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Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases, and these terms are considered synonymous.
The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century. He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.
Major categories of inherited metabolic diseases
Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.
- Disorders of carbohydrate metabolism
- E.g., glycogen storage disease (E74.0)
- Disorders of amino acid metabolism
- Disorders of organic acid metabolism (organic acidurias)
- E.g., alcaptonuria (E70.2)
- Disorders of fatty acid oxidation and mitochondrial metabolism
- E.g., medium chain acyl dehydrogenase deficiency
- Disorders of porphyrin metabolism
- E.g., acute intermittent porphyria (E80.2)
- Disorders of purine or pyrimidine metabolism
- E.g., Lesch-Nyhan syndrome (E79.1)
- Disorders of steroid metabolism
- E.g., congenital adrenal hyperplasia (E25.0)
- Disorders of mitochondrial function
- E.g., Kearns-Sayre syndrome (H49.8)
- Disorders of peroxisomal function
- E.g., Zellweger syndrome (Q87.8)
- Lysosomal storage disorders
- E.g., Gaucher's disease (E75.22)
Manifestations and presentations
Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems:
- Growth failure, failure to thrive, weight loss
- Ambiguous genitalia, delayed puberty, precocious puberty
- Developmental delay, seizures, dementia, encephalopathy, stroke
- Deafness, blindness, pain agnosia
- Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
- Dental abnormalities
- Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
- Many forms of cancer
- Recurrent vomiting, diarrhea, abdominal pain
- Excessive urination, renal failure, dehydration, edema
- Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
- Hepatomegaly, jaundice, liver failure
- Unusual facial features, congenital malformations
- Excessive breathing (hyperventilation), respiratory failure
- Abnormal behavior, depression, psychosis
- Joint pain, muscle weakness, cramps
- Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus
Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.
Common screening tests used in the last sixty years:
- Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)
- Ninhydrin paper chromatography (detected abnormal amino acid patterns)
- Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood)
- Quantitative plasma amino acids, quantitative urine amino acids
- Urine organic acids by mass spectrometry
Specific diagnostic tests (or focused screening for a small set of disorders):
- Tissue biopsy or necropsy: liver, muscle, brain, bone marrow
- Skin biopsy and fibroblast cultivation for specific enzyme testing
- Specific DNA testing
Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially the expanded testing using mass spectrometry. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome.
In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the last two decades, enzyme replacement, gene transfer, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising are listed.
- Dietary restriction
- E.g., reduction of dietary protein remains a mainstay of treatment for phenylketonuria and other amino acid disorders.
- Dietary supplementation or replacement
- Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
- Enzyme replacement
- Gene transfer
- Bone marrow or organ transplantation
- Treatment of symptoms and complications
- Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus
More than most fields in medicine, this specialty has a single definitive, monumental text: The Metabolic and Molecular Bases of Inherited Disease, by Charles R. Scriver (Editor), William S. Sly (Editor), Barton Childs, Arthur L. Beaudet, David Valle, Kenneth W. Kinzler, Bert Vogelstein. New York:McGraw-Hill. 8th edition, 2001, 4 volumes, ISBN 0-07-913035-6
The most useful reference source on the web for these diseases is the Online Mendelian Inheritance database maintained by the National Library of Medicine.
Information on Cystinuria, one of Dr. Archibald Garrod's original Inborn Errors of Metabolism, can be found at the International Cystinuria Foundationhomepage.
fr:Maladie métabolique congénitale lt:Paveldimos metabolinės ligos
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