USMLE (Fach) / Biochemistry - Genetics (Lektion)

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• Von Hippel-Lindau disease Autosomal dominant utation in VHL (tumor suppressor gene) on chromosome 3. The normal gene product's main action is to tag proteins (eg, hypoxia inducible factor 1a) with ubiquitin for degradation. CNS ...
• Autosomal dominant disorders Nervous:- Huntington disease- Neurofibromatosis- Myotonic dystrophy Urinary:- Polycystic kidnesy disease Gastrointestinal:- Familial polyposis coli Hematopoetic:- von Willebrand disease Skeletal:- Achrondroplasia- ...
• Autosomal recessive disorders Metabolic:- Cystic fibrosis- Phenylketonuria- Galactosemia- Homocystinuria- Lysosomal storage diseases- α1-antotrypsin deficiency- Wilson disease- Hemochromatosis- Glycogen storage diseases Hematopoietic- ...
• X-linked dominant disorders - Vitamin D-resistant rickets - Alport syndrome - Rett syndrome Transmitted through both parents. Mother transmit to 50% of daughters and sons; fathers transmit to all daughters but no sons
• X-linked recessive disorders Musculoskeletal- Duchenne muscular dystrophy Blood- Hemophilia A and B- Glucose-6-phosphate dehydrogenase deficiency Metabolic- Lesch-Nyhan syndrome- Fabry disease, Hunter disease- Menkes disease Nervous- ...
• Triplet repeats - Fragile X syndrome - Myotonic dystrophy - Spinocerebellar ataxia - Friedrich ataxia - Synpolydactyly
• Lesch-Nyhan syndrome - Defective purine salvage due to absent HGPRT, which concerts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis - X-linked recessive - intellectual ...
• Adenosine deaminase deficiency - autosomal recessive - excess ATP accumulate in red cells and inhibit ribonucleotide reductase --> decreased production of other precursors for DNA synthesis --> ↓ lymphocyte count - major cause ...
• Osteogenesis imperfecta - brittle bone disease - autosomal dominant - ↓ production of type 1 collagen Manifestations:- multiple fractures with minimal trauma- blue sclerae due to translucency of tissue over the choroidal ...
• Ehlers-Danlos syndrome - faulty collagen synthesis causing hyperextensible skin, tendency to bleed, hypermobile joints - associated with joint dislocation, berry and aortic aneurysms, organ rupture - Hypermobility type (joint ...
• Marfan syndrome Autosomal dominant disorder due to defect in fibrillin (network for elastin) on chromosome 15 - tall, thin build with long extremities- arachnodactyly- ectopia lentis (typically upward and temporally)- ...
• McCune-Albright syndrome Mosaic disease arising from somatic mutations affecting G-protein signaling. Presentation:- Unilateral café-au-lait spots- Polyostotic fibrous dysplasia (bone is replaced by collagen and fibroblasts)- ...
• Prader-Willi syndrome Loss of paternally inherited allele from chromosome 15. Gene from mom is normally silent (maternal imprinting) and paternal gene is deleted/mutated. Etiology:- 25% maternal uniparental disomy (two ...
• Angelman-Syndrome Loss of maternally inherited allele from chromosome 15.Gene from dad is normally silent (paternal imprinting) and maternal gene is deleted/mutated. Etiology:- 5% of cases due to paternal uniparental disomy- ...
• Familial hypercholesterolemia (Type IIa) - autosomal dominant - elevated LDL due to defective/absent LDL receptor - severe atherosclerotic disease early in life - corneal arcus (white ring around cornea) - tendon xanthomas
• Hartnup disease - autosomal recessive - malabsorption of amino acids (especially tryptophan) --> Pellagra (dermatitis, diarrhea, dementia)
• Fragile X syndrome - X-linked dominant- Trinucleotide repeat CGG in FMR1 gene → hypermethylation → ↓ expression.- Most common cause of inherited intellectual disability and 2nd most common cause of genetically associated ...
• Diseases with delayed age of onset - Huntington disease (autosomal dominant) - Hemochromatosis (autosomal recessive) - Acute intermittant porphyria (autosomal dominant)
• Huntington Disease - autosomal dominant, delayed age of onset - gain-of-function mutation - trinucleotide repeat expansion disorder (--> anticipation)- produces a buildup of toxic protein aggregates in neurons- caudate ...
• Anticipation diseases - Huntington disease (autosomal dominant) - Fragile X syndrom (X-linked dominant) - Myotonic dystrophy (autosomal dominant) - Friedrich ataxia (autosomal recessive)
• Patau Syndrome (trisomy 13) - severe intellectual disability- rocker-bottom feet- holoprosencephaly- polydactyly (extra fingers and toes)- cleft lip/palate- cutis aplasia- microphthalmia (small eyes)- microcephaly- congenital heart ...
• Klinefelter Syndrome - 47, XXY - testicular atrophy - infertility - gynecomastia, female distribution of hair - low testosterone - elevated FSH/LH - high-pitched voice
• Turner Syndrome - 45, XO, often mosaics - short stature- low posterior hairline- broad chest and widely set nipples- cubitus valgus (elbows turned in)- "webbed" neck- cystic hygroma- primary amenorrhea- coarctation ...
• Translocations involving oncogenes - t(9;22) chonic myelogenous leukemia (c-abl) - t(15;17) acute myelogenic leukemia (retinoid receptor-a) - t(14;18) follicular lymphomas (bcl-2) - t(8;14) Burkitt lymphoma (c-myc)
• Xeroderma pigmentosum - autosomal recessive - deficiency in the excinuclease enzyme (--> needed for reparation of thymidine dimers) - extreme UV sensitivity - skin freckling - multiple skin cancers - corneal ulcerations
• Hereditary nonpolyposis colorectal cancer (Lynch syndrome) ... - HNPCC results from a mutation in MLH1 or MSH2 (enzymes that carry out DNA mismatch repair) - individual may inherit one deleted copy of MLH1/MSH2. After birth, somatic mutation in the other copy may ...
• β-Thalassemia - deficiency of β-globin protein - found primarily in Mediterranean areas (protects against malaria) - splenomegaly due to the role of the spleen in clearing damaged red blood cells - excessive activity ...
• I-cell disease - autosomal recessive - lysosomal storage disease- defective GlcNAc phosphotransferase (normally phosphorylates mannose residues to mannose-6-phosphate on N-linked glycoproteins targeted to lysosomes) ...
• Menkes disease - X-linked recessive - mutation in the gene ATP7A, which encodes an ATP-dependent copper efflux protein in the intestine--> copper cannot be transported into the bloodstream, ↓ serum copper - Lysyl ...
• Sickle cell anemia - substitution of valine for glutamate in Hb - severe pain in the bones, abdomen, chest - hemolytic problems - episodes of vaso-occlusive pain lasting approx. 1 week - can be resolved in electrophoresis ...
• Galactosemia - autosomal recessive - defective galactokinase or galactose 1-P uridyltransferase - characteristic: cataracts (aldose reductase present in the lens converts galactose to galactitol --> osmotic damage) ...
• Hereditary Fructose Intolerance - autosomal recessive - defect in aldolase B (fructose 1-P dehydrogenase) - accumulation of fructose 1-phosphate causes a ↓ in available phosphate, which results in inhibition of glycogenolysis and ...
• Glucose 6-Phosphate Dehydrogenase Deficiency - X-linked recessive - hemolytic anemia - red blood cells contain a large amount of oxygen and are prone to spontaneously generate ROS that damage protein and lipid in the cell. - In the presence of ROS, ...
• Familial hypercholesterolemia - autosomal dominant - LDL-receptor deficiency - elevated cholesterol in blood - high risk of atherosclerosis and coronary artery disease - if homozygous, death < 20 years - xanthomas of the Achilles ...
• Hyperlipidemia (type I) - autosomal recessive - familial lipoprotein lipase/apoC-II deficiency - elevated triglycerides in blood - elevated chylomicrons in blood - red-orange eruptive xanthomas- fatty liver- acute pancreatitis- ...
• Carnitine Acyltransferase-2 Deficiency - autosomal recessive - late onset - muscle aches, weakness - rhabdomyolysis, myoglobinuria (red urine) - episode provoked by prolonged exercise  - symptoms may be exacerbated by high-fat diet - muscle ...
• Tay-Sachs Disease - autosomal recessive - sphingolipidose (deficient hexosaminidase A, accumulation of ganglioside) - progressive neurodegerneration- cherry red spots in macula- blindness- psychomotor retardation- lysosomes ...
• Gaucher's disease - autosomal recessive - most common sphingolipidose (deficient glucocerebrosidase) - high rate among Ashkenazic Jews - hepatosplenomegaly- bone erosion, fractures- pancytopenia - Gaucher cells with ...
• Niemann-Pick disease - autosomal recessive - sphingolipidose (deficient sphinomyelinase) - hepatosplenomegaly- cherry-red spots in one third- microcephaly, severe mental retardation- foamy macrophages with zebra bodies - ...
• Fabry Disease - X-linked recessive (in contrast to the other sphingolipidoses [Tay-Sachs, Gaucher, Niemann-Pick]) - deficient α-galactosidase with accumulation of ceramide trihexoside - burning sensations in the hands- ...
• Orotic Aciduria - autosomal recessive 1. Megaloblastic anemia, no hyperammonemia = defect UMP synthase- lack of pyrimidines impaires nucleic acid synthesis needed for hematopoiesis --> megaloblastic anemia- Therapy: ...
• Phenylketonuria - Phenylalanine hydroxylase deficiency - infants are normal at birth If untreated:- slow development- severe mental retardation- seizures- musty body odor- pale skin and white-blonde hair - Treatment: ...
• Albinism - deficiency of tyrosinase (cannot be converted to melanin) --> absence of pigment in the skin, hair, and eyes
• Alkaptonuria - autosomal recessive - Homogentisate oxidase deficiency (in the degradative pathway of tyrosine to fumarate) - urine turns black on prolonged exposure to air- ochronosis (black-bluish connective tissue ...
• Maple Syrup Urine Disease Branched-Chain Ketoacid Dehydrogenase Deficiency - unable to matabolize valine, leucine and isoleucine - infants become lethargic, lose weight- alternating episodes of hypertonia and hypotonia- urine ...
• Homocystinemia - deficiency of cystathionine synthase - associated with atherosclerosis in childhood- cardiovascular disease (DVT, stroke)- dislocation of the lens (ectopic)- mental retardation - children often have ...
• Acute intermittent porphyria - autosomal dominant - Porphobilinogen Deaminase Deficiency - late onset - abdominal pain - anxiety, paranoia, depression - excretion of ALA (δ-aminolevulinic acid) and PBG (porphobilinogen) during episodes ...
• Porphyria cutanea tarda Uroporphyrinogen decarboxylase deficiency - autosomal dominant, late onset  - most common porphyria - photosensitivity - inflammation, blistering, shearing of skin in areas exposed to sunlight - hyperpigmentation ...
• Ataxia telangiectasia - autosomal recessive - ataxia and small dilated blood vessels - impairs certain areas of the brain including the cerebellum, causing difficulty with movement and coordination- weakens the immune system, ...
• Fanconi anemia - autosomal recessive - defect nonhomologous end joining--> development of AML, bone marrow failure

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