Inborn errors of metabolism
| Inborn errors of metabolism | |
|---|---|
| Specialty | Medical genetics  |
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.
The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857–1936), in the early 20th century (1908). He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on 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
- Disorders of amino acid metabolism
- Disorders of organic acid metabolism (organic acidurias)
- E.g., alcaptonuria
- Disorders of fatty acid oxidation and mitochondrial metabolism
- E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)
- Disorders of porphyrin metabolism
- Disorders of purine or pyrimidine metabolism
- E.g., Lesch-Nyhan syndrome
- Disorders of steroid metabolism
- Disorders of mitochondrial function
- E.g., Kearns-Sayre syndrome
- Disorders of peroxisomal function
- E.g., Zellweger syndrome
- Lysosomal storage disorders
- E.g., Gaucher's disease
- E.g., Niemann Pick disease
Incidence
In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 70 per 100,000 live births or 1 in 1,400 births,[1] overall representing more than approximately 15% of single gene disorders in the population.[1]
| Type of inborn error | Incidence | |
|---|---|---|
| Disease involving amino acids (e.g. PKU), organic acids, primary lactic acidosis, galactosemia, or a urea cycle disease |
24 per 100 000 births[1] | 1 in 4,200[1] |
| Lysosomal storage disease | 8 per 100 000 births[1] | 1 in 12,500[1] |
| Peroxisomal disorder | ~3 to 4 per 100 000 of births[1] | ~1 in 30,000[1] |
| Respiratory chain-based mitochondrial disease | ~3 per 100 000 births[1] | 1 in 33,000[1] |
| Glycogen storage disease | 2.3 per 100 000 births[1] | 1 in 43,000[1] |
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
Diagnostic techniques
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. There is a revolutionary GC/MS based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 genetic metabolic disorders.
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) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectroscopy (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, GC/MS or DNA Testing.
- Quantitative measurement of amino acids in plasma and urine
- Urine organic acid analysis by Gas chromatography-mass spectrometry
- Plasma acylcarnitines analysis by mass spectrometry
- Urine purines and pyrimidines analysis by Gas chromatography-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
Treatment
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 past twenty years, enzyme replacement, gene transfer, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies 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
- E.g., oral ingestion of cornstarch several times a day helps prevent people with glycogen storage diseases from becoming seriously hypoglycemic.
- Vitamins
- E.g., thiamine supplementation benefits several types of disorders that cause lactic acidosis.
- Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
- Dialysis
- Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease
- Gene transfer
- Bone marrow or organ transplantation
- Treatment of symptoms and complications
- Prenatal diagnosis and avoidance of pregnancy or abortion of an affected fetus
Resources
For clinicians and scientists in the field of inborn errors of metabolism, good resources include books by Scriver,[2] Fernandes,[3] Clarke,[4] Blau (diagnosis),[5] Blau (treatment),[6] Lyon,[7] Nyhan,[8] Hoffmann,[9] and Zschocke.[10] Other resources include genetests, orphanet, OMIM, Metab-L, societies such as the SSIEM, the SIMD and links therein. For medical students and clinicians looking for overviews of the field, such reviews can be found on pubmed and in good pediatric textbooks (e.g. articles by Saudubray,[11] Ellaway,[12] Raghuveer[13] or Burton,[14] and textbooks by Hay[15] or Behrman[16]).
For patients, their families or other individuals seeking good information and support groups, the National Institutes of Health offers the office of rare diseases, genetics home reference, medlineplus and health information. The National Human Genome Research Institute hosts an information center, a section for patients and the public and additional educational resources. Support groups can be found at NORD, Genetic Alliance and Orphanet. The genetic education center at the KUMC has many more useful links.
References
- ^ a b c d e f g h i j k l Applegarth DA, Toone JR, Lowry RB (2000). "Incidence of inborn errors of metabolism in British Columbia, 1969-1996". Pediatrics. 105 (1): e10. doi:10.1542/peds.105.1.e10. PMID 10617747.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Charles Scriver, Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (accessed 2007). The Online Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill. - Summaries of 255 chapters, full text through many universities. There is also the OMMBID blog.
- ^
Fernandes, J. (2006). Inborn Metabolic Diseases : Diagnosis and Treatment (4th ed.). Springer. p. 561 p.
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Clarke, J.T.R. (2005). A Clinical Guide to Inherited Metabolic Diseases (3rd ed.). Cambridge: Cambridge University Press. p. 358 p. doi:10.2277/0521614996. ISBN 978-0521614993.
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Blau, N. (2002). Physician's Guide to the Laboratory Diagnosis of Metabolic Diseases (2nd ed.). Springer. p. 716 p. ISBN 978-3-540-42542-7.
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Blau, N (2006). Physician's Guide to the Treatment And Follow-up of Metabolic Diseases (1st ed.). Springer. p. 416 p. ISBN 3-540-22954-X.
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Lyon, G. (2006). Neurology of Hereditary Molecular & Metabolic Disease of Children (3rd ed.). McGraw-Hill Professional. p. 500p.
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Nyhan, W.L. (2005). Atlas of Metabolic Diseases (2nd ed.). Oxford University Press. p. 800 p.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^
Hoffmann, G.F (2001). Inherited Metabolic diseases. Lippincott Williams & Wilkins. p. 448 p.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^
Zschocke, J (2004). Vademecum Metabolicum (2nd ed.). Schattauer GmbH. p. 176 p.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Saudubray J, Sedel F, Walter J (2006). "Clinical approach to treatable inborn metabolic diseases: an introduction". J Inherit Metab Dis. 29 (2–3): 261–74. doi:10.1007/s10545-006-0358-0. PMID 16763886.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Ellaway C, Wilcken B, Christodoulou J (2002). "Clinical approach to inborn errors of metabolism presenting in the newborn period". J Paediatr Child Health. 38 (5): 511–7. doi:10.1046/j.1440-1754.2002.00047.x. PMID 12354271.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Raghuveer T, Garg U, Graf W (2006). "Inborn errors of metabolism in infancy and early childhood: an update". Am Fam Physician. 73 (11): 1981–90. PMID 16770930.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Burton B (1998). "Inborn errors of metabolism in infancy: a guide to diagnosis". Pediatrics. 102 (6): E69. doi:10.1542/peds.102.6.e69. PMID 9832597.
- ^
Hay, W.H., Jr. (2006). Current Pediatric Diagnosis and Treatment (18th ed.). McGraw-Hill. p. 1306 p.
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Behrman, R.E. (2004). Nelson Textbook of Pediatrics (17th ed.). Elsevier. p. 2672 p.
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