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Inborn error of metabolism

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. more...

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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
    • E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0)
  • Disorders of organic acid metabolism
    • 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


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Folic acid supplementation during pregnancy may reduce risk of Down's syndrome
From Dynamic Chiropractic, 7/14/03 by Meschino, James

It is well-established that folic acid supplementation during pregnancy is associated with a significantly lower risk of having a child with a neural-tube defect (NTD; e.g., spina bifida, anencephaly). However, a recent study in The Lancet (2003; 361 [9366]:1331-5) provides evidence that folic acid supplementation also is associated with reduced risk of Down's syndrome. Researchers compared medical data from approximately 490 families at high risk for NTD with data from 516 families at high risk for Down's syndrome, and discovered that Down's syndrome was much more prevalent in pregnancies involving families at high risk for NTD. The evidence suggests that mothers of children with Down's syndrome experience an abnormal metabolism of folate and methyl, as well as mutations in their folate gene. These traits are also seen in infants affected by NTD.

Folate (folic acid, a B vitamin) is unique in that it contains a methyl group (CH^sub 3^), which it donates to homocysteine to permit its enzymatic conversion to methionine. Once formed within the cells of the body, methionine (a methyl-containing amino acid) extracts the adenosine ring from adenosine triphosphate (ATP) and becomes S-adenosyl methionine (SAMe). SAMe is then able to donate its methyl group (originally derived from folate) to many biochemical reactions, ineluding the synthesis of DNA bases. Consequently, DNA synthesis requires a constant, adequate supply of folate on a daily basis.

During pregnancy, the rapid rate of fetal cell division demands an even greater supply of folic acid; if the demand is not met, DNA defects occur, which most often manifest as neural-tube defects. Evidence from the Lancet study suggests the same may be true for Down's syndrome. To complicate matters, some individuals have an inborn error of folate or methyl metabolism, in that they show a defect in the enzyme that converts homocysteine to methionine, and thus produce insufficient amounts of SAMe. However, studies show that these individuals can improve the conversion of homocysteine to methionine significantly if they are provided with higher supplementation levels of folic acid (which is the coenzyme for this reaction) in many cases. Therefore, mothers identified as high-risk for NTD usually express this type of folate or methyl defect and are prescribed higher supplemental levels of folic acid. The Lancet study provides evidence that these women are also at higher risk for delivering a child with Down's syndrome, indicating that higher folic-acid supplementation may be of great importance in reducing the risk of NTD and Down's syndrome.

The researchers conclude that because of the links in the development of the two complications, folate supplementation before conception has the potential to reduce NTD and Down's syndrome during pregnancy. Most women would benefit from 400 meg of folic acid prior to conception (most multiple vitamins contain this amount) and 800 meg during pregnancy (the amount contained in prenatal vitamins). Women with folate or methyl metabolism problems require additional amounts of supplemental folic acid, which should be prescribed by their attending physicians or specialists, who can best monitor the appropriate biomarkers.


NNFA Supplement (April 28, 2003).

James Meschino, DC, MS. Dr. Meschino's articles, a "Talk Back" forum and a brief biography of the author are available online at

Copyright Dynamic Chiropractic Jul 14, 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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