What genetic mutation causes Huntington disease, what is its inheritance pattern, and what phenomenon explains earlier onset in successive generations?

CAG trinucleotide repeat expansion in the HTT gene on chromosome 4; autosomal dominant. Anticipation occurs primarily during paternal transmission due to repeat expansion in spermatogenesis.

What is the biochemical defect in Von Gierke disease (GSD Type I), and what laboratory abnormalities are seen?

Glucose-6-phosphatase deficiency. Presents with severe fasting hypoglycemia, profound lactic acidosis, hyperuricemia (gout), hyperlipidemia, and marked hepatomegaly with doll-like facies.

What is the rate-limiting enzyme of beta-oxidation and what molecule inhibits it?

Carnitine palmitoyltransferase-1 (CPT-1 / CAT-1). Malonyl-CoA inhibits CPT-1, preventing newly synthesized fatty acids from immediately undergoing mitochondrial oxidation.

What enzyme deficiency causes Maple Syrup Urine Disease (MSUD), and what amino acids accumulate?

Deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC, requiring thiamine/B1). Leads to toxic accumulation of leucine, isoleucine, and valine, producing sweet burnt-sugar urine and severe ketoacidosis.

What enzyme deficiency causes Gaucher disease, and what is the characteristic histological finding?

Glucocerebrosidase (beta-glucosidase) deficiency causing glucocerebroside accumulation. Histology shows 'crumpled tissue paper' lipid-laden macrophages.

What is the rate-limiting enzyme of fatty acid synthesis and what allosteric activator promotes its activity?

Acetyl-CoA carboxylase (ACC), which converts acetyl-CoA to malonyl-CoA. Allosterically activated by citrate and inhibited by long-chain fatty acyl-CoA and glucagon/epinephrine phosphorylation.

What is the biochemical basis of Lesch-Nyhan syndrome, its inheritance, and hallmark symptoms?

Absent HGPRT (hypoxanthine guanine phosphoribosyltransferase) in purine salvage; X-linked recessive. Characterized by hyperuricemia, gout, aggressive self-mutilation (lip/finger biting), and dystonia/chorea.

What is the most common cause of congenital adrenal hyperplasia (CAH), and what serum marker is elevated?

21-hydroxylase deficiency (CYP21A2). Causes virilization/ambiguous genitalia in females, salt-wasting crisis (hypotension, hyponatremia, hyperkalemia) in neonates, and elevated 17-hydroxyprogesterone.

What genetic defect is responsible for Prader-Willi versus Angelman syndrome on chromosome 15q11-q13?

Prader-Willi: loss of paternal expression (maternal uniparental disomy or paternal deletion). Angelman: loss of maternal UBE3A expression (paternal uniparental disomy or maternal deletion).

What is the rate-limiting enzyme in urea synthesis and what is its mandatory allosteric activator?

Carbamoyl phosphate synthetase I (CPS I) in mitochondria; allosterically activated by N-acetylglutamate (NAG).

What is the defective enzyme and pathway in McArdle disease (Glycogen Storage Disease Type V)?

Skeletal muscle glycogen phosphorylase (myophosphorylase). Patients develop painful muscle cramps and myoglobinuria upon strenuous exercise, without a rise in blood lactate.

What enzyme is deficient in classic homocystinuria, and how does it clinically differ from Marfan syndrome?

Cystathionine beta-synthase (CBS) deficiency (requires B6). Both have tall, arachnodactyly stature, but homocystinuria features downward/inward lens subluxation, intellectual disability, and life-threatening thromboembolism; Marfan has upward/outward ectopia lentis and normal intellect.

What enzyme is defective in phenylketonuria (PKU), and what amino acid becomes conditionally essential?

Phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin, BH4). Tyrosine becomes an essential amino acid in diet.

What is the rate-limiting enzyme of glycolysis, and what are its principal allosteric regulators?

Phosphofructokinase-1 (PFK-1). Activated by AMP and fructose-2,6-bisphosphate (F-2,6-BP); inhibited by ATP and citrate.

What is the underlying defect and classic triad of Wernicke encephalopathy?

Thiamine (vitamin B1) deficiency leading to impaired pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Triad: acute confusion/encephalopathy, ataxia, and ophthalmoplegia/nystagmus.

How do you distinguish Niemann-Pick disease from Tay-Sachs disease clinically and enzymatically?

Niemann-Pick has sphingomyelinase deficiency (sphingomyelin accumulation), 'foam cells' on histology, and hepatosplenomegaly alongside the cherry-red macular spot; Tay-Sachs lacks hepatosplenomegaly.

What cellular process is defective in I-cell disease (mucolipidosis type II), and what is the destination of lysosomal enzymes?

Deficiency of UDP-N-acetylglucosamine phosphotransferase prevents mannose-6-phosphate tagging in the Golgi. Lysosomal acid hydrolases are secreted abnormally into the extracellular space/plasma rather than transported to lysosomes.

What is the primary enzyme deficiency and accumulated substrate in Tay-Sachs disease?

Deficiency of Hexosaminidase A leading to GM2 ganglioside accumulation. Characterized by progressive neurodegeneration, cherry-red macular spot, and absence of hepatosplenomegaly (unlike Niemann-Pick).

What is the rate-limiting enzyme in heme biosynthesis and what cofactor is required?

Aminolevulinate synthase (ALAS-1 in liver, ALAS-2 in erythroid cells), requiring pyridoxal phosphate (vitamin B6). ALAS-2 mutation causes X-linked sideroblastic anemia.

What enzyme deficiency causes Fabry disease, and what is its mode of inheritance and classic triad?

Alpha-galactosidase A deficiency (accumulating ceramide trihexoside/Gb3); X-linked recessive. Triad: episodic peripheral neuropathy (acroparesthesias), angiokeratomas, and hypohidrosis; later renal and cardiovascular failure.

What enzyme is deficient in Pompe disease (GSD Type II), and what is its distinctive organ involvement?

Lysosomal acid alpha-1,4-glucosidase (acid maltase). Causes severe hypertrophic cardiomyopathy, generalized hypotonia ('floppy baby'), and cardiomegaly leading to early death.

What is the enzyme deficiency in alkaptonuria, and what are its pathognomonic clinical features?

Homogentisate 1,2-dioxygenase deficiency in tyrosine degradation. Accumulation of homogentisic acid causes urine turning dark on standing, bluish-black connective tissue pigmentation (ochronosis), and debilitating arthropathy.

What is the rate-limiting step and enzyme in de novo purine synthesis?

Glutamine-PRPP amidotransferase, converting PRPP (5-phosphoribosyl-1-pyrophosphate) to 5-phosphoribosylamine. Strongly inhibited by AMP, GMP, and IMP.

What is the metabolic defect in hereditary fructose intolerance and why is it more severe than essential fructosuria?

Aldolase B deficiency. Ingested fructose accumulates as intracellular fructose-1-phosphate, trapping cellular inorganic phosphate, halting glycogenolysis and gluconeogenesis, causing profound postprandial hypoglycemia and hepatic failure.

What is the enzyme deficiency in Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, and what are the classic histological findings on peripheral smear?

G6PD deficiency impairs NADPH production in the pentose phosphate pathway, rendering RBCs vulnerable to oxidative stress. Blood smear shows Heinz bodies (denatured hemoglobin precipitates) and bite cells.

What is the most common urea cycle disorder, its inheritance, and distinguishing laboratory findings?

Ornithine transcarbamylase (OTC) deficiency; X-linked recessive. Laboratory findings show hyperammonemia, low BUN, elevated urinary orotic acid, and normal/undetectable citrulline.

What is the mechanism of uncoupling agents like 2,4-dinitrophenol (DNP) or brown fat thermogenin on oxidative phosphorylation?

They dissipate the mitochondrial proton gradient across the inner mitochondrial membrane, increasing oxygen consumption and electron transport chain activity while releasing energy as heat without ATP synthesis.

What is the deficient transporter in Cystinuria, and what type of urinary stones are formed?

Defective renal proximal tubule amino acid transporter for COLA (Cystine, Ornithine, Lysine, Arginine). Cystine precipitates into pathognomonic hexagonal urinary crystals and radiopaque staghorn or calculi.

What is the mode of inheritance and chromosomal abnormality in fragile X syndrome?

X-linked dominant with CGG trinucleotide repeat expansion in the FMR1 gene (>200 repeats leading to hypermethylation and gene silencing). Manifests with intellectual disability, macroorchidism, long narrow face, and large ears.

What is the biochemical cause and clinical manifestation of Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency?

Deficiency in medium-chain fatty acid oxidation. Presents after fasting or illness with non-ketotic hypoglycemia, lethargy, seizures, hepatic dysfunction, and dicarboxylic aciduria.

What enzyme deficiency causes Acute Intermittent Porphyria (AIP), and what characterizes its neurovisceral attacks?

Porphobilinogen deaminase (hydroxymethylbilane synthase). Attacks are triggered by CYP450 inducers/fasting, presenting with the 5 Ps: Painful abdomen, Polyneuropathy, Psychologic disturbance, Port-wine colored urine, and Precipitated by drugs.

What enzyme is deficient in classic galactosemia, and how does it clinically present?

Galactose-1-phosphate uridylyltransferase (GALT). Presents in early infancy after milk ingestion with failure to thrive, jaundice, hepatomegaly, infantile cataracts, and increased risk of E. coli sepsis.

USMLE Step 1 — Biochemistry, Genetics, Metabolic Pathways & Storage Diseases

High-yield enzymes, rate-limiting steps, glycogen/lysosomal storage disorders, inborn errors of metabolism, and inheritance patterns.

Level: basic
Languages: en → en
Cards: 32
Markdown: USMLE Step 1 — Biochemistry, Genetics, Metabolic Pathways & Storage Diseases (.md)

Flashcards (32)

#	Front (Term / Question)	Back (Definition / Answer)
1	What genetic mutation causes Huntington disease, what is its inheritance pattern, and what phenomenon explains earlier onset in successive generations?	CAG trinucleotide repeat expansion in the HTT gene on chromosome 4; autosomal dominant. Anticipation occurs primarily during paternal transmission due to repeat expansion in spermatogenesis.
2	What is the biochemical defect in Von Gierke disease (GSD Type I), and what laboratory abnormalities are seen?	Glucose-6-phosphatase deficiency. Presents with severe fasting hypoglycemia, profound lactic acidosis, hyperuricemia (gout), hyperlipidemia, and marked hepatomegaly with doll-like facies.
3	What is the rate-limiting enzyme of beta-oxidation and what molecule inhibits it?	Carnitine palmitoyltransferase-1 (CPT-1 / CAT-1). Malonyl-CoA inhibits CPT-1, preventing newly synthesized fatty acids from immediately undergoing mitochondrial oxidation.
4	What enzyme deficiency causes Maple Syrup Urine Disease (MSUD), and what amino acids accumulate?	Deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC, requiring thiamine/B1). Leads to toxic accumulation of leucine, isoleucine, and valine, producing sweet burnt-sugar urine and severe ketoacidosis.
5	What enzyme deficiency causes Gaucher disease, and what is the characteristic histological finding?	Glucocerebrosidase (beta-glucosidase) deficiency causing glucocerebroside accumulation. Histology shows 'crumpled tissue paper' lipid-laden macrophages.
6	What is the rate-limiting enzyme of fatty acid synthesis and what allosteric activator promotes its activity?	Acetyl-CoA carboxylase (ACC), which converts acetyl-CoA to malonyl-CoA. Allosterically activated by citrate and inhibited by long-chain fatty acyl-CoA and glucagon/epinephrine phosphorylation.
7	What is the biochemical basis of Lesch-Nyhan syndrome, its inheritance, and hallmark symptoms?	Absent HGPRT (hypoxanthine guanine phosphoribosyltransferase) in purine salvage; X-linked recessive. Characterized by hyperuricemia, gout, aggressive self-mutilation (lip/finger biting), and dystonia/chorea.
8	What is the most common cause of congenital adrenal hyperplasia (CAH), and what serum marker is elevated?	21-hydroxylase deficiency (CYP21A2). Causes virilization/ambiguous genitalia in females, salt-wasting crisis (hypotension, hyponatremia, hyperkalemia) in neonates, and elevated 17-hydroxyprogesterone.
9	What genetic defect is responsible for Prader-Willi versus Angelman syndrome on chromosome 15q11-q13?	Prader-Willi: loss of paternal expression (maternal uniparental disomy or paternal deletion). Angelman: loss of maternal UBE3A expression (paternal uniparental disomy or maternal deletion).
10	What is the rate-limiting enzyme in urea synthesis and what is its mandatory allosteric activator?	Carbamoyl phosphate synthetase I (CPS I) in mitochondria; allosterically activated by N-acetylglutamate (NAG).
11	What is the defective enzyme and pathway in McArdle disease (Glycogen Storage Disease Type V)?	Skeletal muscle glycogen phosphorylase (myophosphorylase). Patients develop painful muscle cramps and myoglobinuria upon strenuous exercise, without a rise in blood lactate.
12	What enzyme is deficient in classic homocystinuria, and how does it clinically differ from Marfan syndrome?	Cystathionine beta-synthase (CBS) deficiency (requires B6). Both have tall, arachnodactyly stature, but homocystinuria features downward/inward lens subluxation, intellectual disability, and life-threatening thromboembolism; Marfan has upward/outward ectopia lentis and normal intellect.
13	What enzyme is defective in phenylketonuria (PKU), and what amino acid becomes conditionally essential?	Phenylalanine hydroxylase (or its cofactor tetrahydrobiopterin, BH4). Tyrosine becomes an essential amino acid in diet.
14	What is the rate-limiting enzyme of glycolysis, and what are its principal allosteric regulators?	Phosphofructokinase-1 (PFK-1). Activated by AMP and fructose-2,6-bisphosphate (F-2,6-BP); inhibited by ATP and citrate.
15	What is the underlying defect and classic triad of Wernicke encephalopathy?	Thiamine (vitamin B1) deficiency leading to impaired pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase. Triad: acute confusion/encephalopathy, ataxia, and ophthalmoplegia/nystagmus.
16	How do you distinguish Niemann-Pick disease from Tay-Sachs disease clinically and enzymatically?	Niemann-Pick has sphingomyelinase deficiency (sphingomyelin accumulation), 'foam cells' on histology, and hepatosplenomegaly alongside the cherry-red macular spot; Tay-Sachs lacks hepatosplenomegaly.
17	What cellular process is defective in I-cell disease (mucolipidosis type II), and what is the destination of lysosomal enzymes?	Deficiency of UDP-N-acetylglucosamine phosphotransferase prevents mannose-6-phosphate tagging in the Golgi. Lysosomal acid hydrolases are secreted abnormally into the extracellular space/plasma rather than transported to lysosomes.
18	What is the primary enzyme deficiency and accumulated substrate in Tay-Sachs disease?	Deficiency of Hexosaminidase A leading to GM2 ganglioside accumulation. Characterized by progressive neurodegeneration, cherry-red macular spot, and absence of hepatosplenomegaly (unlike Niemann-Pick).
19	What is the rate-limiting enzyme in heme biosynthesis and what cofactor is required?	Aminolevulinate synthase (ALAS-1 in liver, ALAS-2 in erythroid cells), requiring pyridoxal phosphate (vitamin B6). ALAS-2 mutation causes X-linked sideroblastic anemia.
20	What enzyme deficiency causes Fabry disease, and what is its mode of inheritance and classic triad?	Alpha-galactosidase A deficiency (accumulating ceramide trihexoside/Gb3); X-linked recessive. Triad: episodic peripheral neuropathy (acroparesthesias), angiokeratomas, and hypohidrosis; later renal and cardiovascular failure.
21	What enzyme is deficient in Pompe disease (GSD Type II), and what is its distinctive organ involvement?	Lysosomal acid alpha-1,4-glucosidase (acid maltase). Causes severe hypertrophic cardiomyopathy, generalized hypotonia ('floppy baby'), and cardiomegaly leading to early death.
22	What is the enzyme deficiency in alkaptonuria, and what are its pathognomonic clinical features?	Homogentisate 1,2-dioxygenase deficiency in tyrosine degradation. Accumulation of homogentisic acid causes urine turning dark on standing, bluish-black connective tissue pigmentation (ochronosis), and debilitating arthropathy.
23	What is the rate-limiting step and enzyme in de novo purine synthesis?	Glutamine-PRPP amidotransferase, converting PRPP (5-phosphoribosyl-1-pyrophosphate) to 5-phosphoribosylamine. Strongly inhibited by AMP, GMP, and IMP.
24	What is the metabolic defect in hereditary fructose intolerance and why is it more severe than essential fructosuria?	Aldolase B deficiency. Ingested fructose accumulates as intracellular fructose-1-phosphate, trapping cellular inorganic phosphate, halting glycogenolysis and gluconeogenesis, causing profound postprandial hypoglycemia and hepatic failure.
25	What is the enzyme deficiency in Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, and what are the classic histological findings on peripheral smear?	G6PD deficiency impairs NADPH production in the pentose phosphate pathway, rendering RBCs vulnerable to oxidative stress. Blood smear shows Heinz bodies (denatured hemoglobin precipitates) and bite cells.
26	What is the most common urea cycle disorder, its inheritance, and distinguishing laboratory findings?	Ornithine transcarbamylase (OTC) deficiency; X-linked recessive. Laboratory findings show hyperammonemia, low BUN, elevated urinary orotic acid, and normal/undetectable citrulline.
27	What is the mechanism of uncoupling agents like 2,4-dinitrophenol (DNP) or brown fat thermogenin on oxidative phosphorylation?	They dissipate the mitochondrial proton gradient across the inner mitochondrial membrane, increasing oxygen consumption and electron transport chain activity while releasing energy as heat without ATP synthesis.
28	What is the deficient transporter in Cystinuria, and what type of urinary stones are formed?	Defective renal proximal tubule amino acid transporter for COLA (Cystine, Ornithine, Lysine, Arginine). Cystine precipitates into pathognomonic hexagonal urinary crystals and radiopaque staghorn or calculi.
29	What is the mode of inheritance and chromosomal abnormality in fragile X syndrome?	X-linked dominant with CGG trinucleotide repeat expansion in the FMR1 gene (>200 repeats leading to hypermethylation and gene silencing). Manifests with intellectual disability, macroorchidism, long narrow face, and large ears.
30	What is the biochemical cause and clinical manifestation of Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency?	Deficiency in medium-chain fatty acid oxidation. Presents after fasting or illness with non-ketotic hypoglycemia, lethargy, seizures, hepatic dysfunction, and dicarboxylic aciduria.
31	What enzyme deficiency causes Acute Intermittent Porphyria (AIP), and what characterizes its neurovisceral attacks?	Porphobilinogen deaminase (hydroxymethylbilane synthase). Attacks are triggered by CYP450 inducers/fasting, presenting with the 5 Ps: Painful abdomen, Polyneuropathy, Psychologic disturbance, Port-wine colored urine, and Precipitated by drugs.
32	What enzyme is deficient in classic galactosemia, and how does it clinically present?	Galactose-1-phosphate uridylyltransferase (GALT). Presents in early infancy after milk ingestion with failure to thrive, jaundice, hepatomegaly, infantile cataracts, and increased risk of E. coli sepsis.