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MCD Genetics - 5 Genetics of childhood diseases Anil Chopra 1. Explain the underlying defects for phenylketonuria and other diseases in the same biochemical pathway. There are over 200 known childhood genetic diseases known. They can be of metabolites, metabolic pathways, enzyme function and cellular organelles. They are mostly X-linked or autosomal recessive diseases resulting from defective enzymes. Phenylketonuria (PKU) Pathogenesis Has an incidence of 1:10,000. Caused by a deficiency of the enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase converts phenylalanine to tyrosine which is used to synthesise melanin. Phenylalanine therefore accumulates in the brain issue and causes damage as the brain is developing. Signs and Symptoms This leads to mental retardation and convulsions (seizures). Patients will have blonde hair and blue eyes. Patients may encounter microcephaly (small head) heart defects. Treatment If detected early, then no mental retardation takes place. Newborn babies have the Guthrie test – heel prick gets drop of blood which is then examined for its phenylalanine levels. If somebody is diagnosed with PKU they are advised to remove phenylalanine from their diet and monitor the blood levels of this essential amino acid 2. Describe the clinical features and genetic defects in common disorders of carbohydrate metabolism Galactosaemia Pathogenesis Disorder of carbohydrate metabolism. Has an incidence of 1:30 000. It is autosomal recessive. There is a deficiency of the enzyme galactose -1-phosphate uridyl transferase. 70% have Q188R mutation which makes them unable to metabolise sugar. Signs and Symptoms Newborn babies present with vomiting, lethargy, failure to thrive and jaundice in second week of life. Complications include mental retardation, cataracts, cirrhosis. Treatment Screen for galactose in urine If diagnosed early then the phenotype can be prevented. Feed infants with milk substitutes, lacking galactose and lactose Hereditary Fructose intolerance Pathogenesis Disorder of carbohydrate metabolism It is autosomal recessive. There is a deficiency of the enzyme fructose -1- phosphate aldolase. Fructose is present in honey, fruit and certain vegetables and cane sugar. Signs and Symptoms Presents at different ages with vomiting, lethargy, failure to thrive and jaundice depending on time of fructose use. Treatment Diagnosed by the presence of fructose in urine and enzyme assay in liver or intestinal mucosa biopsy. Treatment includes dietary restriction of fructose. Generally has good long term prognosis. 3. Describe the clinical features and genetic defects in common disorders of steroid metabolism Congenital adrenal hyperplasia Pathogenesis Has an incidence of 1: 15 000. It is autosomal recessive and affects boys and girls. 3/4 of those suffering have the simple form. 1/4 of those suffering have the salt-losing form. 90% of patients have deficiency of the enzyme 21-hydroxylase. 11-hydroxylase - less common 3-dehydrogenase - less common 17-hydroxylase - very rare 17,20-lyase - very rare Lack of cortisol and aldosterone, but too much androgen. Signs and Symptoms Newborn female infants presenting virilization of external genitalia – pseudohermaphroditism. Those suffering from the salt-losing form may have circulatory collapse in 2nd week of life (in males and females) Treatment Patients have to be assigned a gender. This may have psychological effects later in life. They are treated with cortisol, and fludrocortisone if salt-losing form. Their steroids are increased for surgery or recurrent illness. In due course, patients will have to receive plastic surgery 4. Describe the clinical features and genetic defects in common sphingolipidoses. Tay-Sachs Disease Pathogenesis Affects 1 in 3600 Ashkenazi-Jews Reduced hexosaminidase A due to deficiency of subunit of -hexosaminidase Signs and symptoms At 6-12 months o poor feeding, lethargy, floppiness o developmental milestones lacking o deafness, visual impairment, spasticity o death by 3 years due to respiratory infection Treatment There is very little in the way of treatment but enzyme replacement therapy and gene therapy appear to be methods being looked into. Gaucher’s disease Pathogenesis, Signs and Symptoms Type I Adult onset. Patients will experience febrile episodes (fever), limb/joint pain, pathologic fractures. Enlarged liver and spleen, mild anaemia. Type II Infantile onset (3-6 months), Babies will experience failure to thrive, hepatosplenomegaly, (enlargement of spleen and liver) developmental regression, neurological deterioration, spasticity, fits and death in the second year. Treatment Diagnosis - reduced glucosylceramide -glucosidase in white blood cells. Treatment for type I - pain relief, removal of spleen as it causes secondary anaemia. Urea Cycle Disorders In the liver waste nitrogen is removed by a 5 step enzymatic pathway. NH4 + HCO-3 + 2ATP UREA Deficiencies of enzymes in the cycle result in protein intolerance, due to increased ammonia. This has serious deleterious effects of the CNS and can lead to death if untreated. CPSI deficiency carbamyl phosphate synthase I OTC deficiency ornithine transcarbamylase ASS - citrullinaemia arginosuccinc acid synthetase ASL - arginosuccinic aciduria arginosuccinic acid lyase ARG - hyperargininaemia arginase deficiency 5. Explain the classification of congenital defects Congenital Abnormality: this is any abnormality that is present in a person from their birth. They are apparent at 1 in 40 of all live births and responsible for 20-25% of all childhood and perinatal death. Genetic factors contribute to about 40% of all congenital abnormalities. Malformation: this is a structural defect in an organ e.g. atrio-septal defect/ cleft lip. It usually occurs in a single organ and shows multifactorial inheritance. (attributed to more than 1 gene). Disruption – this is a secondary abnormal structure of an organ or tissue e.g. amniotic band causing digital amputation. Genetic factors can predispose people to these defects but cannot directly cause them. They are caused by ischaemia, infection, trauma e.t.c. Deformation – this is when an abnormal mechanical force distorts a structure e.g. clubbed foot, hip dislocation. It occurs late in the pregnancy and conveys a good prognosis since organ is normal in structure. Syndrome – this is a consistent pattern of abnormalities for a specific underlying cause e.g. Down’s syndrome. It is caused by chromosome abnormalities. Sequence – this is where a primary factor initiatesmultiple abnormalities e.g. leakage of amniotic fluid leads to Potter sequence. The initial factor could have a genetic component. Dysplasia – this is the abnormal organisation of cells into tissue e.g thanatophoric dysplasia, ectodermal dysplasia. This can be caused by a single gene defect. There is usually a high recurrence risk for siblings and offspring. Association – this is a non-random occurrence of abnormalities not explained by syndrome e.g. VATER association. This usually does not have a genetic cause. Neural Tube Defect Has multifactorial inheritance e.g. spina bifida, anencephaly. Conseqences are very severe. It results from defective closure of the neural tube during 1st embryonic month. There is a recurrence risk of 4-5% to first degree relatives and a high risk in Celtic populations possible due to a susceptibility gene. 6. Explain how non-genetic factors lead to congenital abnormalities Environmental effects can also lead to congenital abnormalities: - tetratogens (such as thalidomide and rubella virus) interfere with the normal embryonic/foetal development. - Vitamin A, alcohol, thalidomide, lithium, tetracyline, warfarin, streptomycin are all teratogenic, during pregnancy in humans. - Rubella damages babies if the mother gets it. It can lead to microcephaly, cataracts and heart defects. - CMV retinitis can also affect babies causing eye defects, deafness and microcephaly. - Toxoplasmosis can cause microcephaly, eye defects, deafness, hydrocephalus.