (Simeonsson and Sharp 1992). The prevalence of developmental delay is 1 to 3% in patients of severe mental retardation. Although there are state to state variation in rates (Centers for Disease Control and Prevention 1996). The rate of 2.44% clinically significant in developmental disability. It is similar to 2–3% frequency reported from the UK (Christianson et al. 2002). Indeed most early intervention programmes for children with developmental delays address adaptive skills such as functional communication, socialization, life skills, and leisure activities within their curricula because these skills play an essential role in supporting daily functioning (McCollum 2002, Blackman 2002 and Lovaas 2003). 2.8. CHROMOSOMAL ABNORMALITIES Chromosomal abnormalities are the single most common cause of mental retardation. Chromosomal abnormalities affect approximately 7 out of every, 1000 infants (AAMR, 1992). The reported frequency of chromosome anomalies detected by high resolution karyotyping (>650 bands) in patients evaluated for developmental delay and mental retardation varies between 9% and 36% (Schreppers-Tijdink, 1998). The range of chromosomal abnormalities on routine cytogenetic analysis is 2.93% to 11.6%, with median of 3.7% (Shevell et al., 2003). Chromosome abnormalities were present in all categories of mental retardation (mild to profound). Authors performed karyotyping in 266 children in Amsterdam and found that 21 children (8.3%) had abnormalities (8 numerical, 13 structural) (Van et al., 2005). It is particularly important to recognize chromosomal disorders among the non-Mendelian genetic causes of mental retardation. Mental retardation associated with congenital malformations, developmental delay and abnormal dermatoglyphics are characteristic findings with chromosomal aberrations (Scriver et al. 1995). Chromosomal abnormalities are responsible for upto 28% of all mental retardation cases (Curry et al. 1997). Most chromosomal disorders happen sporadically. They 32 are not necessarily inherited (Even though they are considered to be genetic disorders). In order for a genetic condition to be inherited, the disease causing gene must be present within one of the parent’s genetic code. Many researchers had done biological & genetic study of mental retardation. Faed et al. (1979) had done the chromosomal survey of a hospital for mentally retarded persons. The cytogenetic analysis was done of 756 patients. A total of 103 patients were to have an abnormal chromosome complement, of whom 91 had Down syndrome, 6 had some other autosomal abnormality & 6 had an abnormality of sex chromosome complement, among them two had XXYY complement. A cytogenetic survey of mentally retarded persons was made by Rasmussen et al. in 1982 in order to establish the frequency of chromosome abnormalities Chromosome analysis was performed in 1905 cases: 359 (18.8%) of these had a chromosome anomaly, 281 (14.7%) Down syndrome, 45 (2.55%) autosomal anomaly other than Down syndrome and 33 (18%) sex chromosomal anomaly. They concluded that mental retardation in total number of mentally retarded persons living within a limited area is determined by many factors. Li et al. (1983) have done a cytogenetic study on mentally retarded children in Taichung city, Changhua country (China) & Taiwan. Abnormal karyotypes were found in 23 (9.43%) individuals, of whom 20 (8.2%) had Down syndrome, 1(0.41%) de novo double translocation and 2 (0.82%) sex chromosome abnormalities. Later on, Wuu et al. (1984) have done cytogenetic studies of 470 mentally retarded children in Taiwan. Thirty eight patients (8.08%) were found to have recognizable chromosomal abnormalities, including 4 cases of sex chromosomes & 34 cases of autosomes. The most prominent category of abnormalities was trisomy 21, a total of 26 cases of this type were found in this study. Sex chromosomal abnormalities constitute very little to the etiology of mental retardation. They concluded that more severe the degree of mental retardation higher the incidence of chromosomal abnormalities. Fryns et al. (1984) have reported cytogenetic findings in 1991 moderate and severe mental retardation. In 21.3% of these patients, a chromosomal aberration was diagnosed (14.9%) Down syndrome patients and 6.4% other chromosomal abnormalities. Fragile –X screening was performed in 354 males which were found 33 to be positive in 57 (16%). Hirayana et al. (1985) had studied chromosomal aberrations among 866 children with mental retardation. Chromosomal anomalies were found in 260 patients. Among these disorders, Down syndrome was the the most frequently encountered, being found in 266 patients. The numbers of patients with super numerary chromosomes for autosomes other than Down syndrome were 15 (1.7%) while that of patients with autosomal deletions were 12 (1.4%). There were 2 patients having balanced structural rearrangements and 5 patients (0.58%) having a karyotype of sex chromosome aberrations. A cytogenetic survey was carried out by Noor et al (1987), to determine the contribution of chromosomal abnormalities to the etiology of mental retardation in 124 children. Out of 124 children, 43 (34.7%) with an abnormal chromosomal complement, 40 had Down syndrome & 3 had other chromosome abnormalities, namely a translocation 1;17, trisomy 18 and Klinefelter syndrome. Xiange and Xianghe (1987) had reported 10 cases of new chromosome abnormalities in the world, not reported previously: 46,XY(t 1;6)(q44;q21), 46XX t(2;22)(q21;q13), 46, XY t(4;14)(q21;q32), 46XY,t(5,15) p(15;q15), 46, XX, t(6;12)(p23;q15), 46, XY, t(12;20)(q22; q 13), 46, XY, inv (6),(P23; q 21), 46,XY,(Xq), t(6; 12)(p23;q10), 44XX, t(13;14)(p11;q11)/45 Xi (Xq),+ (13;14)(p11;q11)(2). The frequency of various chromosome heteromorphisms was examined in 125 patients with non-specific mental retardation and 125 controls by Dereymaeker et al. (1988). The incidence of larger variant was significantly higher in patients than in controls. In 72 patients a constitutional cause of their impairment was found: chromosomal abnormalities in 21, a Mendelian disorder in 36 (autosomal disorders:23; autosome dominant: 12 and X-linked recessive :1), a MR syndrome in 9 and a CNS malformation in 6 patients. Another cytogenetic study by (Mitra et al 1988) concluded that most patients belonged to categories of Down syndrome, primary amenorrhea and congenital malformation. A total of 77 (23.6%) patients were found to have chromosomal abnormalities, including 57 autosomal and 20 sex chromosomal abnormalities. The chromosomal anomalies were trisomy 21, robertsonian translocation, Philadelphia chromosome, monosomy x, trisomy X, XXY mosaics. Wuu et al. in 1991 have done chromosomal & biochemical screening on mentally retarded school in Taiwan. They found that majority of chromosome 34 abnormalities was trisomy 21. A remarkable difference in the percentage of mentally retarded children with chromosome abnormalities was observed between the moderate (7.87%) & severe (17.5%) retardation. While Farang et al. (1993) have given disease profile of 400 mentally retarded children in Kuwait having IQ>50. Chromosome abnormalities were found in 37. Chromosomal abnormalities include numerical chromosome abnormalities, partial chromosomal abnormalities and microdeletion. 2.8.1. NUMERICAL CHROMOSOME ABNORMALITIES The normal diploid number of human chromosomes is 46, and was established by Tjio and Levan in 1956. This was a landmark in the history of human cytogenetics because, until then, human diploid constitution was believed to be 48. The impact of this discovery was soon felt in medical cytogenetics when Lejeune et al. (1959) reported that the common retardation disorder Down syndrome was caused by trisomy of one the G-group chromosomes, resulting in chromosome number 47. A numerical chromosome abnormality is caused by additional (Polyploidy) or missing (monosomy) chromosomes from the normal set of 46. Reported live born autosomal chromosome polyploidies are restricted to trisomy 13 (Patau’s syndrome), 18 (Edward’s syndrome) and 21 (Down syndrome). Trisomy 16 is one of the most frequent chromosome aberrations of early pregnancy, but it is completely absent from live or still birth. The frequency of live births in trisomies of chromosome 18 and 13 is much lower (Hassold and Hunt, 2001). 2.8.2. DOWN SYNDROME It is most frequent and common genetic cause of mental retardation accounting for 25-30% worldwide (Mclaren & Bryson, 1987; Winnepenickx et al.,2003). Sheth et al. (2007) have reported that Down syndrome with trisomy 21 was one of the most common aneuploidy in humans. Down syndrome is one of the first recognized and best studied of the autosomal syndrome in man (Mikkelsen, 1997). It was associated with mental retardation and developmental delay with the incidence of 1 per 920 births in India (Verma 2000). 35 Diverse physical & clinical features characterize Down syndrome patients. Facial features being strongly symptomatic of the syndrome. In general, a rounded face, brachycephaly, epicanthic folds, flattened nasal bridge, oblique palpebral fissure, narrow palate, folded ear, nuchal thickening, in curved 5th finger (clinodactyly), wide gap between 1st & 2nd toes (sandal sign), protruding tongue, and single palmer crease (simian crease) are some of the diagnostic features. Recent work on patients with Down syndrome and partial duplications of chromosome 21, has suggested small chromosomal regions located in band q22, that are likely to contain the genes for some of these features. The studies provided the molecular basis for the constriction of Down syndrome phenotypic map and focused the search for genes responsible for physical features, congenital heart diseases and duodenal stenosis of Down syndrome (Tolmie, 1997). Mental retardation is a prominent symptom of Down syndrome. However, a great deal of heterogeneity is encountered in the expression of the most symptoms and extent of abnormality. The measure of intelligence (IQ) in Down syndrome varied from 20-85. That is, its highest value may reach close to the lower values revealed highly challenged condition. 2.8.3. PATAU SYNDROME AND EDWARD SYNDROME Other types of polyploidies which are restricted to trisomy 13 (Patau syndrome) and 18 (Edward syndrome) share many features in common. Patients are always severely mentally retarded and most affected children die during the 1st week after birth. The frequency of live births in trisomies of chromosome was found to be 0.12 and 0.08/1000 live births. While Naguile et al. (1987) have reported the incidence of trisomy 18 as 4.61/1000 which was significantly higher than the international incidence in previous years. Adeyokunnu (1983) have done clinical, cytogenetic and dermatoglyphic study on 14 cases of trisomy 18, as well as 7 cases of trisomy 13 and found two unusual cases; 1 case was mosaic for trisomy 18 and another case of trisomy 13, seemed to have derived an extra chromosome of the D group from or reciprocal D/S translocation that was maternally carried. Blattner et al. 36 (1980) have found unbalanced translocation 46, XX,-13, +der (13), t (13; 18) (p13; q13) mat in a patient having characteristic features of trisomy 18. Both syndromes had certain physical features in common which sometimes made clinical diagnosis difficult but each had diagnostic features of its own. While himangima and polydactyly form the hallmark of trisomy 13, the protruding heel make the appearance of trisomy 18. Neural tube defects, craniorachischis, large omphalocele and bilateral cleft lip and cleft palate are also part of trisomy 18 (Moore et al., 1988). Based on liveborn & stillborn probands, the prevalence at birth was 1 per 29,374 for trisomy 13 and 1 per 6806 for trisomy 18. The median survival for trisomy 13 was 2.5 days while the same figure for trisomy 18 was 6.0 days. The rate was lower as compared to other studies. Since, liveborn patients suffering with Edwards’s syndrome (Trisomy 18) and Patau’s syndrome (Trisomy 13) are rare. Intrauterine fetal death occurred at the 32nd week of gestation (Goldstein et al., 1988). In addition to numerical chromosomal anomalies deletions, insertions, inversions, translocation etc. may occur on any part of chromosome. 2.8.4. DELETIONS Deletions may cause diverse phenotypes, depending on both the size & location of the deletions, but invariably including mental retardation. As a general rule, deletions spanning more than 2% of the total genome are not viable. Deletions with a minimum size of roughly, a single chromosome band or 5.15Mb can be detected under a microscope on chromosome spreads made of blood cells. Example of such cytogenetically visible deletions include Cri-du-chat syndrome. Its main features are protruding mandibles, prominent chin, and prominent root of nose, subnormal skull perimeter & low IQ. Jacobsen syndrome is also a rare chromosomal disorder, caused by terminal 11q deletion. Prominent features are growth and psychomotor retardation and a characteristic facial dysmorphism, but many different abnormalities like duodenal atresia and annular pancreas. Clinical manifestations of Jacobsen syndrome depend 37 on the size of the 11q ter deletion which usually varies between approximately 7 and 20 Mb. (Bernaciak et al., 2008). Detailed molecular and clinical characterization of three patients with 21q deletions was performed by Lindstrand et al. (2009). Duplication/deletion rearrangement in the short arm of chromosome 4 can result in two different clinical entities. Wolf-Hirschhorn syndrome, characterized by severe growth delay, mental retardation, microcephaly, ‘Greek Helmet’ facies & closure defects of partial 4p trisomy associated with multiple congenital anomalies, mental retardation and facial dysmorphisms (Rosello et al, 2009). In the early 1990s, recurrent small microdeletions of the genome not visible by light microscopy were identified, associated with characteristic syndromes. These were only detected by fluorescence in situ hybridization (FISH) or similar techniques and include the common microdeletion syndromes of: Prader Willi syndrome and Angelman syndrome etc. Although each syndrome has characteristic distinguishing features. All are also associated with varying degree of mental retardation and in some cases associated with specific areas of intellectual impairment (Raymond & Tarpey, 2006). Such deletions do not occur at random positions in the genome but tend to cluster in specific regions (Winnepennickx et al, 2003). These syndromes were reviewed by many scientists. 2.8.5. ANGELMAN SYNDROME Angelman syndrome result from a loss of gene activity in a specific part of chromosome 15, the 15q11-q13 region. This region contain a gene called UBE3A that, when mutated or absent, likely causes the characteristic features of this condition (Karen and Harum, 2006). People normally have two copies of UBE3A gene one from each parent. Both copies of this gene are active in many of the body’s tissue. In the brain, however, only the copy inherited from a person’s mother (the maternal copy) was active. If the maternal copy is lost because of a chromosomal change or a gene mutation, a person would have no working copies of the UBE3A gene in the brain. In most cases (about 70%), people with Angelman syndrome have a deletion in the maternal copy of chromosome 15. This chromosomal change deleted the 38 region of chromosome 15 that included the UBE3A gene, the copy of the gene inherited. About 3% of Angelman syndrome cases are caused by the defect in the DNA region that controls the activation of the UBE3A gene and other genes on the maternal copy of chromosome 15. In a small percentage of cases, Angelman syndrome may be caused by a chromosomal rearrangement called a translocation or by a mutation in a gene other than UBE3A. These genetic change can abnormally inactivate the UBE3A gene (Clayton-Smith and Laan, 2003). 2.8.6. PRADER-WILLI SYNDROME Another type of deletion syndrome Prader-Willi syndrome is caused by the loss of active genes in a specific part of chromosome 15, the 16q 11-13 region. Prader-willi syndrome usually occurs sporadically. About 60% of the patients show a chromosomal deletion of proximal 15q. People normally have two copies of this chromosome in each cell, one copy from each parent. Prader-willi syndrome occurs when the paternal copy is partly or entirely missing (Bittel and Butler, 2005). In about 25% of cases, a person with Prader-willi syndrome has two maternal copies of chromosome 15 in each cell instead of one copy from each parent. This phenomenon is called maternal uniparental disomy (Kokkonen et al, 1995). Because some genes are normally active on the paternal copy of this chromosome, a person with two maternal copies of chromosome 15 would have no active copies of these genes. In a small percentage of cases, Prader-willi syndrome is caused by a chromosomal rearrangement called translocation. 2.8.7. TRANSLOCATIONS Translocations can remain without clinical consequences as long as they are balanced, without loss or gain of genetic material and do not interrupt an important gene. A well known example is the robertsonian translocation, which results from the breakage of the two acrocentric chromosomes (13, 14, 15, 21 or 22) at or close to their centromeres, followed by the fusion of the long arms. The resulting hybrid chromosome consists of two long arms of for instance chromosome 14 & 21. As the short arm of these acrocentric chromosome contains abundant ribosomal sequences. 39 Only the carriers of this translocation remains unaffected. However, the progeny of such a patient may inherit an extra copy of the long arm of chromosome 14 and not be viable (Winnepenninckx et al, 2003). Reciprocal balanced translocation was found to be associated with mental retardation. A unbalanced translocation (18,22)(18qter-cent-22qter) was detected in a boy aged 4 years with congenital mental deficiencies and multiple anomalies of its phenotype by Gizburg et al(1988). 2.8.8. DUPLICATIONS Duplications are seldom seen in contrast to the more common duplication deficiencies generated by aberrant meiotic segregation in translocation and inversion heterozygotes. Floridia et al (1996) have reported 16 case of 8p duplications with a karyotype 46, XX or XY, dup (8p), associated with mental retardation, facial dysmorphism and brain defects. Using fluorescence in situ hybridization (FISH) and short tandem repeat polymorphism (STRP), Shimokawa et al. (2004) have analysed five patients with inverted duplication deletion of 8p. A 6 years old boy having small stature, madelung deformity, facial dysmorphism, mental retardation and behavioural problems was found by Dupont et al (2007). G-banding has shown normal male karyotype. Molecular analysis indicated an inverted duplication of Xp22.31-Xp22.32 region. 2.8.9. INVERSIONS Inversion-duplication structures were confirmed in two cases by Daniel et al. (2008) by various FISH studies. Inverted duplications of a terminal chromosome region are a partial tetrasomy when accompanied by a deleted chromosome (Carreira et al, 2009). The most common frequent cytological visible paracentric inversions have breakpoints in chromosome arms 11q, 7q and 3p. Of the 184 inversions cited by Madan (1995), 38 had a breakpoint in 11q and in 31 of these it was 11q21-q23 although these were not so tightly clustered. 2.8.10. RING CHROMOSOMES 40 Ring chromosome 15 is associated with a rather uniform phenotype, characterized by moderate mental retardation, marked pre and postnatal growth failure, triangular face with short hands and feet (Mariotti et al. 1983). The son has microcephaly, ptosis, short stature and mental retardation, the mother was mentally retarded & had a similar facial appearance due to inheritance of ring chromosome 18. Another case of 8 months old female infant with mental & growth retardation, muscular hypotonia, flat occiput, round face, hypertelorism, Epicanthal fold, saddle nose, high arched palate,carp shaped mouth, short neck and slightly prominent heels was reported in whom by means of g-banding technique the karyotype of the patient was shown to be, 46, XX, r(18)(p11q23) (Kogame et al., 1987). Since the ring involves a deletion at both ends of the chromosome, the resulting phenotypes overlap that of deletion syndrome for each type of chromosome. The ring 14 (r14) syndrome is a rare condition, whose precise, clinical & genetic characterization is still lacking. Zollino et al. (2009) has analysed cytogenetically a total of 20 patients with r14 and another 9 patients with a linear 4p deletions. Clinically r14 chromosome is characterized by a recognizable phenotype, consisting of shortness of stature, a distinctive facial appearance, microcephaly, ocular abnormalities etc. All patients except one had mental retardation. They concluded that deleted ring chromosomes were 70% paternal and 30% maternal. In Turkey with the aim of finding out the etiology of the genetic diseases, 4659 patients who were classified into mental retardation and multiple congenital abnormalities and mental retardation (MR and MCA/MR) group were referred to Istanbul University (Yuksel et al.,2007). 2847 patients have had an etiological diagnosis (61.10%): from these patients,1541 out of them had a chromosomal abnormality (33.07%), 555 were known as single gene mutations (11.91%), 20 were recognized syndromes (00.42%), 567 were sequences (12.16%) ,6 were associations (00.12%), 29 had spectrums (00.62%), 98 had structural abnormalities of CNS (2.10%), and finally 31 suffered from prematurity and its complications , toxic drugs, infections and hypoxic ischemic encephalopathy. The first report from India on cytogenetic abnormalities was published by Moghe et al. (1981). Jain et al. (1998) screened 1206 children with MR and found 41 6.38 percent positive for fragile- X syndrome. Sex anomalies were also established by many scientists which include Turner syndrome, Klinefelter’s syndrome. Micro deletion syndromes were detected in 73 cases among 374 by Madon prochi et al. (2010). First report from Jammu and Kashmir on chromosomal anomalies was reported by Parvinder Kumar et al. (2010) and they reported 11.2 percent Turner syndrome cases and 6.8 percent Klinefelter syndrome cases. Rajasekhar et al. (2010) analyzed 1400 referral cases for cytogenetic analysis and reported karyotype 45X in 36.17 percent cases. A prospective and retrospective cytogenetic study was conducted on 1760 MR cases for chromosomal abnormalities using routine GTG and high resolution banding methods of karyotyping. Out of 1760 MR cases, 555 cases showed abnormal chromosomal constitution (31.5%), and males were more than females (2.1: 1). Numerical chromosomal abnormalities were detected in 40.4% (224 of 555), out of which autosomal abnormalities were 36% (199 of 555) and sex chromosomal abnormalities were 4.5% (25 of 555). Structural chromosomal abnormalities were detected in 52% (289 of 555), out of which autosomal abnormalities were 28.6% (159 of 555) and sex chromosomal abnormalities were 29.5% (164 of 555), with some having both numerical-structural (7.6%) and autosomal-sex abnormalities (1.4%). The chromosomal study revealed Down syndrome as the most common chromosomal abnormality i.e. 45% (250 of 555). There were 144 males (57.6%) and 106 females (42.4%). Free trisomy was found in 88.8% (222 of 250), mosaic cell line was found in 8% (20 of 250) and translocation was seen in 3.2% (8 of 250). Other variations/ abnormalities were also seen in the Down syndrome patients namely 9qh+(9 cases), 15p+ (3 cases), 14p+(2 cases), 13p+(1case), 22pstk +(1 case), inv9(2 cases), t(1q;5q) (1 case), small Y(6 cases), long Y(4 cases) and inv Y(2 cases). (Dave and Shetty 2010.) All 30 subjects of both sexes in the age group of 05-50 years for Karyotypic study are known mentally retarded patients, among them 66.66 percent were under weight, 13.33 percent were dumb, 10 percent were suffering from dermatological disorders like dry skin, 16.60 percent were with skeletal deformities, 10 percent were microcephalic, 6.66 percent were suffering from seizures and 6.66 percent 42 were with long faces. Fifty percent of the subjects are categorized as Mild MR, 30 percent are Moderate MR and 20 percent are suffering from severe Mental Retardation. Out of 30 subjects, 9 showed chromosomal aberrations (30.0%) included 7 (23.3%) structural variations, 2 (6.66%) numerical anomalies. Structural variations include Deletions, Inversions, Translocations and Additions. Numerical variations included Down syndrome. Surprisingly no sex chromosomal abnormalities were noticed. Sex-wise 36.36 percent males and 12.5 percent females were suffering from chromosomal anomalies. Age showed no impact on chromosomal aberrations (Mythili and Jaya Kumari 2011). 2.8.11. X-LINKED MENTAL RETARDATION Lehrke (1972) was the first to suggest that there may be genes coding for intellectual functioning located on the X-chromosome. Nomenclature guidelines for X-linked mental retardation are proposed for non syndromic and syndromic forms of mental retardation. MRX is a very common disorder homogeneous but genetically heterogenous which affects ~1 in 600 males (Herbst and Miler, 1980). Non-specific mental retardation (MRX) are given unique symbols for each family (MRX1, MRX2…..MRXS3…..MRXSN). In a family, 6 males were found to have non-specific X-linked mental retardation (MRX) by polymorphic DNA probes (Schwartz et al, 1992). Non-specific mental retardation is conditions where mental retardation appears to be the only significant clinical findings, without any clear underlying causative factors and no relevant pedigree information (Harper, 2002). The first gene to be identified was FMR1 that causes Fragile-X syndrome and still remains the commonest single gene abnormality to be identified (Crawford et al, 2001). 2.8.12. FRAGILE- X Fragile- X is the most frequent and the best studied X-linked syndrome. Herbst and Miller (1980) estimated the prevalence of Fragile-X syndrome is to be 183 per 1000 males and carries frequency among females as 2.44 per 1000. A typical affected male is mentally retarded but heterozygous females also have a 3035% chance of being retarded. Since fragile sites are also present in normal human being but the probability that of MR male offspring’s with Fragile-X is very large 43 (Silverman et al, 1983). It is well known that the fragile Xq27 is strongly associated with X-linked mental retardation in males but Takimoto et al. (1985) found a normal male who carried fragile Xq27. The phenotype is currently viewed as including; mild to moderate mental retardation, coarsening of facial features, long and narrow face, macroorchidism, large and prominent ears, prominent jaw, high forehead, high pitched and jocular speech. Fragile- X is the most frequent and the best studied Xlinked syndrome. It is an X-linked recessive disorder with unusual pattern (Faradz et al, 2002). The genetics of Fragile-X syndrome is complex and follows an X-linked ‘semi-dominant’ inheritance pattern. The pedigree analysis may reveal presence of normal transmitting males, whose daughters would all be carriers. These carrier daughters may have affected sons and daughters (Kumar 2004). The introduction of specific molecular genetic testing for Fragile X syndrome has lead to a downward revision of the prevalence of this diagnosis in the Australian population from 0.08% (1:1,250) to 0.025% (1:4,000) in predominantly Caucasian males with intellectual disability as the result of improved discrimination between fragile sites molecularly and prenatal diagnosis (Turner et al, 1996). Cytogenetically the fragile-X syndrome is characterized by the presence of a break (fragile site) at the end of long arm of the X chromosome after culturing peripheral blood lymphocytes in a folate-deficient medium. The molecular basis of the diseases is an expanded trinucleotide repeat in the 5' untranslated region of the FMR-1 gene (Fragile X Mental Retardation -1 gene). The length of the trinucleotide repeat is polymorphic in the population. Normal individuals have fewer than 50 copies of the trinucleotide repeat (CGG)n. Carriers of permutation alleles have between 52 and 230 (CGG)n repeats and affected people have greater than 230 repeats up to2,000(CGG)n. When the trinucleotide repeat expands beyond 230 copies the repeat array becomes methylated, which results in transcriptional silencing of the FMR-1 gene. First screening in MR children has shown that the frequency of fragile X syndrome in Indonesia to be 2% in Central Java, which is comparable to Caucasian data. In the same study, 53% of the male and female Fragile X patients in an institution of isolated village in central Java could be retraced to one ancestor. It is an X-linked recessive disorder with unusual pattern. In unselected male population 44 of 10 ethnic groups in Indonesia carrier ship rates has shown to be 0.3% (Faradz et al, 2002). Molecular diagnostics of CGG amplification which constitutes 99% fragile mutation has been available since the cloning of FMR 1 gene 1991and relies on PCR and southern blotting by hybridization with probes specific for the promoter region (Fu et al. 1991). Due to the increased prevalence direct DNA analysis of the CGG expansion mutation by PCR has begun to replace cytogenetic analysis for laboratory diagnosis of Fragile X syndrome ( Roussean et al. 1991). A DNA test for Fragile X was developed in 1992. There are two to three loci of gene which are responsible for mutation fmr 1 and fmr 2 being predominant genes. FRAXA, FRAXE, FRAXD, FRAXF are some of the fragile site loci. Genotypes of individuals with symptoms of FXS and individuals at risk for carrying the mutation can be determined by examining the size of the trinucleotide repeat segment and the methylation status of the fmr1 gene. PCR analysis utilizes flanking primers to amplify a fragment of DNA spanning the repeat region. Thus the sizes of the PCR products are indicative of the approximate number of repeats present in each allele of the individual being tested. The efficiency of the PCR reaction is inversely related to the number of CGG repeats, so large mutations are more difficult to amplify and may fail to yield a detectable product in the PCR assay. However, there is a limitation to PCR, that no information about fmr1 methylation status can be obtained. On the other hand PCR analysis permits accurate sizing of alleles in the normal and the permutation size ranges. Also on a small amounts of DNA in a relatively short turn around time. The assay is not affected by skewed X chromosome inactivation. A diagnosis of fragile X syndrome influences treatment and intervention strategies which can contribute to improvement in outcome. Because the symptoms of Fragile X can be quite difficult to detect, especially in young children testing for Fragile X may be considered for any individual with otherwise unexplained mental retardation. There are recommendations on who should be tested for fragile X syndrome. These include individuals of either sex with mental retardation, developmental delay or autism. Especially if they have any physical or behavioral characteristics of fragile X syndrome, a family history of fragile X syndrome or a relatives with undiagnosed mental retardation. Individuals seeking reproductive counselling who have a family 45 history of fragile X syndrome or a family history of undiagnosed mental retardation must be checked for fragile X mutations. Fetuses of known carrier mothers should also be tested. Since the cytogenetic tests were used prior to the identification of the FMR 1 gene and is significantly less accurate than the current DNA test. DNA testing on such individuals is important to accurately identify the mutations. For a family the diagnosis marks the end of uncertainty about the cause of a child's difficulties. The family studies may be initiated which bring forward the diagnosis of some affected relative. Knowledge of the diagnosis can direct the family to appropriate information and to social organizations. Results of fragile X DNA testing allow accurate genetic counselling to be provided. Data on prevalence and on attributable risk are especially important for the research on the prevention of mental retardation. Carrier testing for at risk individuals for families to make informed reproductive decisions. Thus, the identification of cause can be important in planning for the medical, educational, and treatment needs of a particular individual. Mental retardation in population has been burden not only on traditional mental health system but also on other multiple service systems that support these people and their families. 2.8.13. SEX CHROMOSOMAL ABNORMALITY The sex chromosomes show a much wider range of viable aneuploidy than do the autosomes. These abnormalities are the most common ones observed (Pavri, 1978). Several reports about many families with idiopathic mental retardation segregating in sex-linked fashion followed the Martin Bell pattern (Dunn et al, 1963). The uncommon aberrations reported are 46, XX/47, XXY mosaicism and 46 XX/ 47 XYY mosaicism (Chaudhuri et al, 1971). Fryns et al. (1984) have reported a moderately mentally retarded patient with Klinefelter syndrome, in whom two fragile-x chromosome were found in 20% of cells. 2.9. SINGLE GENE DISORDER The majority of single genes that have been identified, which give rise to mental retardation are on the X chromosome. There is a male excess of affected individuals compared with females (ratio1: 1.3) which has been assumed to be due 46 to X-linked inheritance both due to the retention of X-linked genes in the population by the maintenance of reproductive fitness in females contributing to the prevalence in the population and the large number of genes on the X chromosome that gives rise to the condition (Penrose 1938.). The first gene to be identified was FMR1 that causes fragile X syndrome and still remains the commonest single gene abnormality to be identified (Crawford et al 2001). Since 1990, a series of genes have been identified either by positional cloning or translocation breakpoint mapping methodologies. Some are only associated with mental retardation and are not reported to be associated with dysmorphic or other neurological symptoms and others are more syndromic although the distinction between these are gradually becoming less clear as syndromic and non-syndromic phenotypes are described for several of the genes (Frints et al 2002). Currently, genes that are classified as non-syndromic mental retardation genes are: IL1RAPL1 (Carrie et al 1991), TM4SF2 (Zemni et al 2002), ZNF41 (Shoichet et al. 2003), FTSJ1 (Freude et al. 2004), DLG3 (Tarpey et al. 2004), FACL4 (Meloni et al 2002), PAK3 (Allen et al 1998), ARHGEF6 (. Kutsche et al. 2000), FMR2 (Gecz : 2000; Gu et al 1996), GDI (D’Adamo et al. 1998), ZNF81 (Kleefstra et al. 2004) and ZNF674 (Lugtenberg et al 2005), whereas the genes where syndromic forms of mental retardation is described are NLGN4 (Jamain, et al. 2003), RPS6KA3 (RSK2) (Merienne et al 1999), OPHN1 (Billuart et al 1998; Philip et al 2003), ATRX (Guerrini et al 2000), SLC6A8 (Salomons et al. 2001), ARX (. Stromme et al. 2002; Kitamura, et al 2002), SYN1 (Garcia et al. 2004), AGTR2 (Vervoort et al 2002.), MECP2 (Orrico et al. 2000; Meloni et al. 2000; Klauck et al 2002), PQBP1 (Kleefstra et al 2004; Kalscheuer et al 2003), FGD1 (Pasteris et al 1994; Lebel et al. 2002), SMCX (Jensen et al. 2005) and SLC16A2 (Friesema et al. 2004; Dumitrescu et al. 2004; Schwartz et al. 2005). 2.10. FLUORESCENT IN SITU HYBRIDIZATION (FISH) The screening of individuals with mental retardation for subtelomeric abnormalities was proposed by Ledbetter as early as 1992 (Ledbetter, 1992). A polymorphism at the 2q telomere was first identified by Macina et al (Macina et al., 1994). The First study using abnormal inheritance of hypervariable subtelomeric 47 DNA polymorphism carried out only three years later by Flint et al. (Kirchhoff et al., 2001). In 1996, a complete set of fluorescence in situ hybridization (FISH) probes located within a distance of 300kb from the telomeric repeats were presented ,and an updated set was announced. These probes made it possible to analyze all chromosome ends for subtelomeric rearrangements in one experiment (Knight et al., 2000). There was only one prospective study of consecutive group of children with mental retardation of unknown etiology (VanKarnebeek et al., 2002). Contrary to the published reports, this study showed that the frequency of subtelomeric rearrangements detected using FISH is very low. Cytogenetic methodology has been merged with the DNA technology through fluorescent in situ hybridization (FISH). It allows the visualization of specific nucleic acid sequences in morphologically preserved chromosomes, cells or tissue sections. and is based on the precise annealing of a single standard DNA probe with a fluorescein to complementary target sequences. The site of hybridization of the probe with cellular DNA is visible as fluorescent signals when observed under fluorescence microscope. The probe (DNA or RNA sequence) of the interest and the locus (i.e. the target sequence to which the probe hybridizes) are major components of the FISH procedure. A fluorescent tag is attached to the probe in order to visualize the hybridization of the probe to the target (Guan et al., 1994). FISH technique can also be used on previously banded slides that can not only yield immediate results that can also be correlated with those of conventional cytogenetics (Delhanty, 1997). Although conventional cytogenetics remains the ‘gold standard’ for whole genome screening. Problems are encountered while dealing with tissue that yields a low mitotic index with poor quality metaphases. The advent of fluorescent in situ hybridization (FISH) has been a boon in such cases, as it offers an unprecedented opportunity for analysis of non-dividing cells (interphase cells) (Berstein et al., 1993). Fluorescent in situ hybridization is a powerful sensitive molecular cytogenetic technique which can be used as an adjunct to conventional chromosomal analysis. FISH has the potential to be used in identifying the desired DNA in the 48 interphase nucleus and poorly spread metaphase. Since each nucleus is independently analysed without gene amplification, false positive results are infrequent. Interphase FISH anlysis has been successfully applied in diagnosis of chromosome aberrations in uncultured or short-term cultured amniocytes and chronic villus cells (Pergament et al., 2000). Numerical chromosomal abnormalities (trisomy 21, trisomy 13, trisomy 18, monosomy 7 etc.) can be detected readily using chromosome enumerisation probes e.g. alpha-satellite probe specific for chromosome 21 can be used to detect trisomy 21 or Down syndrome. This is particularly helpful in cases with low level of mosaicism. A variety of tissues that are not amenable to conventional cytogenetic analysis can be anaslysed using FISH for aneuploidies (Burke et al., 1996). Out of 374 samples tested in 5 years at Jaspal Hospital in Mumbai, 73(20%) were found to be positive for various microdeletions. Among the 73 positive cases, 29(40%) had Angelman syndrome, 16(22%) had PraderWilli syndrome, 24(33%) had Williams syndrome and 4(5%) had DiGeorge syndrome. There was a male preponderance in DiGeorge syndrome (3/4 cases). Out of the suspected cases tested syndrome-wise, the percentage of positive cases detected by FISH was 36% (24/67) for Williams syndrome, 18% (29 of 163) for Angelman, 17% (4/23) for DiGeorge and 13% (16/121) for PraderWilli syndrome. One suspected case of Prader-Willi syndrome had a Robertsonian translocation t(14;15)(q10;q10) which led to a deletion of a major part of the SNRPN region in 10% cells, resulting in low-grade mosaicism. Another FISH-positive case was due to a reciprocal translocation t(2;15)(q37;q11), where loss of critical genes at the breakpoint on chromosome 15 caused the Prader-Willi phenotype (Madon et al. 2010). Mental retardation is one of the most frequent handicaps among children and can be a serious and lifelong disability placing heavy demands on the society and the Health System. Combinations of multiple gene and environmental factors lead to mental retardation. Therefore effective prevention requires better information on risk factors and causes. The disabilities are substantial and therefore early detection is mandatory. 49 There is a great need to evaluate all idiopathic mentally retarded males for Fragile X syndrome. Individuals experiencing late-onset sporadic cerebellar ataxia and intention tremor of unknown etiology and females experiencing reproductive or fertility problems associated with elevated follicle stimulating hormone levels are diagnosed for the FRAXA mutation. Hence prenatal diagnosis and genetic counseling can be the best method to reduce the burden of the disease. The American College of Medical Genetics (2006) recommends testing in some of the conditions like diagnostic testing for individuals with unexplained mental retardation, developmental delay or autism. A confirmation of a cytogenetic test result inconsistent with clinical phenotype. A carrier testing for individuals with a family history of Fragile X syndrome or mental retardation of unknown etiology and prenatal testing is highly recommended for fetuses of carrier mothers. An important implication of finding a cause and knowing the aetiology is that patients and their families can be educated about the long term issues such as life span and progression of disease, deciding about child bearing and antenatal monitoring of subsequent pregnancies. 2.11. INFORMATION ABOUT ASSOCIATED DISORDER The number of associated disorders increases with the level of severity of mental retardation (Baird & Sadovnick 1985). A variety of disorders are associated with mental retardation such as epilepsy, cerebral palsy, vision & hearing impairment, speech/language problems and behavior problems (McLaren & Bryson, 1987). Some neurological disorders like microcephaly also leads to mental retardation in which there is reduction in brain cortex volume (McCeary et al 1996). Metabolic disorders like galactosemia, mucopolysaccharides, phenylketoneuria, etc. also lead to mental retardation. Galactosemia occurs due to deficiency of enzyme galactose-1-phosphate uridinyl transferase present in liver, skin & RBCs. (Kahler & Fahey, 2003). Mucopolysaccharidosis is an X-linked recessive disease occurs due to mutation of 1DS gene present in Xq28, which codes for iduronate 2-sulphatase (Wraith et al 2008). Phenylketoneuria (PKU) is a rare metabolic disorder in which baby appears normal but lacks enzyme Phenylalanine 50 hydroxylase needed to breakdown phenylalanine. Hence phenylalanine accumulated in the blood leading to brain damage (Centerwall & Centerwall, 2010). Screening individuals with IMR for telomeric imbalances was first proposed by Ledbetter in 1992. This publication was followed by several others confirming the value of such a screen and outlining practical approaches to performing the investigation (Wilkie 1993, Flint et al. 1995; Lese and Ledbetter 1998). FISH with multiple subtelomeric probes has been proved to be useful in the study of IMR cases. The first screen was carried out by Flint et al. (1995) and, although only 28 chromosome ends were examined in 99 IMR patients, their results indicated that at least 6% of IMR cases could be caused by cryptic telomeric imbalances. This frequency was later refined as 7.4% after including a marker for the telomeric region of 1p (Giraudeau et al. 1997). High-resolution G-banded analysis, together with fluorescence in situ hybridization (FISH) and molecular techniques, has resulted in the delineation of further syndromes caused by terminal rearrangements, e.g. deletions of 1p (Shapira et al. 1997; Slavotinek et al. 1999b) and 22q (Nesslinger et al. 1994; Praphanphoj et al. 2000). 2.12. FINDING A CAUSE OF MMR To qualify as a causative factor a variable must be associated with an increased probability of disorder and must help in the onset of disorder. Variables that may be risk factors at one life stage may or may not be risk factors at a later stage of development. Embryological timetables are helpful in studying the etiology of human malformations. Risk factors can reside with the individual or within the family, community or institutions that surround the individual. They can be biological or psychosocial in nature. These factors are hard to isolate for two reasons. First, they are very closely related and complex in nature. Secondly they do not individually result in impairment. For example, risks among people of low socioeconomic class can run through generations because the cycle of poverty creates conditions which contribute to the incidence of disabilities. But at the same time it should be realized that heredity and prenatal environment work together to produce the infant. Identifying such factors in idiopathic cases can be a first step toward 51 determining a cause behind mental retardation and then developing preventive interventions. The Indian subcontinent has relatively higher incidence & prevalence of genetic diseases. There are a number of factors that significantly increases the prevalence of genetic disorders in this subcontinent. The factors may be malnutrition, poverty, low socioeconomic status & deprivation syndrome. Consanguineous marriages and high birth rates are also major factors behind this (Verma and Bijarnia, 2002). In India, the incidence of mental retardation is reported to be 2-3%. Of these, 30% cases of severe mental retardation are genetically determined. (Kaur et al., 2003). The etiology of mental retardation is still unexplained in at least 50% of cases. Etiology of MR should be conceptualized as a specific diagnosis that can be translated into useful clinical information for the family including prognosis, recurrence risks & preferred modes of available therapy. The diagnostic process is aided considerably if the timing of a developmental insult can be determined: prenatal, perinatal, and postnatal (not mutually exclusive). So, the term etiology has a broad interpretation in mental retardation that can be caused by genetic, environmental & ecogenetic factors. Specific diagnosis for the patients provides a better understanding of the possible reasons of pathogenesis and possible treatment options. The scientific field of genetics can help families affected by MR to have better understanding about heredity, what causes mental retardation to occur and what possible prevention strategies can be used to decrease its incidence. Some genetic disorders are associated with mental retardation, chronic health problems and developmental delay. Because of the complexity of human body, there are no easy answers to the question of what causes mental retardation. Keeping in view of above information on mental retardation and need of the society present research of “Etiologic and Pathogenetic study of patients of Moderate Mental Retardation” has been planned. 52