Download Genetics of Childhood Diseases

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.