Inborn error of metabolism
|Inborn error of metabolism|
|Classification and external resources|
Inborn errors of metabolism form a large class of genetic diseases involving congenital 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 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.
Traditionally the inherited metabolic diseases were classified 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.
- Disorders of carbohydrate metabolism
- E.g., glycogen storage disease
- Disorders of amino acid metabolism
- Urea Cycle Disorder or Urea Cycle Defects
- Disorders of organic acid metabolism (organic acidurias)
- Disorders of fatty acid oxidation and mitochondrial metabolism
- E.g., Medium-chain acyl-coenzyme A dehydrogenase deficiency (often shortened to MCADD.)
- 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
Signs and symptoms
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, low platelet count, low red blood cell count, enlarged spleen, enlarged lymph nodes
- Many forms of cancer
- Recurrent vomiting, diarrhea, abdominal pain
- Excessive urination, kidney failure, dehydration, edema
- Low blood pressure, heart failure, enlarged heart, hypertension, myocardial infarction
- Liver enlargement, 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
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 Gas chromatography–mass spectrometry-based technology with an integrated analytics system, which has now made it possible to test a newborn for over 100 mm 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 Spectrometry (MS/MS). This given an indication for a disorder. The same has to be further confirmed by enzyme assays, IEX-Ninhydrin, GC/MS or DNA Testing.
- Quantitative measurement of amino acids in plasma and urine
- IEX-Ninhydrin post column derivitization liquid ion-exchange chromatography (detected abnormal amino acid patterns and quantitative analysis)
- 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
A 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patient’s clinical course." 
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 therapy, 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
- Dietary supplementation or replacement
- Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
- Enzyme replacement E.g. Acid-alpha glucosidase for Pompe disease
- Gene therapy
- Bone marrow or organ transplantation
- Treatment of symptoms and complications
- Prenatal diagnosis
In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 1,400 births, overall representing more than approximately 15% of single gene disorders in the population.
|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 in 4,200|
|Lysosomal storage disease||8 per 100 000 births||1 in 12,500|
|Peroxisomal disorder||~3 to 4 per 100 000 of births||~1 in 30,000|
|Respiratory chain-based mitochondrial disease||~3 per 100 000 births||1 in 33,000|
|Glycogen storage disease||2.3 per 100 000 births||1 in 43,000|
- Archibald Garrod. 1923. Inborn Errors of Metabolism at Electronic Scholarly Publishing site
- Vernon, Hilary (Jun 2015). "Inborn Errors of Metabolism: Advances in Diagnosis and Therapy". JAMA Pediatrics.
- Applegarth DA, Toone JR, Lowry RB (January 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.
The National Institutes of Health offers the office of rare diseases, 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. Metab-L is a mailing list for professionals in the diagnosis, care and research on rare metabolic diseases. The genetic education center at the KUMC has many more useful links.