USMLE Step 1: Biochemistry & other

Neither of 2 alleles is dominant

Nature and severity of phenotype vary from 1 individual to another

Not all individuals with a mutant genotype show the mutant phenotype

1 gene has > 1 effect on an individual's phenotype

Differences in phenotype depend on whether the mutation is of maternal or paternal origin

Prader-Willi and Angelman's syndrome

Severity of disease worsens or age of onset of disease is earlier in succeeding generations

Huntington's disease

If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

Retinoblastoma

• exerts a dominant effect
• a heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning

• 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

• Occurs when cells in the body differ in genetic makeup due to postfertilization loss of genetic information during mitosis
• can be a germ-line mosaic (gonadal mosaicism), which may produce disease that is not carried by parent's somatic cells

Mutations at different loci can produce the same phenotype

Marfan's syndrome, MEN 2B, and homoystinuria; all cause marfanoid habitus

Albinism

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

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent

• at some loci only 1 allele is active, the other is inactive
• with 1 allele inactivated, deletion of the active allele –> disease
• Both syndromes due to inactivations of deletion of genes on chromosome 15
• can also occur as a result of uniparental disomy

1. individual has normally inactivated maternal allele, paternal allele should be active but is deleted
   • mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
2. individual has normally inactivated paternal allele, maternal allele should active but is deleted
   • mental retardation, seizures, ataxia, inappropriate laughter

• often due to defects in structural genes
• many generations, both male and female, affected
• often pleiotropic and, in many cases, present clinically after puberty

• 25% of offspring from 2 carrier parents are affected
• often due to enzyme deficiencies
• usually seen in only 1 generation
• commonly more severe than dominant disorders
• patients often present in childhood

• Sons of hererozygous mothers have a 50% chance of being affected
• No male-to-male transmission
• Commonly more severe in males
• females must be homozygous to be affected

• transmitted through both parents
• either male or female offspring of the affected mother may be affected, while all female offspring of the affected father are diseased
• hypophospatemix rickets (formerly vitamin D-resistant rickets): inherited disorder resulting in increase of phosphate wasting at proximal tubule; rickets-like presentation

• Transmitted only through mother
• all offspring of affected females may show signs of disease
• often due to failures in oxidative phosphorylation
• variable expression in population due to heteroplasmy

• Blocked degradation of branched amino acids (valine, leucine, isoleucine) due to decreased alpha-ketoacid-DH
• causes increase in alpha-ketoacids in the blood, especially leucine
• causes severe CNS defects, mental retardation and death

1. lacks proofreading 3' –> 5' exonuclease activity in its RNA-polymerase
2. envelope glycoprotein contains hypervariable region prone to frequent genetic mutation

• enzyme deficiencies of early steps in porphyrin synthesis –> neuropsychiatric manifestaitons without photosensitivity
• late steps –> photosensitivity

Lactose

1. Ferrochelatase and ALA dehydratase
2. Protoporphyrin
3. Microcytic anemia, GI and kidney disease.
   • Children: mental deterioration
   • Adults: headache, memory loss, demyelination

1. Porphobilinogen deaminase (aka uroporphyrinogen-I-synthase)
2. Porphobilinogen, Delta-ALA, uroporhyrin (urine)
3. symptoms
   • painful abdomen
   • red wine-colored urine
   • polyneuropathy
   • psychological disturbances
   • precipitated by drugs
4. glucose and heme, which inhibit ALA synthase

1. Fructose + glucose
2. Galactose + glucose
3. Glucose + glucose

• alpha-ketoglutarate-DH requires thiamine as a cofactor
• glucose administration –> increase in thiamine demand –> Wernicke encephalopathy: acute confusion, ophthalmoplegia, ataxia

Aldolase-B deficiency

• similar structure to TSH
• testicular germ cell tumor
• can cause hyperthyroidism

• found in a variety of poisonous mushrooms
• inhibit RNA polymerase II –> halting mRNA synthesis

• congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine to fumarate
• autosomal recessive
• benign disease
• findings:
  • dark connective tissue
  • brown pigmented sclera
  • urine turns black on prolonged exposure to air
  • may have debilitating arthralgias

• product of heme metabolism
• is removed from blood by liver, conjugated with glucuronate and excreted in bile
• direct bilirubin: conjugated with glucuronic acid, water soluble
• indirect bilirubin: unconjugated, water insoluble

impairs fatty acid transport into mitochondria –> restricted ketone body production

• inside:
  1. synthesis (RER): translation of collagen alpha-chains (preprocollagen) - usually Gly-X-Y polypeptide (X and Y are proline, hydroxyproline or hydroxylysine)
  2. hydroxylation (ER): hydroxylation of specific proline and lysine residues (requires vitamin C)
  3. glycosylation (ER): glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollagen via hydrogen and disulfide bonds (triple helix of 3 collagen alpha chains)
  4. exocytosis: exocytosis of procollagen into extracellular space
• outside:
  • 5. proteolytic processing: cleavage of terminal regions of procollagen transforms it into insoluble tropocollagen
  • 6. cross-linking: reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage to make collagen fibrils