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Inherited metabolic diseases — when a single enzyme deficiency disrupts the chemistry of life. Early diagnosis transforms outcomes.
Inherited metabolic diseases (IMDs), also called inborn errors of metabolism, are a group of over 1,000 genetic disorders caused by defects in enzymes, transporters, or cofactors required for normal biochemical pathways. Individually rare, collectively they affect approximately 1 in 1,000 newborns.
The concept was introduced by Sir Archibald Garrod in 1908 with his description of alkaptonuria as a "chemical individuality" — one of the foundational insights of medical genetics.
PKU, maple syrup urine disease, homocystinuria, tyrosinemia. Detected by newborn screening. Diet-treatable in many cases.
Methylmalonic acidemia, propionic acidemia, isovaleric acidemia. Accumulation of toxic organic acids. Metabolic crises can be life-threatening.
MCADD, VLCADD, LCHAD. Impaired energy production from fat. Hypoketotic hypoglycemia during fasting. Avoidable with dietary management.
Gaucher, Fabry, Pompe, MPS disorders. Progressive accumulation of undegraded substrates. Many now treatable with enzyme replacement or substrate reduction therapy.
OTC deficiency, citrullinemia, ASA lyase deficiency. Hyperammonemia is the hallmark. Nitrogen scavenger therapy and sometimes liver transplant.
Mitochondrial disorders, glycogen storage diseases, congenital disorders of glycosylation. Affect virtually every organ system.
Next-generation sequencing has transformed IMD diagnosis. Gene panels covering 200-500 metabolic genes achieve diagnostic yields of 40-60% in suspected IMD patients. Whole exome and genome sequencing can identify novel genes and expand the phenotypic spectrum of known disorders. Combined metabolomic + genomic approaches (multi-omic diagnosis) are emerging as the most powerful strategy.