Metabolic Disorders

4 min read Updated Apr 18, 2026

A classic MCAT topic: given a patient with specific symptoms, identify the deficient enzyme or metabolic defect. Below are the most-tested disorders.

Diabetes Mellitus

Type 1 diabetes: autoimmune destruction of pancreatic beta cells. Absolute insulin deficiency. Early onset, thin patients, ketoacidosis-prone. Treatment: insulin replacement.

Type 2 diabetes: insulin resistance + relative insulin deficiency. Later onset, typically associated with obesity. Hyperglycemia without severe ketoacidosis (some insulin still present suppresses lipolysis). Treatment: lifestyle, metformin, eventually insulin.

Diabetic ketoacidosis (DKA): insulin absent → unopposed lipolysis and ketogenesis → acidosis, dehydration, hyperglycemia. Kussmaul respiration (deep, rapid breathing to exhale CO2), fruity breath (acetone), and altered mental status. Life-threatening if untreated.

PKU (Phenylketonuria)

Defect: phenylalanine hydroxylase.
Accumulation: phenylalanine → phenylpyruvate, phenyllactate.
Consequences: intellectual disability (damages developing brain), musty odor.
Treatment: low-phenylalanine diet (no aspartame), tyrosine supplementation. Newborn screening detects.

Galactosemia

Defect: galactose-1-phosphate uridyltransferase (GALT). Classic galactosemia.
Accumulation: galactose-1-phosphate → toxic to liver, brain, and kidneys.
Consequences: failure to thrive, jaundice, hepatomegaly, cataracts, intellectual disability.
Treatment: lactose- and galactose-free diet.

Glycogen Storage Diseases

Type	Enzyme deficient	Main findings
I (Von Gierke)	Glucose-6-phosphatase	Severe fasting hypoglycemia, hepatomegaly
II (Pompe)	Lysosomal alpha-glucosidase	Cardiomegaly, muscle weakness
III (Cori)	Debranching enzyme	Short outer branches, milder hypoglycemia
V (McArdle)	Muscle glycogen phosphorylase	Exercise intolerance, muscle cramps

Lysosomal Storage Diseases (Sphingolipidoses)

Tay-Sachs (hexosaminidase A): GM2 ganglioside, cherry-red macula.
Gaucher (glucocerebrosidase): most common, hepatosplenomegaly.
Niemann-Pick (sphingomyelinase): severe neurological form.
Fabry (alpha-galactosidase A): X-linked, angiokeratomas.

Other

Maple syrup urine disease: branched-chain α-ketoacid dehydrogenase deficiency. Sweet-smelling urine. Leu/Ile/Val accumulate.
Alkaptonuria: homogentisate oxidase deficiency. Dark urine on standing, arthritis.
Homocystinuria: cystathionine β-synthase deficiency. Marfanoid, lens dislocation, atherosclerosis.

What is the biochemical defect in phenylketonuria (PKU), and what accumulates?

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Phenylalanine hydroxylase (PAH) deficiency. PAH normally converts phenylalanine to tyrosine. Without it, phenylalanine accumulates. Excess Phe is converted to phenylpyruvate and phenyllactate, which damage the developing brain. Treatment: low-Phe diet and tyrosine supplementation. Newborn screening prevents the severe intellectual disability seen in untreated PKU.

Why does DKA occur almost exclusively in type 1 diabetes rather than type 2?

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Type 1 diabetes has absolute insulin deficiency. Without any insulin, adipose lipolysis is unopposed, fatty acids flood the liver, and ketogenesis runs full speed - producing the severe ketoacidosis. Type 2 patients usually retain some residual insulin, which is enough to suppress lipolysis and prevent full-blown DKA. In severe type 2 decompensation (HHS), hyperglycemia is severe but ketoacidosis is absent or mild.

Which glycogen storage disease causes severe fasting hypoglycemia and hepatomegaly?

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Von Gierke disease (Type I, glucose-6-phosphatase deficiency). Without G6Pase, neither glycogenolysis nor gluconeogenesis can produce free glucose for the blood. Glycogen and G6P accumulate in the liver (hepatomegaly). Fasting causes severe hypoglycemia because no pathway can deliver glucose to the blood. Also produces hyperuricemia and hyperlipidemia from intermediary metabolism being redirected.