- These findings are most consistent with a deficiency in which of the following enzymes?
Answer: Glycogen debranching enzyme
This patient has Cori disease (Glycogen Storage Disease Type III), caused by a deficiency of the glycogen debranching enzyme (amylo-1,6-glucosidase). This leads to the accumulation of limit dextrin, a form of glycogen with short outer branches. Glycogenolysis is incomplete. Because gluconeogenesis is intact, fasting does not produce severe lactic acidosis or hyperuricemia, distinguishing it from GSD Type I (von Gierke).
- The pathophysiology of the neurologic deficits in this disease is most directly related to the accumulation of a substrate in which cellular organelle?
Answer: Lysosome
The patient has Tay-Sachs disease, which is a classic example of a lysosomal storage disorder. The deficient enzyme, hexosaminidase A, is a lysosomal hydrolase. Its absence leads to the accumulation of its substrate, GM2 ganglioside, within the lysosomes of neurons, causing progressive neurodegeneration.
- A deficiency in which of the following enzymes is the most likely cause of this patient's condition?
Answer: Glucose-6-phosphatase
This is a classic presentation of Von Gierke disease (Glycogen Storage Disease Type I), caused by a deficiency of glucose-6-phosphatase. This enzyme is required for the final step of both glycogenolysis and gluconeogenesis. Its deficiency leads to severe fasting hypoglycemia and a shunt of metabolic intermediates towards lactate (lactic acidosis), uric acid (hyperuricemia), and lipid synthesis (hyperlipidemia).
- A deficiency in which of the following enzymes is responsible for this patient's condition?
Answer: Glucocerebrosidase
The presentation of bone pain, hepatosplenomegaly, and pancytopenia, along with the characteristic lipid-laden macrophages ('Gaucher cells') in the bone marrow, is diagnostic of Gaucher disease. This is the most common lysosomal storage disorder and is caused by a deficiency of the enzyme glucocerebrosidase (β-glucosidase), leading to the accumulation of glucocerebroside.
- This disorder is caused by a deficiency of an enzyme in the degradation pathway of which amino acid?
Answer: Tyrosine
This is a presentation of hereditary tyrosinemia type I, an autosomal recessive disorder caused by a deficiency of fumarylacetoacetate hydrolase, the final enzyme in the tyrosine degradation pathway. This leads to the accumulation of toxic metabolites, particularly succinylacetone, which causes severe liver and kidney damage. The cabbage-like odor is due to accumulated tyrosine metabolites.
- A defect in which of the following metabolic pathways is the most likely cause of this presentation?
Answer: Fatty acid β-oxidation
The clinical picture of hypoketotic hypoglycemia during a period of fasting is a hallmark of a fatty acid oxidation disorder, most commonly Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. During fasting, the body relies on β-oxidation to produce acetyl-CoA for ketone body synthesis and ATP for gluconeogenesis. A defect in this pathway prevents ketone production and impairs gluconeogenesis, leading to severe hypoglycemia.
- A deficiency in which of the following urea cycle enzymes best explains these findings?
Answer: Ornithine transcarbamylase
This patient presents with hyperammonemia, characteristic of a urea cycle defect. The key finding is the elevated orotic acid. Ornithine transcarbamylase (OTC) deficiency, an X-linked recessive disorder, leads to the accumulation of carbamoyl phosphate in the mitochondria. This excess carbamoyl phosphate leaks into the cytosol and enters the pyrimidine synthesis pathway, resulting in orotic aciduria. Deficiencies in other urea cycle enzymes do not typically cause orotic aciduria.
- This fatal disorder results from a defect in the biogenesis of which cellular organelle?
Answer: Peroxisomes
This is a classic presentation of Zellweger syndrome, which is the most severe form of the peroxisome biogenesis disorders. Peroxisomes are required for several metabolic functions, including the initial beta-oxidation of very-long-chain fatty acids (VLCFAs). The inability to form functional peroxisomes leads to the accumulation of VLCFAs and other substrates, causing widespread organ dysfunction and the characteristic clinical features.
- This genetic disorder, characterized by a deficiency of α-galactosidase A, follows which pattern of inheritance?
Answer: X-linked recessive
This patient's symptoms of acroparesthesias, hypohidrosis, angiokeratomas, and renal dysfunction are classic for Fabry disease. It is a lysosomal storage disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of globotriaosylceramide. Fabry disease is inherited in an X-linked recessive pattern.
- A deficiency in which of the following enzymes is the most likely diagnosis?
Answer: Fructokinase
This patient has essential fructosuria, a benign autosomal recessive condition caused by a deficiency of fructokinase. This enzyme is responsible for the first step of fructose metabolism. Its absence prevents fructose from being metabolized in the liver, leading to its excretion in the urine. Because fructose is a reducing sugar, it gives a positive copper reduction test (detects reducing substances), but the glucose-specific glucose oxidase test is negative. The condition is asymptomatic.
- The formation of cataracts in this patient is due to the action of which enzyme on excess galactose?
Answer: Aldose reductase
This patient has galactokinase deficiency. In this condition, galactose cannot be phosphorylated to galactose-1-phosphate. The excess galactose is shunted into an alternative pathway where the enzyme aldose reductase converts it to galactitol. Galactitol is an osmotically active alcohol that accumulates in the lens, causing swelling and cataract formation. Unlike classic galactosemia, the more toxic galactose-1-phosphate does not accumulate, so systemic symptoms are absent.
- This X-linked recessive disorder is caused by a severe deficiency of which of the following enzymes?
Answer: Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
This patient has Lesch-Nyhan syndrome, an X-linked recessive disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). HGPRT is a key enzyme in the purine salvage pathway. Its absence leads to increased degradation of purines into uric acid (hyperuricemia) and increased de novo purine synthesis. The neurologic features and self-mutilation are characteristic.
- This condition is caused by a deficiency in which of the following enzymes?
Answer: Aldolase B
This patient has hereditary fructose intolerance, an autosomal recessive disorder caused by a deficiency of aldolase B. Upon ingestion of fructose, fructose-1-phosphate accumulates, which depletes intracellular phosphate stores and inhibits glycogenolysis and gluconeogenesis, leading to severe hypoglycemia and liver damage. Fructokinase deficiency (essential fructosuria) is a benign condition.
- This patient's condition is caused by a deficiency of an enzyme primarily responsible for which process in skeletal muscle?
Answer: Glycogenolysis
This patient has McArdle disease (Glycogen Storage Disease Type V), an autosomal recessive disorder caused by a deficiency of myophosphorylase (muscle glycogen phosphorylase). This enzyme is the first step in muscle glycogenolysis. The inability to break down muscle glycogen for energy during intense exercise leads to cramps and rhabdomyolysis. The 'second wind' phenomenon is due to increased blood flow delivering glucose and fatty acids to the muscle.
- This disorder is caused by a deficiency in which of the following enzymes?
Answer: Branched-chain α-ketoacid dehydrogenase
This infant has Maple Syrup Urine Disease (MSUD), an autosomal recessive disorder caused by a deficiency in the branched-chain α-ketoacid dehydrogenase complex. This enzyme is required for the degradation of the branched-chain amino acids (leucine, isoleucine, and valine), leading to their accumulation and the characteristic sweet-smelling urine.
- This patient's progressive neurologic decline is caused by a deficiency in which enzyme?
Answer: Arylsulfatase A
The clinical presentation of progressive motor and cognitive decline with demyelination, combined with elevated urine sulfatides, is characteristic of metachromatic leukodystrophy. This autosomal recessive lysosomal storage disease is caused by a deficiency of arylsulfatase A. The deficiency leads to the accumulation of sulfatides, which are toxic to the oligodendrocytes and Schwann cells that produce myelin.
- Which of the following amino acids becomes essential for this patient?
Answer: Tyrosine
This patient has classic phenylketonuria (PKU), caused by a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Since the body can no longer synthesize tyrosine from phenylalanine, tyrosine becomes an essential amino acid and must be supplied in the diet. Phenylalanine is the amino acid that accumulates and must be restricted. Tryptophan and methionine are unrelated essential amino acids.
- This neurodegenerative disorder is caused by the accumulation of which of the following substances due to an enzyme deficiency?
Answer: GM2 ganglioside
This is a classic presentation of Tay-Sachs disease, a lysosomal storage disorder caused by a deficiency of the enzyme hexosaminidase A. This deficiency leads to the accumulation of GM2 ganglioside, primarily in the neurons of the central nervous system. The lack of hepatosplenomegaly helps distinguish it from Niemann-Pick disease, which can also present with a cherry-red spot.
- A deficiency of which of the following enzymes is responsible for this patient's condition?
Answer: Homogentisate oxidase
The patient's presentation of ochronosis (dark pigment deposition in connective tissue), debilitating arthritis, and urine that darkens upon exposure to air is classic for alkaptonuria. This autosomal recessive disorder is caused by a deficiency of homogentisate oxidase, leading to the accumulation of homogentisic acid.
- A deficiency of which of the following enzymes is the most common cause of this condition?
Answer: Cystathionine β-synthase
The combination of marfanoid habitus, ectopia lentis (lens dislocation, typically downward), intellectual disability, and thromboembolism is characteristic of classic homocystinuria. This autosomal recessive disorder is most commonly caused by a deficiency of cystathionine β-synthase, which requires pyridoxine (vitamin B6) as a cofactor. The deficiency leads to an accumulation of homocysteine and its precursor, methionine.
