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Introduction to Inherited Disorders of Metabolism

By

Matt Demczko

, MD, Sidney Kimmel Medical College of Thomas Jefferson University

Last full review/revision Apr 2020| Content last modified Apr 2020
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Most inherited disorders of metabolism (also called inborn errors of metabolism) are caused by mutations in genes that code for enzymes; enzyme deficiency or inactivity leads to

  • Accumulation of substrate precursors or metabolites or

  • Deficiencies of the enzyme’s products

Hundreds of disorders exist, and although most inherited disorders of metabolism are extremely rare individually, collectively they are not rare.

Inherited metabolic disorders are typically grouped by the affected substrate, for example:

Most states in the US routinely do neonatal screening Screening Tests for Newborns Screening recommendations for newborns vary by clinical context and state requirements. Blood typing is indicated when the mother has type O or Rh-negative blood or when minor blood antigens... read more of all newborns for specific inherited disorders of metabolism and other conditions, including phenylketonuria Phenylketonuria (PKU) Phenylketonuria is a disorder of amino acid metabolism that causes a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine... read more , tyrosinemia Tyrosine Metabolism Disorders Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more , biotinidase deficiency, homocystinuria Classic homocystinuria A number of defects in methionine metabolism lead to accumulation of homocysteine (and its dimer, homocystine) with adverse effects including thrombotic tendency, lens dislocation, and central... read more , maple syrup urine disease Maple syrup urine disease Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of enzymes involved in their metabolism leads to accumulation of organic acids with severe metabolic acidosis. There... read more , and galactosemia Galactosemia Galactosemia is a carbohydrate metabolism disorder caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive... read more . Many states have an expanded screening program that covers many more inherited disorders of metabolism, including disorders of fatty acid oxidation Overview of Fatty Acid and Glycerol Metabolism Disorders Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body’s energy needs... read more and other organic acidemias. For a comprehensive review of each of these conditions, see also the American College of Medical Genetics and Genomics' (ACMG) newborn screening ACT sheets and algorithms.

Metabolic defects that primarily cause disease in adults (eg, gout Gout Gout is a disorder caused by hyperuricemia (serum urate > 6.8 mg/dL [> 0.4 mmol/L]) that results in the precipitation of monosodium urate crystals in and around joints, most often causing recurrent... read more Gout , porphyria Overview of Porphyrias Porphyrias are rare disorders in which hemoglobin is abnormally metabolized due to genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies allow heme... read more ), are organ-specific (eg, Wilson disease Wilson Disease Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more Wilson Disease , congenital adrenal hyperplasia Overview of Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a group of genetic disorders, each characterized by inadequate synthesis of cortisol, aldosterone, or both. In the most common forms, accumulated hormone precursors... read more ), or are common (eg, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more Cystic Fibrosis , hemochromatosis Overview of Iron Overload Typical adults lose about 1 mg iron (Fe) per day in shed epidermal and gastrointestinal cells; menstruating females lose on average an additional 0.5 to 1 mg/day from menses. This iron loss... read more ) are discussed elsewhere in THE MANUAL. For inherited disorders of lipoprotein metabolism, see Table: Genetic (Primary) Dyslipidemias Genetic (Primary) Dyslipidemias Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis. Causes... read more Genetic (Primary) Dyslipidemias .

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