USMLE (Subject) / Biochemistry - Genetics (Lesson)

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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 Hemangioblastomas (mostly in cerebellum)- headaches- vomiting- weakness- ataxia (loss of muscle coordination)- retinal angiomas can cause vision loss Cysts in the kidney → multiple bilateral renal cell carcinomas Associated with pheochromocytoma- hypertension
• Autosomal dominant disorders Nervous:- Huntington disease- Neurofibromatosis- Myotonic dystrophy Urinary:- Polycystic kidnesy disease Gastrointestinal:- Familial polyposis coli Hematopoetic:- von Willebrand disease Skeletal:- Achrondroplasia- Marfan syndrome- Osteogenesis imperfecta Metabolic:- Familial hypercholesterolemia (LDL receptor deficiency)- Acute intermittent porphyria
• Autosomal recessive disorders Metabolic:- Cystic fibrosis- Phenylketonuria- Galactosemia- Homocystinuria- Lysosomal storage diseases- α1-antotrypsin deficiency- Wilson disease- Hemochromatosis- Glycogen storage diseases Hematopoietic- Sickle cell anemia- Thalassemias Skeletal:- Alkaptonuria
• 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- Fragile X syndrome Immune- Bruton Agammaglobulinemia- Wiskott Aldrich syndrome Genitourinary- Testicular feminization (androgen insensitivity syndrome)
• 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 disability, self-mutilation, aggression, hyperuricemia, gout, dystoniaH: HyperuricemiaG: GoutP: Pissed off (agression, self-mutilation)R: RetardationT: DysTonia - orange crystals in diapers (sodium urate) Treatment: allopurinol or febuxostat
• 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 of SCID (severe combined immunodeficiency), because T-cells are unable to develop
• 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 veins- hearing loss- dental imperfections due to lack of dentin
• 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 instability): most common- Classical type (joint and skin symptoms): mutation in type V collagen- Vascular type (vascular and organ rupture): deficient type III collagen
• 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)- mitral valve prolapse- dilation of the ascending aorta with cystic medial degeneration- hypermobile joints- pectus excavatum (inwardly depressed sternum), pectus carinatum
• 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)- Multiple endocrine abnormalities (eg, precocious puberty) - Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.
• 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 maternally imprinted genes are received)- Paternal microdeletion - Affects males and females Clinical features:- Mental retardation- Short stature- Neonatal hypotonia- Hyperphagia/obesity- Hypogonadism- Small hands and feet- Dysmorphic facies
• 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- Maternal microdeletion - Affects males and females Clinical features:- Poor motor and language development- Inappropriate laughter/smiling ("happy puppet")- Epilepsy/seizures- Ataxic gait/tremors- Intellectual disability
• 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 mental deficiency (after Down syndrome). Males: 100% penetrance, females 60% penetrance - Post-pubertal macro-orchidism- Autism- Large everted ears- Long face with a large jaw- Mitral valve prolapse- Hyperlaxity of the joints in the hand CCG: Chin (protruding), Giant Gonads
• 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 atrophy-  ↑ dopamine, ↓ GABA, ↓ Ach - progressive dementia- loss of motor control (chorea)- mood disturbance - common causes of death: aspiration pneumonia, head trauma
• 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 disease- polycystic kidney disease- umbilical hernia - Incidence 1:15,000 - ↓ β-hCG, ↓ PAPP-A in 1st trimester- Normal values in 2nd trimester
• 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 of the aorta- infertility- gonadal dysgenesis- pigmentent nevi (brown spots)- peripheral lymphedema (swollen feet)
• 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 occur --> retained errors in many other loci, microsatellite instability - manifested in intestinal cells because they are constantly undergoing cell division
• 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 of bone marrow produces bone deformities of the face and other areas - long bones of the arms and legs fracture easily - treatment: blood transfusions
• 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) --> enzymes are secreted into the extracellular space - build-up of substances making I-cells ("inclusion" cells) - high levels of lysosomal enzymes in blood
• 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 oxidase requires copper and plays a direct role in the cross-linking of collagen fibrils- Dopamine- β-hydroxylase requires copper --> ↑ dopamine, ↓ noradrenalin levels Presentation:- kinky hair- growth failure- elongation and tortuosity of major arteries- hypopigmented irises
• 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 (one negative charge less from glutamate)
• Galactosemia - autosomal recessive - defective galactokinase or galactose 1-P uridyltransferase - characteristic: cataracts (aldose reductase present in the lens converts galactose to galactitol --> osmotic damage) - vomiting and diarrhea after milk ingestion
• 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 gluconeogenesis Symptoms:- hypoglycemia- jaundice- vomiting, diarrhea
• 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, hemoglobin may precipitate (Heinz bodies) - NADPH required by glutathione reductase is supplied by the HMP shunt - increased resistance to malaria
• 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 tendon, elbows- xanthelasmas- corneal arcus
• 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- abdominal pain after fatty meal
• 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 biopsy shows elevated muscle triglyceride detected as lipid droplets in cytoplasm
• Tay-Sachs Disease - autosomal recessive - sphingolipidose (deficient hexosaminidase A, accumulation of ganglioside) - progressive neurodegerneration- cherry red spots in macula- blindness- psychomotor retardation- lysosomes with onion skin- no hepatosplenomegaly (vs Niemann-Pick) - death < 2 years
• Gaucher's disease - autosomal recessive - most common sphingolipidose (deficient glucocerebrosidase) - high rate among Ashkenazic Jews - hepatosplenomegaly- bone erosion, fractures- pancytopenia - Gaucher cells with tissue paper cytoplasm- no brain involvement - compatible with long life
• Niemann-Pick disease - autosomal recessive - sphingolipidose (deficient sphinomyelinase) - hepatosplenomegaly- cherry-red spots in one third- microcephaly, severe mental retardation- foamy macrophages with zebra bodies - early death
• 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- reddish-purple blemishes on the skin (angiokeratomas)- cloudiness of the cornea- impaired arterial circulation- enlargement of heart, kidneys - presents during childhood or adolescence
• 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: uridine administrations--> uridine is salvaged to UMP, which feedback-inhibits orotic acid formation 2. Hyperammonemia, no megablastic anemia = defect OTC (ornithine transcarbamylase)
• 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: diet restricted in phenylalanine- should avoid aspartame (artificial sweetener), which contains phenylalanine
• 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 and sclerae)- arthritis (homogentisic acid toxic to cartilage)
• 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 develops a characteristic odor of maple syrup - ketosis, coma and death ensue if not treated
• Homocystinemia - deficiency of cystathionine synthase - associated with atherosclerosis in childhood- cardiovascular disease (DVT, stroke)- dislocation of the lens (ectopic)- mental retardation - children often have myocardial infarction before 20 years of age - can present similarly to Marfan syndrome Treatment: diet low in methionine
• 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 - dark port-wine color to urine
• 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 - exacerbated by alcohol - red-brown to deep-red urine when left to stand
• 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, causing a predisposition to infection- defective nonhomologous end joining, increasing the risk of cancer
• Fanconi anemia - autosomal recessive - defect nonhomologous end joining--> development of AML, bone marrow failure

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