Usmle Biochem Genetics

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An autosomal dominant disease in which there is a cell-signaling defect of fibroblast growth factor (FGF) receptor 3. Results in dwarfism; short limbs, but head and trunk are normal size. Associated with advanced paternal age.

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Achondroplasia

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An autosomal dominant disease in which always bilaterally massive enlargement of kidneys due to multiple large cysts. Patients present with flank pain, haematuria, hypertension, progressive renal failure. 90% of cases are due to mutation in APKD 1 (chromosome 16). Associated with polycystic liver disease, berry aneurysms, mitral valve prolapse. Infantile form is recessive.

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Autosomal dominant polycystic kidney diseas (ADPKD)

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An autosomal dominant disease in which colon becomes covered with adenomatous polyps after puberty, Progresses to colon cancer unless resected. Deletion on chromosome 5 (APC gene)

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Familial adenomatous polyposis

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An autosomal dominant disease in which elevated LDL due to defective or absent LDL receptor. Heterozygotes (1:500) have cholesterol around 300mg/dL. Homozygotes (very rare) have cholesterol around 700+ mg/dL, severe atherosclerotic disease in early life, and tendon xanthomas; MI may develop before age 20.

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Familial hypercholesterolemia (Hyperlipidemia type IIA)

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An autosomal dominant disease in which there is a disorder of the blood vessles. Finding are telangiectasia, rucurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs)

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Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

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An autosomal dominant disease in which there are spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; inc. MCHC, splenectomy is curative.

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Hereditary spherocytosis

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An autosomal dominant disease in which presentation is depression, progressive dementia, choreiform movements, caudate atrophy and dec. levels of GABA and ACh in the brain. Symptoms manifest in affected individuals between the ages of 20 and 50. Gene located on chromosome 4; trinucleotide repeat disorder: (CAG)

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Huntington's disease

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An autosomal dominant disease in which Fibrillin gene mutation- connective tissue disorder affecting skeleton, heart and eyes. Findings: tall with long extremities, pectus excavatum, hyperextensive joints, and long tapering fingers and toes (arachnodactyly); cystic medial necrosis of aorta- aortic incompetence and dissecting aortic aneurysms; floppy mitral valve. Subluxation of lenses.

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Marfan's syndrome

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An autosomal dominant disease in which several distinct syndromes )1. 2A. 2B) characterized by familial tumours of endocrine glands, including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla. 2A and 2B associated with ret gene.

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Multiple endocrine neoplasias (MEN)

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An autosomal dominant disease in which there are cafe ole spots, neural tumours, lisch nodules (pigmented iris hamartomas). Also marked by skeletal disorders (e.g scoliosis), optic pathway gliomas, pheochromocytoma and inc. tumour susceptibility. On long arm of chromosome 17.

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Neurofibromatosis type 1 (von Reckinghausen's disease)

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An autosomal dominant disease in which there is bilateral neuroma, juvenile cataracts. NF2 gene on chromosome 22

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Neurofibromatosis type 2

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An autosomal dominant disease in which there are facial lesions (adenoma sebaceum), hypopigmented "ash leaf spots" on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and renal angiomyolipomas, cardiac rhabdomyomas, increase incidence of astrocytomas. Incomplete penetrance, variable presentation

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Tuberous sclerosis

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An autosomal dominant disease in which there are hemangioblastomas of retina/ cerebellum/ medulla; about half of affected individuals develop multiple bilateral renal cell carcinomas and other tumours. Associated with deletion of VHL gene (tumour supressor) on chromosome 3 (3p). Results in constitutive expression of HIF (transription factor) and activation of angiogenic growth factors.

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con Hippel-Lindau disease

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Albinism, ARPKD, cystic fibrosis, glycogen storage diseases, hemochromatosis, mucopolyscharidoses (except Hunter's), phenylkeonuria, sickle cell anemias, sphingolipidoses (except Fabry's), thalassemias

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Autosomal recessive diseases

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Autosomal-recessive defect in CFTR gene on chromosome 7. Commonly deletion of Phe 508

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Cystic Fibrosis

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X-linked recessive disorders

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Bruton's agammaglobulinemia, Wiskott-Aldrich syndrome, Fabry's disease, G6PD deficiency, Ocular albinism, Lesch-Nyhan syndrome, Duchenne's (and Becker's) muscular dystrophy, Hunter's Syndrome, Hemophilia A and B.
(Be, Wise, Fool's, GOLD, Heeds, Silly, Hope)

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x-linked frame shift mutation. Deletion of dystrophin gene. Accelerated muscle breakdown. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle; cardiac myopathy. Use of Gower's maneuver, requiring assistance of the upper extremities to stand up is characteristic. Onset before 5 years of age.

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Duchenne's muscular dystrophies

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X-linked mutated dystrophin gene. Less severe than the other similar disease. Onset in adolescence or early childhodd

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Becker's

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X-linked defect affecting the methylation and expression of the FMR1 gene. Associated with chromosomal breakage. The 2nd most common cause of genetic mental retardation. Presents as: macro-orchidism (enlarged testes)

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Fragile X syndrome

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Trinucleotid repeat expansion disease CAG

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Huntington's

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Trinucleotid repeat expansion disease CTG

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Myotonic dystrophy

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Trinucleotid repeat expansion disease CGG

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Fragile X syndrome

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Trinucleotid repeat expansion disease GAA

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Fredreich's ataxia

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Mental retardation, flat facies, prominent epicanthal folds, simina crease. (Classic)
Gap between 1rst 2 toesm duodenal atresia, congenital heart disease (most commonly septum primum-type ASD) Associated with inc. risk of ALL and Alzheimer's disease (Greater than age 35) 1:700

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Autosomal trisomy 21- Down syndrome

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Causes of down syndrome

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95% meiotic nondisjunction of homologous chromosomes (assoc. advancing maternal age- 1:1500 in women <20 to 2:25 in women >45)
4% of cases due to robertsonian translocation
1% due to Down mosaicism (no maternal assoc)

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Most common chromosomal disorder and most common cause of congenital mental retardation

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Autosomal trisomy 21- Down Syndrome

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Pregnancu quad screen reveals: Dec. alpha feto protein, inc beta -hCG, decrease in estriol, inc. inhibin A

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Autosomal trisomy 21- Down Syndrome

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Severe mental retardation, rocker bottom feet, micrognathia (small jaw), low-set ears, clenched hands, prominent occiput, congenital heart disease. Death usually occurs within 1 year of birth. 2nd most common trisomy 1:8000

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Trisomy 18- Edward's syndrome

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Severe mental retardation, rocker bottom feet, microphthalmia, microcephaly, cleft lip/ Palate, holoProsencephaly, Polydactyly, congenital heart disease. Death usually with 1 year of birth. 1: 15 000

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Trisomy 13- Patau's syndrome

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Nonreciprocal 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 with centromeres near their ends) fuse at the centromere and the 2 short arms are lost. Balanced translocation normally do not cause any abnormal phenotype. Unbalanced translocation can result in miscarriage, stillbirth and chromosomal imblance (eg. Down syndrome, Patau's syndrome).

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Robertsonian translocation

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Microcephaly, moderate to severe mental retardation, high pitched crying/ mewing, epicanthal folds, cardiac abnormalities. What is this and what is the genetic malformation?

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Cri-du-chat syndrome- Congenital microdeletion of short arm of chromosome 5. (46XX or XY, 5p-).

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Distinctive "elfin" facies, mental retardation, hypercalcemia (inc. sensitivity to vit D_ well- developed verbal skills, extreme friendliness with strangers, cardiovascular problems. What is this and what is the genetic malformation?

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Williams syndrome- congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

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Variable presentation, including cleft palate, abnormal facies, thymic aplasia--> T-cell deficiency, Cardiac defects, Hypocalcemia secondary to parathyroid aplasia. What is this and what is the genetic defect?

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22q11 deletion syndromes, microdeletion at chromosome 22q11.
DiGeorge syndrome- thymic, parathyroid and cardiac defects.
Velocardiofacial syndrome- palate, facial, and cardiac defects.

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Neither of 2 alleles is dominant. What is this called and give an example.

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Codominance, blood groups ( A, B and AB)

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Nature and severity of phenotype vary from 1 individual to another. What is this called and give an example.

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Variable expression ie. 2 patients with neurofibromatosis may have varying disease severity.

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1 gene has >1 1 effect on an individual's phenotype. What is this called and give an example.

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Pleiotropy. ie. PKU causes many seemingly unrelated symptoms ranging from mental retardation to hair/ skin changes.

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Severity of disease worsens or age of onset of disease is earlier in succeeding generations. What is this called and give an example.

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Anticipation- Huntington's disease

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If a pt. inherits or develops a mutation in a tumour suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes. What is this called and give an example.

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Loss of heterozygosity. ie. Retinoblastoma

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Exerts a dominant effect. A heterozygote produces a non-functional altered protein that also prevents the normal gene product from functioning. What is this called and give an example.

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Dominant negative mutation. ie. Mutation of Tx factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild- type Tx factor from binding.

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Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations. What is this called?

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Linkage disequilibrium.

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Occurs when cells in the body have different genetic makeup. Can be germ-line mosaic, which may produce disease that is not carried by parent's somatic cells. What is this called and give an example.

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Mosaicism ie. Lyonization- random x inactivation in females

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Mutations at different loci can produce the same phenotype. What is this called and give an example.

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Locus heterogeneity. ie. Marfan's syndrome, MEN 2B, and homocystinuria; all cause marfanoid habitus. Albinism.

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Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease.

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Heteroplasmy

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Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease. What is this called?

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Heteroplasmy

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Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. What is this called?

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Uniparental disomy.

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Presents with mental retardation, hyperphagia, obesity, hypogonadism and hypotonia. An example of imprinting. What is this called and where is the genetic defect?

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Prader-Willi syndrome. Deletion of genes on chromosome 15, deletion of normally active paternal allele.

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Presents with mental retardation, seizures, ataxia, inappropriate laughter ("happy puppet"). An example opf imprinting. What is this called and where is the genetic defect?

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Angelman's syndrome. Deletion of genes on chromosome 15, deletion of normally active maternal allele.

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Mode of inheritance in whichit is often due to defects in structural genes. Many generations both male and female affected. (Often pleiotropic and in many cases present clinically after puberty, fam hx crucial)

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Autosomal dominant

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Mode of inheritance in which 25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies, usually seen in only 1 generation. Horizontal distribution, often from cousins marrying. Pt. often present in childhood and is more severe than the opposite mode.

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Autosomal recessive

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Mode of inheritance in which Sons of heterozygous mothers have a 50% chance of being affected. No male to male transmission.

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X-linked recessive

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Mode of inheritance in which transmission is through both parents. Either male or femal offspring of the affected mother may be affected, while all female offspring of the affected father are diseased.

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X-linked dominant

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Mode of inheritance in which transmision is only through mother. All offspring of affected females may show signs of disease.

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Mitochondrial inheritance