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.

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, [http://www.esp.org/books/garrod/inborn-errors/facsimile/ 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
E.g., phenylketonuria , maple syrup urine disease, glutaric acidemia type 1
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
E.g., acute intermittent porphyria
Disorders of purine or pyrimidine metabolism
E.g., Lesch-Nyhan syndrome
Disorders of steroid metabolism
E.g., congenital adrenal hyperplasia
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

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

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).
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

Newborn screening

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 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., cornstarch several times a day helps prevent people with glycogen storage disease from becoming hypoglycemic as quickly.
Vitamins
E.g., thiamine supplementation benefits several types of lactic acidosis.
Intermediary metabolites, compounds, or drugs that facilitate or retard specific metabolic pathways
Dialysis
Enzyme replacement Eg. Acid-alpha glucosidase for Pompe's 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

Translation of "Inborn error of metabolism"

Spanish: Error congénito del metabolismo, French: Maladie métabolique génétique, Lithuanian: Paveldimos metabolinės ligos, Polish: Wrodzone błędy metabolizmu, Portuguese: Erros metabólicos hereditários, Russian: Метаболические заболевания, Turkish: Doğuştan metabolizma bozuklukları.