Inborn errors of metabolism

Inborn errors of metabolism
Specialty	Medical genetics

Inborn errors of metabolism form a large class of genetic diseases involving disorders of metabolism and are congenital. 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.

Categories

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.

• Disorders of carbohydrate metabolism
  • E.g., glycogen storage disease, glucosemia
• Disorders of amino acid metabolism
  • E.g., phenylketonuria, maple syrup urine disease, glutaric acidemia type 1
• Urea Cycle Disorder or Urea Cycle Defects
  • E.g., Carbamoyl phosphate synthetase I deficiency
• 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
  • E.g., acute intermittent porphyria
• Disorders of purine or pyrimidine metabolism
  • E.g., Lesch-Nyhan syndrome
• Disorders of steroid metabolism
  • E.g., lipoid congenital adrenal hyperplasia, 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

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

Diagnosis

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, 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

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 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
  • 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 therapy
• Bone marrow or organ transplantation
• Treatment of symptoms and complications
• Prenatal diagnosis

Epidemiology

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

External links

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.