Genetic Disorders

Genetic Disorders Autosomal Syndromes Non-Dysjunction Down Syndrome Trisomy 21 Most common chromosomal disorder. Most common cause of inherited mental retardation. Findings:  sever mental retardation  Mongoloid facial features  Brushfield spots (speckled irises)  Simial Palmar crease  Congenital heart defects  Duodenal atresia (double-bubbel sign) Edward Syndrome Trisomy 18 Findings:  Mental retardation  Lowset ears and micrognathia  Congenital heart defects  Rocker-bottom feet Patau syndrome Trisomy 13  Mental retardation  Cleft lip and/or palate  Cardiac defects  renal abnormality  Microcephaly  polydactyly Deletion Cri du Chat syndrome Deletion of short arm of 5.  High pitched cat-like cry  Mental retardation Microdeletions 13q14 – retinoblastoma gene 11p13 – Wilm tumor gene. Autosomal Recesive disorders. Cystic fibrosis Most common lethal genetic disorder in Caucasians. Defect in CFTR gene on chromosome 7 Distrobution:  Lungs: Recurrent pulmonary infection with P. Ariginosum and S. Aureus.  Pancreas  Male reproductive system  Liver  GI tract Most common cause of death in pulmonary infections. Diagnosed with sweat test. Phenylketonuria (PKU) Defect in phenylalanine hydroxylase resulting in toxic levels of phenylalanine.  Normal at birth, profound mental retardation by 6 months.  Lack tyrosine so have light colored skin and hair.  mousy Odor to sweat and urine. Alkaptonureia deficiency in homogentisic acid oxigenase. ↑homogentisic acid.  Black urine and cartilage.  discolorization of nose and ears Glycogen storage Diseases: 1. Type I (Von Gierke disease)  defect in glucose 6 phosphae.  hepatomegaly and hyopglycimea. 2. Type I (McArdle syndrome)  deficiency in muscle phosphorylase  exercise induced muscle cramps. Tay-Sachs deficiency in hexosaminidase A Accumulation of GM2 Gangliosides in the lysosomes of the CNS and retina. Common in Ashenazi Jews  Crerry red spot in retina  Dilated CNS neurons with cytoplasmic vacules.  onset at 6 months, death by 2-3 years. diagnosis by enzyme assays and DNA probes. Neimann Pick disease Deficiency in sphingomylin within lysosomes of CNS and reticuloendothelial system Common in Ashenazi Jews  Crerry red spot in retina  Distended CNS neurons with FOAMY cytoplasmic vaculization  Hepatosplenomegaly  bone marrow involvement. onset at 6 months, death by age 2. On EM Lysosomes contain “zebra bodies” Gaucher disease Most common lysosomal storage disease. Leads to the accumulation of glucocerebrocides in the lysosomes of the reticuloendothelial system, due to a deficiency in Glucocerebrosidase.  Type 1 99% present in adult hood  hepatosplenomegaly  Hypersplenism  Bone marrow involvement leading to bone pain, deformities, and fractures.  CNS manifistations occur in Type II & III Gaucher cells are present – enlarged macrophages with tissue-papper-like cytoplasm. Mucopolysacroidosis. Group of lysosomal storage diseases that have a deficiency in lysosomal enzymes needed to degrade mucopolysacarides.  mental retardation  Cloudy cornea  skeletal deformities and coarse facial features.  joint abnormalities  Cardiac leasions. 1. Hurler syndrome (MPS I) a. Deficiency in α-1-iduronidase b. This is the SEVERE form 2. Hunter syndrome (MPSII) a. X-linked recessive b. Deficiency in L-iduronosulfate sulfatase. c. Milder form Autosomal Dominate Disorders. Familial hypercholesterolemia This is the most common inherited disorder. Defect in LDL receptor gene on chromosome 19  loss of feedback by HMG coenzyme A reductase.  ↑↑↑ Cholesterol and phagositosis of LDL by macrophages.  Skin Xanthomas (collections of lipid laden macrophages)  Premature Aterosclerosis. Marfan syndrome Mutation in the fibrillin gene on chromosome 15q21.  Tall thin build with hyperextendable joints.  bilateral subluxation of the lenses  Aortic dissection is a mojor cause of death. Ehlers-Danlos Syndrome (EDS) Defect in collagen structure and synthesis.  Hyperextendable skin  hyperextensible joints. Has different modes of inheritance depending on type: EDS Type 3 – Dom. Most common type. Unknown defect. EDS Type 4 – Dom. Defect in type III collagen. EDS Type 6 – Recessive. Defect in Lysyl Hydroxilase EDS Type 9 – X-linked Recessive. Defect in copper metabolism Complications include: poor wound healing joint dislocations diaphragmatic hernias(type I) retinal detachment & Kyphosis (type 6) Arterial or colonic ruptures (type 9) Neurofibromatosis 1. Type I (von Ricleinghausen Disease) a. Accounts for 90% i. Tummor repressor gene NF-1, 17q11.2, ii. The normal proguct inhibits p21 ras oncoprotein b. Multiple benign peripheral nerve tumors c. Café-au-lait-spots d. pigmented iris haratomas e. increased risk of menigiomas and phrochromocytoma. 2. Type II (bilateral acoustic neurofibromas) a. NF-2 chromosome 22. Normal product has unknown function. b. Bilateral acoustic neuromas c. Café-au-lait-spots d. increased risk of menigiomas and phrochromocytoma. Von Hippel-Lindau disease  Chromosome 3p  Retinal hemangioblastoma  Cysts in liver pancreas and kidneys  multiple bilateral renal carcinomas Sex Linked Syndromes Klinefelter syndrome XXY Common cause of male Hypogonadism. Elevated FSH and LH  testicular atrophy  Female distribution of hair  Gynecomastia. Turner syndrome XO Common cause of female hypogonadism.  No Barr body present.  Streaked ovaries  Congenital heart disease (bicuspid aortic valve and coarctation of the aorta common)  Hydrops fetalis Hermaphoditism True hermaphrodite. Either testis and ovary on opposite sides, or has Ovatesties. Ambiguous genitalia. Female Pseudohermaphotite. 46 XX phenotypic sex is ambiguous or virilized. Exposure to androgens in utero  Congenital hyperplasia  androgen producing tumors  exogenous androgens. Male Pseudohermaphodite 46 XY Ambiguous or female genetailia. Most common cause is androgen receptor mutation (Xq11-12) Triplet Repeat Mutations Fragile X Syndrome. CGG repeated hundreds to thousands of times in the FMR-1 gene (familial mental retardation 1 gene)  Mental retardation  Large everted ears  elongated face and jaw. Huntington’s disease CAG repeats in the Huntington Gene produce a toxic Huntington protein.  Progressive dementia due to atrophy of the caudate nucleus. Genomic Imprinting Differential expression of genes based on chromosomal inheritance from maternal vs paternal origin. Prader-Willi Syndrome Deletion of paternal chromosome 15  Mental retardation  Obesity  Hypogonadism  Hypotonia Angelman syndrome Deletion of Maternal Chromosome 15  Mental retardation  Seizures  Ataxia  Inappropriate laughter.