USMLE (Fach) / Biochemistry - Genetics (Lektion)

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  • Ornithine transcarbamylase deficiency - most common urea cycle disorder - X-linked recessive (vs other urea cycle enzyme deficiencies!) - often present in the first few days of life - ↑ orotic acid in blood and urine- ↓ BUN (blood urea ...
  • Cystinuria - autosomal recessive - defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystein, Ornithine, Lysine, and Arginine (COLA) - excess cystein in the urine can lead to ...
  • Neurofibromatosis - autosomal dominant Neurofibromatosis type 1 = Recklinghausen disease- Mutation of the tumor suppressor gene NF1 located on chromosome 17- café-au-lait spots- peripheral neurofibromas- Lisch nodules ...
  • Hurler Syndrome - most severe mucopolysaccharidosis  - deficient iduronidase --> accumulation of heparan and dermatan slfate - coarse facies- enlarged skull- corneal clouding- hepatosplenomegaly- thickened skin- hernias- ...
  • Hunter Syndrome - Mucopolysaccharidosis II - X-linked - progressive - symptoms between ages 2 and 4 years - abdominal hernias- atypical retinitis pigmentosa
  • Duchenne muscular dystrophy - X-linked disorder typically due to frameshift or nonsense mutations → truncated or absent dystrophin protein → progressive myofiber damage. - Weakness begins in pelvic girdle muscle and progresses ...
  • Achondroplasia - autosomal dominat- gain-of-function in fibroblast growth receptor 3 (FGR3) - short limb dwarfism (most common form) - proliferation of cartilage is greatly retarded in the metaphyses of long bones
  • Hardy-Weinberg population genetics If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of seperate alleles, then p2 + 2pq + q2 = 1 and p + q = 1, which implies that: p2 = frequency of homozygosity for allele ...
  • Cystic fibrosis Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.Most common lethal genetic disease in Caucasian population. - CFTR encodes an ATP-gated Cl- channel that secretes ...
  • Edwards syndrome (trisomy 18) - severe intellectual disability- rocker-bottom feet- micrognathia (small jaw)- low-set ears- clenched hands with overlapping fingers- prominent occiput- congenital heart disease - 2nd most common autosomal ...
  • Down syndrome (trisomy 21) - intellectual disability- flat facies- prominent epicanthal folds- single palmar crease- gap between 1st 2 toes- duodenal atresia- Hirschsprung disease- congenital heart disease (eg, atrioventricular ...
  • Cri-du-chat syndrome Congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-). - Microcephaly- Moderate to severe intellectual disability- High-pitched crying/meowing- Epicanthal folds- Cardiac abnormalities ...
  • Williams syndrome Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene). Findings:- Distinctive "elfin" facies- Intellectual disability- Hypercalcemia (↑ sensitivity to vitamin D)- ...
  • Familial adenomatous polyposis - Autosomal dominant disease - Colon becomes covered with adenomatous polyps after puberty - Progresses to colon cancer unless colon is resected - mutation on APC gene
  • Hereditary hemorrhagic telangiectasia Autosomal dominant disorder; also known as Osler-Weber-Rendu syndrome - inherited disorder of blood vessels - branching skin lesions (telangiectasias)- recurrent epistaxis- skin discolorations- arteriovenous ...
  • Hereditary spherocytosis Autosomal dominant disorder - Spheroid erythrocytes due to spectrin or ankyrin defect - hemolytic anemia-  ↑ MCHC-  ↑ RDW Treatment: splenectomy
  • Li-Fraumeni syndrome Abnormalities in TP53 --> multiple malignancies at an early age - Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland)
  • Multiple endocrine neoplasias (MEN) Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, thyroid, and adrenal medulla. MEN 1 is associated with MEN1 gene.--> ...
  • Tuberous sclerosis Autosomal dominant disorder Neurocutaneous disorder with multi-organ system involvement - characterized by numerous benign hamartomas- adenoma sebaceum- white spots- Koenen-tumor (under nails)
  • Genetic disorder by chromosome: 3 - von Hippel-Lindau - Renal cell carcinoma
  • Genetic disorder by chromosome: 4 - ADPKD (PKD2) - Achondroplasia - Huntington disease
  • Genetic disorder by chromosome: 5 - Cri-du-chat syndrome - Familial adenomatous polyposis
  • Genetic disorder by chromosome: 6 - Hemochromatosis (HFE gene)
  • Genetic disorder by chromosome: 7 - Williams disease - Cystic fibrosis
  • Genetic disorder by chromosome: 9 - Friedreich ataxia - Tuberous sclerosis (TSC1)
  • Genetic disorder by chromosome: 11 - Wilms tumor - β-globulin gene defects (e.g. sickle cell anemia, β-thalassemia) - MEN1
  • Genetic disorder by chromosome: 13 - Patau syndrome - Wilson disease - Retinoblastoma (RB1) - BRCA2
  • Genetic disorder by chromosome: 15 - Praderman-Willi syndrome - Angelman syndrome - Marfan syndrome
  • Genetic disorder by chromosome: 16 - ADPKD (PKD1) - α-thalassemia
  • Genetic disorder by chromosome: 17 - Neurofibromatosis type 1 - BRCA1 - p53
  • Genetic disorder by chromosome: 22 - Neurofibromatosis type 2 - DiGeorge syndrome (22q11)
  • Becker muscular dystrophy X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). - Less severe than Duchenne. - Onset in adolescence or early adulthood. - Deletions ...
  • Myotonic dystrophy type 1 - Autosomal dominant - CTG trinucleotide repeat expansion in the DMPK gene → abnormal expression of myotonin protein kinase → myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, ...
  • Rett syndrome - Sporadic disorder seen almost exclusively in girls (affected males die in utero or shortly after birth). - Most cases are caused by de novo mutation of MECP2 on X chromosome. Symptoms usually appear ...
  • Trinucleotide repeat expansion diseases Huntington disease: (CAG)n- Caudate has ↓ ACh and GABA Myotonic dystrophy: (CTG)n- Cataracts, Toupee, Gonadal atrophy Fragile X syndrome: (CGG)n- Chin (protruding), Giant Gonads Friedreich ataxia: ...
  • 22q11 deletion syndromes Microdeletion at chromosome 22q11 → variable presentations including cleft palate, abnormal facies, thymic aplasia → T-cell deficiency, cardiac defects, and hypocalcemia 2˚ to parathyroid aplasia. ...
  • Variable expressivity Patients with the same genotype have varying phenotypes. Example: 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity.
  • Incomplete penetrance Not all individuals with a mutant genotype show the mutant phenotype. % penetrance x probability of inheriting genotype = risk of expressing phenotype. Example: BRCA1 gene mutations do not always result ...
  • Codominance Both alleles contribute to the phenotype of the heterozygote. Example: Blood groups A, B, AB; α1-antitrypsin deficiency; HLA groups.
  • Pleiotropy One gene contributes to multiple phenotypic effects. Example: Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor.
  • Loss of heterozygosity If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. Example: Retinoblastoma and the "two-hit hypothesis," ...
  • Dominant negative mutation Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning. Example: Mutation of a transcription factor in its allosteric ...
  • Mosaicism Presence of genetically distinct cell lines in the same individual.  Somatic mosaicism – mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs. Gonadal ...
  • Locus heterogeneity Mutations at different loci can produce a similar phenotype. Example: Albinism
  • Allelic heterogeneity Different mutations in the same locus can produce the same phenotype. Example: β-thalassemia
  • Heteroplasmy Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease. Example: mtDNA passed from mother to all children.
  • Linkage disequilibrium Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.
  • Uniparental disomy Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heterodisomy (heterogenous) indicates a meiosis I error.Isodisomy (homozygous) indicates a meiosis II error ...
  • Mitochondrial diseases Mitochrondrial DNA codes for mitochondrial oxidative phosphorylation enzxmes.- Inheritance is only from mother to child Leber hereditary optic neuropathy- Loss of retinal cells, which leads to central ...
  • Robertsonian translocation Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.One of the most common types of translocation. Occurs when the long arms of 2 acrocentric chromosomes (chromosomes ...