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Metabolic Disease

Major Classes Of Metabolic Disorders

Cells are constructed from four major types of molecules: carbohydrates, proteins, fats, and nucleic acids. The metabolic pathways involving each are

Disease	Defective Enzyme or System	Symptoms	Treatment
Disorders of Amino Acid Metabolism
Phenylketonuria (PKU)	phenylalanine hydroxylase	severe mental retardation	screening; dietary modification
Malignant PKU	biopterin cofactor	neurological disorder	—
Type 1 tyrosinemia	fumarylacetoacetate hydrolase	nerve damage, pain, liver failure	liver transplantation; preceding enzyme inhibitor plus dietary modification
Type 2 tyrosinemia	tyrosine aminotransferase	irritation to the corneas of the eyes	diet with reduced phenylalanine and tyrosine content
Alkaptonuria	disorder of tyrosine breakdown	progressive arthritis and bone disease; dark urine	—
Homocystinuria and Hyperhomocysteinemia	cystathionine-β-synthase or methylenetetrahydrofolate reductase or various deficiencies in formation of the methylcobalamin form of vitamin B₁₂	hypercoagulability of the blood; vascular eposides; dislocation of the lens of the eye, elongation and thinning of the bones, and often mental retardation or psychiatric abnormalities	vitamin B₁₂, folic acid, betaine, a diet limited in cysteine and methionine
Maple Syrup Urine disease	branched-chain ketoacid dehydrogenase complex	elevations of branched-chain amino acids, characteristic odor of the urine, episodes of ketoacidosis, death	thiamine; careful regulation of dietary intake of the essential branched-chain amino acids
Disorders of Organic Acid Metabolism
Propionic Acidemia	propionyl-CoA carboxylase	generalized metabolic dysfunction; ketoacidosis; death	diet with limited amounts of the amino acids which are precursors to propionyl-CoA
Multiple Carboxylase deficiency	pyruvate carboxylase and 3-methylcrotonyl-CoA carboxylase	—	biotin
Methylmalonic Acidemia	methylmalonyl-CoA mutase; defects in the enzyme systems involved in vitamin B₁₂ metabolism	—	supplementation with large doses of vitamin B₁₂; diet
Disorders of Fatty Acid Metabolism
Hyperlipidemia and hypercholesterolemia	regulation or utilization of lipoproteins	cardiovascular disease	dietary modifications and use of drugs that inhibit fatty acid synthesis.
Fatty Acid Oxidation disorders	very long chain acyl-CoA dehydrogenase; long chain hydroxyacyl-CoA dehydrogenase; dehydrogenase; medium chain acyl-CoA dehydrogenase; short chain acyl CoA dehydrogenase; short chain hydroxyacyl-CoA dehydrogenase	low blood sugar (hypoglycemia); muscle weakness; cardiomyopathy	avoidance of fasting, intravenous glucose solutions; carnitine; medium chain triglycerides
Glycogen Storage diseases	defects in glycogenolysis	liver enlargement or damage; muscle weakening or breakdown; disturbed renal tubular function; risk of brain damage	—
Galactosemia	galactose-1-phosphate uridyl transferase	liver failure in infancy	newborn screening; milk avoidance
Congenital Disorders of Glycosylation	defects in the enzymes that build the carbohydrate side-chains on proteins	quite variable; multisystem	—
Disorders of Purine and Pyrimidine Metabolism
Purine Overproduction	imbalance between purine synthesis and disposal	gout	—
Lesch-Nyhan syndrome	hypoxanthine phosphoribosyl-transferase	defective salvage of purines; increase in the excretion ofuricacid; brain neurotransmitter dysfunction; severe spastic movement disorder; self-injurious behavior	allopurinol (does not treat neurological symptoms)
Lysosomal Storage Disorders
Gaucher disease Types I and II	cerebrosidase	enlargement of the spleen and liver; painful and crippling effects on the bones; severe brain disease and death (Type II)	enzyme replacement (Type I)
Tay-Sachs disease	beta-hexosaminidase A	neurological disorders; enlarged head; death in early childhood	—
Table 1 (continued on next page).

Disease	Defective Enzyme or System	Symptoms	Treatment
Lysosomal Storage Disorders [CONTINUED]
Fabry disease	α-galactosidase	severe pain; renal failure; heart failure	enzyme replacement
Hurler syndrome, Hunter syndrome	α-iduronidase (Hurler syndrome);iduronate sultatase (Hunter syndrome) iduronate sultatase (hunter syndrome)	enlargement of the liver and spleen; skeletal deformities; coarse facial features; stiff joints; mental retardation; death within 5-15 years	enzyme replacement
Sanfilippo syndrome	enzymes for heparan sulfate degradation	enlargement of the liver and spleen	enzyme replacement
Maroteaux-Lamy syndrome	arylsulfatase B	progressive, crippling and life-threatening physical changes similar to Hurler syndrome, but generally with normal intellect	—
Morquio syndrome	galactose 6-sulfatase; β-galactosidase	truncal dwarfism; severe skeletal deformities; potentially life-threatening susceptibility to cervical spine dislocation; valvular heart disease	—
Disorders of Urea Formation
	carbamyl phosphate synthetase deficiency; ornithine transcarbamylase deficiency, citrullinemia, argininosuccinic aciduria	hyperammonemia; mental retardation; seizures; coma; death	limitation of dietary protein; phenylacetate; liver transplantation
Disorders of Peroxisomal Metabolism
Refsum disease	branched-chain fatty acid buildup	neurologic symptoms	—
Alanine-glyoxylate transaminase defect	alanine-glyoxylate transaminase	oxalic acid increase; organ dysfunction; renal failure	liver transplantation
Table 1, continued.

the basis for classification of many of the metabolic disorders. The mitochondria in cells are organelles that play a major role in most metabolic pathways, and mitochondrial disorders are one of the most significant and common types of metabolic disorders. Defects in the storage and disposal of molecules also give rise to metabolic disorders.

Carbohydrates are used primarily as fuel and can be built and broken down rapidly. The major storage form is glycogen. They are also added to proteins to make glycoproteins. Fatty acids are long-chain molecules that are used to construct membranes. Fatty acids are derived from dietary fats. Excess fat is used as fuel by mitochondria. Proteins are made of amino acids.

Humans must eat eight kinds of amino acids and then convert these into twelve other types to make the twenty amino acids found in our proteins. Excess amino acids in the diet are used for fuel by mitochondria. Along the way, they generate organic acids. Nucleic acids—DNA and RNA—are the molecules that store and process genetic information. They must be built from smaller units, called nucleotides. The storage and interconversion of different types of nucleotides assures a steady supply.

Below, representative disorders of each system are discussed. Other disorders are listed in Table 1. Many of the disease names end in "emia." This suffix indicates a blood disorder, and the names are derived from the fact that most metabolic disorders are diagnosed by detecting abnormal levels of intermediates or other substances in the blood.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 3Metabolic Disease - Enzymes Control Metabolic Reactions, Enzyme Defects Cause Metabolic Disorders, Approaches To Treatment, Major Classes Of Metabolic Disorders - Disorders of Amino Acid Metabolism, Disorders of Organic Acid Metabolism, Disorders of Fatty