100 Questions that appear on every NBME
BIOCHEMISTRY
1. Autosomal dominant or X-linked or mitochondrial
Autosomal dominant: often due to defects in structural genes. Many generations, both males and females are affected.
Often pleiotropic (multiple apparently unrelated effects) and variable expressive (different between individuals).
Family history crucial to diagnosis. With one affected (heterozygous) parent, on average, ½ of children affected
(50% offspring with disease).
Examples: Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis, familial
hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), hereditary
spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias,
myotonic muscular dystrophy, neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2,
tuberous sclerosis, von Hippel-Lindau disease.
Autosomal recessive: with 2 carrier (heterozygous) parents, on average:
¼ of children will be affected (homozygous),
½ of children will be carriers, and
¼ of children will be neither affected nor carrier.
Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe than dominant disorders;
patients often present in childhood. Increased risk in consanguineous families. Unaffected individual with affected
sibling has 2/3 probability of being carrier.
Examples: Oculocutaneous albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, Friedreich
ataxia, glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease), thalassemias,
Wilson disease.
X-Linked recessive: disease gene on X chromosome. sons of heterozygous mothers have a 50% chance of being affected.
No male-to-male transmission. Skips generations.
Only males are sick. Commonly more severe in males. Females usually must be homozygous to be affected, they very
rarely develop disease. They can develop disease with Skewed Lyonization
Example: Hemophilia A and B, Fabry disease, G6PD deficiency, Hunter syndrome, Lesch-Nyhan syndrome, Duchenne
dystrophy
,X-Linked dominant: Transmitted through both parents (both sexes). Mothers transmit 50% of daughters and sons; fathers
transmit to all daughters but no sons. NO MALE-TO-MALE.
Examples: Fragile X syndrome, Alport syndrome, Hypophosphatemic Rickets (also called X-Linked Hypophosphatemia)-
phosphate wasting at proximal tubule à rickets-like presentation.
Mitochondrial inheritance: transmitted only through the mother. All offspring of affected females may show signs of
disease. Variable expression in a population or even within a family due to heteroplasmy.
If the mother is homoplasmic: all children have mutation
If mother is heteroplasmic: variable
Mitochondrial Myopathies: rare disorders, often present with myopathy, lactic acidosis and CNS disease, eg, MELAS
syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). 2ry to failure in oxidative
phosphorylation. Muscle biopsy often shows “ragged red fibers” (due to accumulation of diseased mitochondria
in the subsarcolemma of the muscle fibers).
Leber hereditary optic neuropathy: cell death in optic nerve neurons à subacute bilateral vision loss in teens/oung adults,
90% males. Usually permanent.
2. Patau vs. Edwards vs. Down Syndrome
Down syndrome (trisomy 21) Findings: intellectual disability, flat facies, prominent epicanthal folds, single palmar
crease, incurved 5th finger, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg,
ASD), Brushfield spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor
protein), risk of AML/ALL. 95% of cases due to meiotic nondisjunction (Increased with advanced maternal age; from
1:1500 in women < 20 to 1:25 in women > 45 years old). 4% of cases due to unbalanced Robertsonian translocation, most
typically between chromosomes 14 and 21. Only 1% of cases are due to postfertilization mitotic error.
Incidence 1:700. Drinking age (21).
Most common viable chromosomal disorder and most common cause of genetic intellectual disability.
,First-trimester ultrasound commonly shows Inceased nuchal translucency and hypoplastic nasal bone. Markers for Down
syndrome are HI up: Increased hCG, INcreased inhibin.
The 5 A’s of Down syndrome:
Advanced maternal age
Atresia (duodenal)
Atrioventricular septal defect
Alzheimer disease (early onset)
AML/ALL
Edwards syndrome (trisomy 18) Findings: PRINCE Edward—Prominent occiput, Rocker-bottom feet, Intellectual
disability, Nondisjunction, Clenched fists with overlapping fingers, low-set Ears, micrognathia (small jaw), congenital
heart disease, omphalocele, myelomeningocele. Death usually occurs by age 1 year.
Incidence 1:8000. Election age (18).
2nd most common autosomal trisomy resulting in live birth (most common is Down syndrome).
Patau syndrome (trisomy 13) Findings: severe intellectual disability, rockerbottom feet, microphthalmia, microcephaly,
cleft liP/Palate, holoProsencephaly, Polydactyly, cutis aPlasia, congenital heart (Pump) disease, Polycystic kidney
disease, omphalocele. Death usually occurs by age 1.
Incidence 1:15,000. Puberty (13).
Defect in fusion of prechordal mesoderm → midline defects
, 3. Collagen/Elastin/insulin synthesis and corresponding diseases
Collagen Synthesis:
Synthesis: translation of collagen α chains (preprocollagen)-usually Gly-X-Y (X and Y are proline or lysine). Collagen
is 1/3 glycine; glycine content of collagen is less variable than that of lysine and proline. Hydroxyproline is used for lab
quantification of collagen.
Hydroxylation: hydroxylation of specific proline and lysine residues. Requires vitamin C; deficiency → scurvy.
Glycosylation: glycosylation of pro-α-chains hydroxylysine residues and formation of procollagen via hydrogen and
disulfide bonds (triple helix of 3 collagen α chains). Problems forming triple helix → osteogenesis imperfecta.
Exocytosis: exocytosis of procollagen into extracellular space.
Proteolytic processing: cleavage of disulfide-rich terminal regions of procollagen → insoluble tropocollagen.
Cross-linking: reinforcements of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-
linkage (by copper-containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking Menkes disease.
BIOCHEMISTRY
1. Autosomal dominant or X-linked or mitochondrial
Autosomal dominant: often due to defects in structural genes. Many generations, both males and females are affected.
Often pleiotropic (multiple apparently unrelated effects) and variable expressive (different between individuals).
Family history crucial to diagnosis. With one affected (heterozygous) parent, on average, ½ of children affected
(50% offspring with disease).
Examples: Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis, familial
hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), hereditary
spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias,
myotonic muscular dystrophy, neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2,
tuberous sclerosis, von Hippel-Lindau disease.
Autosomal recessive: with 2 carrier (heterozygous) parents, on average:
¼ of children will be affected (homozygous),
½ of children will be carriers, and
¼ of children will be neither affected nor carrier.
Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe than dominant disorders;
patients often present in childhood. Increased risk in consanguineous families. Unaffected individual with affected
sibling has 2/3 probability of being carrier.
Examples: Oculocutaneous albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, Friedreich
ataxia, glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease), thalassemias,
Wilson disease.
X-Linked recessive: disease gene on X chromosome. sons of heterozygous mothers have a 50% chance of being affected.
No male-to-male transmission. Skips generations.
Only males are sick. Commonly more severe in males. Females usually must be homozygous to be affected, they very
rarely develop disease. They can develop disease with Skewed Lyonization
Example: Hemophilia A and B, Fabry disease, G6PD deficiency, Hunter syndrome, Lesch-Nyhan syndrome, Duchenne
dystrophy
,X-Linked dominant: Transmitted through both parents (both sexes). Mothers transmit 50% of daughters and sons; fathers
transmit to all daughters but no sons. NO MALE-TO-MALE.
Examples: Fragile X syndrome, Alport syndrome, Hypophosphatemic Rickets (also called X-Linked Hypophosphatemia)-
phosphate wasting at proximal tubule à rickets-like presentation.
Mitochondrial inheritance: transmitted only through the mother. All offspring of affected females may show signs of
disease. Variable expression in a population or even within a family due to heteroplasmy.
If the mother is homoplasmic: all children have mutation
If mother is heteroplasmic: variable
Mitochondrial Myopathies: rare disorders, often present with myopathy, lactic acidosis and CNS disease, eg, MELAS
syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). 2ry to failure in oxidative
phosphorylation. Muscle biopsy often shows “ragged red fibers” (due to accumulation of diseased mitochondria
in the subsarcolemma of the muscle fibers).
Leber hereditary optic neuropathy: cell death in optic nerve neurons à subacute bilateral vision loss in teens/oung adults,
90% males. Usually permanent.
2. Patau vs. Edwards vs. Down Syndrome
Down syndrome (trisomy 21) Findings: intellectual disability, flat facies, prominent epicanthal folds, single palmar
crease, incurved 5th finger, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease (eg,
ASD), Brushfield spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for amyloid precursor
protein), risk of AML/ALL. 95% of cases due to meiotic nondisjunction (Increased with advanced maternal age; from
1:1500 in women < 20 to 1:25 in women > 45 years old). 4% of cases due to unbalanced Robertsonian translocation, most
typically between chromosomes 14 and 21. Only 1% of cases are due to postfertilization mitotic error.
Incidence 1:700. Drinking age (21).
Most common viable chromosomal disorder and most common cause of genetic intellectual disability.
,First-trimester ultrasound commonly shows Inceased nuchal translucency and hypoplastic nasal bone. Markers for Down
syndrome are HI up: Increased hCG, INcreased inhibin.
The 5 A’s of Down syndrome:
Advanced maternal age
Atresia (duodenal)
Atrioventricular septal defect
Alzheimer disease (early onset)
AML/ALL
Edwards syndrome (trisomy 18) Findings: PRINCE Edward—Prominent occiput, Rocker-bottom feet, Intellectual
disability, Nondisjunction, Clenched fists with overlapping fingers, low-set Ears, micrognathia (small jaw), congenital
heart disease, omphalocele, myelomeningocele. Death usually occurs by age 1 year.
Incidence 1:8000. Election age (18).
2nd most common autosomal trisomy resulting in live birth (most common is Down syndrome).
Patau syndrome (trisomy 13) Findings: severe intellectual disability, rockerbottom feet, microphthalmia, microcephaly,
cleft liP/Palate, holoProsencephaly, Polydactyly, cutis aPlasia, congenital heart (Pump) disease, Polycystic kidney
disease, omphalocele. Death usually occurs by age 1.
Incidence 1:15,000. Puberty (13).
Defect in fusion of prechordal mesoderm → midline defects
, 3. Collagen/Elastin/insulin synthesis and corresponding diseases
Collagen Synthesis:
Synthesis: translation of collagen α chains (preprocollagen)-usually Gly-X-Y (X and Y are proline or lysine). Collagen
is 1/3 glycine; glycine content of collagen is less variable than that of lysine and proline. Hydroxyproline is used for lab
quantification of collagen.
Hydroxylation: hydroxylation of specific proline and lysine residues. Requires vitamin C; deficiency → scurvy.
Glycosylation: glycosylation of pro-α-chains hydroxylysine residues and formation of procollagen via hydrogen and
disulfide bonds (triple helix of 3 collagen α chains). Problems forming triple helix → osteogenesis imperfecta.
Exocytosis: exocytosis of procollagen into extracellular space.
Proteolytic processing: cleavage of disulfide-rich terminal regions of procollagen → insoluble tropocollagen.
Cross-linking: reinforcements of many staggered tropocollagen molecules by covalent lysine-hydroxylysine cross-
linkage (by copper-containing lysyl oxidase) to make collagen fibrils. Problems with cross-linking Menkes disease.
