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.
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
- Urea Cycle Disorder or Urea Cycle Defects
- Disorders of organic acid metabolism (organic acidurias)
- E.g., alcaptonuria
- 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
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, 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|
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: many manifestations may develop
- 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
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 Spectrometry (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
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 and avoidance of pregnancy or abortion of an affected fetus
Affects one in three adults
Affecting about 35 percent of all adults in the United States according to the CDC, metabolic syndrome contributes to weight gain, by causing a state of internal starvation called metabolic starvation. This in turn leads to increases hunger, sugar cravings and increased portions leading to overeating and weight gain.
Cause and effect misunderstood
Since we traditionally thought that the portion control (which in turn was attributed wrongly to poor will power)is the cause of weight gain, rather than the effect of this metabolic starvation, all our traditional ideas about cause and effect of obesity were not only wrong but lead to the “blame the victim” attitude when it comes to obesity.
Secret of weight gain revealed
Secret of weight gain, and metabolic syndrome revealed - it has been recently proven that metabolic syndrome, and the weight gain itself are caused by a process called insulin resistance. Check your metabolic syndrome risk using the free Metabolic syndrome meter. Watch this amazing Ted Med video that reveals the secret of weight loss - Stop blaming the victim for obesity
The National Institutes of Health offers theoffice of rare diseases, home reference, medlineplus andhealth information. The National Human Genome Research Institute hosts an information center, a section forpatients and the public and additionaleducational resources. Support groups can be found atNORD, Genetic Alliance and Orphanet. The genetic education center at the KUMC has many more useful links.
Template:Medical conditions Template:Carbohydrate metabolic pathology Template:Amino acid metabolic pathology Template:Fatty-acid metabolism disorders Template:Lipid metabolism disorders Template:Heme metabolism disorders Template:Inborn errors of purine-pyrimidine metabolism Template:Other metabolic pathology Template:Defects of steroid metabolism Template:Metabolic disorders of vitamins, coenzymes, and cofactors
|Policies / Guidelines||Social Media|
|Patient Resources / Community|
Evidence Based Medicine
|Healthcare Provider Resources|
|External:W8MD Weight Loss, Sleep & MedSpa||Wellness Topics A-Z||Other resources|
World's largest food, health, weight loss, wellnesspedia and encyclopedia
If you are a medical professional or an expert in any field of medicine, please join us in building the world's largest weight loss and wellness encyclopedia created by experts in the field, not by the crowd. WikiMD is sponsored by W8MD weight loss, sleep and medical aesthetic centers
W8MD Weight Loss, Sleep & Medical Aesthetic Centers
Since its inception in 2011, W8MD’s insurance physician weight loss program has successfully helped thousands of patients succeed in not only losing weight but also keep it off with an ongoing maintenance plan.
FANTASTIC PROGRAM. TRULY A LIFE CHANGER. D.M. LOST 100 LBS^^
^^Individual results may vary.
W8MD weight loss, sleep and medical spa blogs
Support our sponsors
W8MD weight loss, sleep and medspa centers sponsors WikiMD.
W8MD's Locations for losing weight, sleeping better and looking your best
King of Prussia
Other W8MD blogs