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Examples of Chromosomal or Mendelian Disorders

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Presentation on theme: "Examples of Chromosomal or Mendelian Disorders"— Presentation transcript:

1 Examples of Chromosomal or Mendelian Disorders
Trisomies 16 most common in spontaneous lost pregnancies, does not survive to birth 21,18,13 Sex Chromosomes Turner Vs Noonan Klinefelter Dominant Structural Protein Disorders X-linked disorder

2 Clinical features of DS 1
Physical Characteristic flat facies, oblique palpebral fissures, epicanthal folds, Dysplastic ear, narrow palate, abnormal teeth, protruding tongue Cardiac malformations (40%) Gastrointestinal obstruction, duodenal atresia, Hirschsprung disease Premature aging, Alzheimer-like symptoms in 40s Hypotonia, palmar/digital anomalies Male sterility

3 Clinical features of DS 2
Mental retardation IQ 75 if mother has >16 years of schooling IQ 30 if both parents have <12 years of schooling Some selective deficits in rule-based systems such as numbers and grammar May be able to function with minimal assistance

4 Clinical features of DS 3
Hearing 40% Thyroid dysfunction x general population Increased risk of Diabetes mellitus Leukemoid response or congenital leukemia Increased risk of ALL, AML and ANLL x general population Immunodeficiency

5 Trisomy 21 Facts Heart defects may not be apparent at birth
sensitivity of PE: 61-74% ECG improves sensitivity by 15% Echo is needed 19/52 have normal PE and significant intracardiac defect at birth Survival in DS without heart disease is 99% at one year


7 Trisomy 21 About 70% of conceptions are lost
20% between 16 weeks and term 20% between 10 and 16 weeks Maternal non-disjunction in 86% 75% are meiosis I errors Paternal origin 9% almost equal MI and MII Somatic mutations 5%

8 Clinical Features Trisomy 18
Prenatal onset Growth Retardation Single umbilical artery Prominent occiput, lowset, malformed auricles, short palpebral fissures,small mouth Clenched hand, overlap of 2nd on 3rd and 5th on 4th finger Cardiac (VSD, ASD, ductus), Renal, GU (cryptorchidism, hypoplastic labia), Skeletal, Abdominal anomalies Early demise: 60% first 2 months, 90% by one year.

9 Clinical features Trisomy 13
Holoprosencephaly, defects of optic and olfactory nerves Microcephaly with sloping forehead Defects of eyes Cleft lip and/or palate Scalp defect: aplasia cutis at vertex Cardiac defects (80%) VSD, PDS,ASD Polydactyly, prominent heel, flexion deformities, abnormal creases 5% survive the first 6 months, median survival 2.5 days

10 Common Trisomies

11 Clinical Features of Turner Syndrome 1
Congenital lymphedema Puffy feet and hands Leads to the ‘webbed neck’ Low posterior hair line Absence of secondary sex characteristics Scanty axillary or pubic hair Lack of breast development Amenorrhea Streak gonads/rudimentary ovaries Infertility Mosaicism

12 Clinical Features of Turner Syndrome 2
Short stature Coarctation of the aorta Renal anomalies (40%) Normal intelligence Short metacarpal IV Multiple pigmented nevi Facial features: downturned mouth, narrow palate, small mandible 99% fetal losses of X fetuses 2-4% all concepti but 1/5000 live births

13 Noonan syndrome Short Stature 50%
Turner-like features: sternum, neck, cubitus valgus Hypertelorism, ptosis, down-slanting palpebral fissures Pulmonary stenosis, cardiomyopathy Normal chromosomes Either sex; AD, mutations in PTPN11, a gene encoding the non-receptor protein tyrosine phosphatase SHP2 in 50% , 12q24.1 Variable fertility (cryptorchidism) Bleeding diathesis in 1/3 Mental retardation 25%

14 XXY: Klinefelter Syndrome
May have mental retardation Growth Tendency for long limbs Height mean 75th centile Hypogonadism Childhood Adolescence/adult Small testicular volume Inadequate testosterone production Infertility Fibrosis/hyalinization of seminiferous tubules Gynecomastia in 25-50% Normal sexual functioning




18 Dominant disorders of Structural Proteins
Marfan ocular, skeletal, cardiac disease chromosome 15q21.1 defect in fibrillin-1 effect on elastic fibers as disruption of microfibrillar component elastin unaffected Osteogenesis imperfecta collagen defect skeletal system; sclera AD and AR forms; type II lethal as neonate

19 Dominant disorders of Structural Proteins 2
Ehlers-Danlos defect in collagen synthesis or assembly synthesized as precursor; hydroxylated; glycosylated; assembled; secreted; cleaved; aggregation; cross-linked Hyperextensibility of joints and of skin, altered wound healing and scar formation Premature rupture of membranes/premature birth Skin, cardiac, vascular, joint, ocular, hollow viscera multiple types

20 Defects in Receptor Proteins
Familial Hypercholesterolemia Autosomal dominant heterozygotes manifest disease signs milder and later than homozygotes LDL receptor defects type 1 no receptors; type 2 dysfunctional binding at receptors; type 3 internalization defect decreased transport of LDL cholesterol into cells; upregulation of hepatic cholesterol synthesis early onset atherosclerosis hypercholesterolemia 12-25mMol mg/dl xanthomas, corneal arcus early death Gene Therapy

21 Single Gene, Multiple Mutations
Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Acts as chloride channel Reduced chloride transport (and water) increased sweat electrolytes viscous secretions Chronic lung disease, pancreatic insufficiency, hepatic disease Autosomal recessive gene at 7q31 Many mutations; D F508 is the most common

22 Lesch-Nyhan syndrome Spasticity after 4-6 months of age
Choreoathetosis Self-mutilation despite pain sensation intact Mental retardation usually mild Articulation defects / autistic features Growth deficiency Uric acid stones which leads to renal failure Hypoxanthine-Guanine PhosphoRibosylTransferase deficiency mutations range from point to deletions

23 One Gene Many Diseases Chromosome 17, PMP22 gene; peripheral myelin protein Duplication of PMP Mb (3 copies) gives AD Charcot-Marie-Tooth disease Type 1 Deletion (1 copy) is Hereditary Neuropathy with Liability to Pressure Palsies Point mutations are Dejerine-Sottas syndrome characterized by distal muscle weakness, sensory alterations, muscle atrophy and enlarged spinal nerve roots

24 ‘Common’ Single Gene Defects
Cystic Fibrosis Sickle Cell Disease Thalassemias Hemophilias Huntington Chorea Gain of function Post-axial Polydactyly Retinoblastoma Alpha-1 Antitrypsin Disease Familial Isolated Growth Hormone Deficiency Dominant negative Thyroid Binding Globulin deficiency X-linked Neurofibromatosis type 1 50% new mutations

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