Carnosinemia

Carnosinemia
Synonyms	Carnosinase deficiency<ref name=omim>Online Mendelian Inheritance in Man (OMIM) 212200 </ref> or Aminoacyl-histidine dipeptidase deficiency,<ref>DDB 29672 </ref>
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Carnosinemia, is a rare autosomal recessive<ref name=chroc>,

 A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency, 
 Pediatr. Res., 
 1997,
 Vol. 41(Issue: 2),
 pp. 210–213,
 DOI: 10.1203/00006450-199702000-00009,
 PMID: 9029640,</ref> metabolic disorder<ref name=ce>, 
 Carnosinemia. A new metabolic disorder associated with neurological disease and mental defect, 
 N. Engl. J. Med., 
 1967,
 Vol. 277(Issue: 23),
 pp. 1219–1227,
 DOI: 10.1056/NEJM196712072772302,
 PMID: 6058610,</ref> caused by a deficiency of carnosinase', a dipeptidase (a type of enzyme that splits dipeptides into their two amino acid constituents).<ref name=lcarn>, 
 L-carnosine, a substrate of carnosinase-1, influences glucose metabolism, 
 Diabetes, 
 2007,
 Vol. 56(Issue: 10),
 pp. 2425–2432,
 DOI: 10.2337/db07-0177,
 PMID: 17601992,</ref>

Carnosine is a dipeptide composed of beta-alanine and histidine, and is found in skeletal muscle and cells of the nervous system.<ref name=carny>,

 Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro, 
 FEBS Lett., 
 2007,
 Vol. 581(Issue: 5),
 pp. 1067–1070,
 DOI: 10.1016/j.febslet.2007.01.082,
 PMID: 17316626,</ref> This disorder results in an excess of carnosine in the urine, cerebrospinal fluid, blood, and nervous tissue.<ref name=iech>, 
 Inborn errors of carnosine and homocarnosine metabolism, 
 J Neural Transm Suppl, 
 1990,
 Vol. 29,
 pp. 91–106,
 DOI: 10.1007/978-3-7091-9050-0_10,
 PMID: 2358806,</ref> Neurological disorders associated with a deficiency of carnosinase, and the resulting carnosinemia ("carnosine in the blood") are common.<ref name=chroc/><ref name=histop>, 
 Histopathology of the nervous system in carnosinase enzyme deficiency with mental retardation, 
 Neurology, 
 1972,
 Vol. 22(Issue: 6),
 pp. 644–655,
 DOI: 10.1212/wnl.22.6.644,
 PMID: 4673339,</ref><ref name=neurp>, 
 Neurological diseases in a child with carnosinase deficiency, 
 Neuropediatrics, 
 1981,
 Vol. 12(Issue: 2),
 pp. 143–151,
 DOI: 10.1055/s-2008-1059647,
 PMID: 7266778,</ref>

Symptoms

A variety of neurological symptoms have been associated with carnosinemia. They include: hypotonia, developmental delay, mental retardation, degeneration of axons, sensory neuropathy, tremors, demyelinization, gray matter anomalies, myoclonic seizures, and loss of purkinje fibers.<ref name=chroc/><ref name=ce/><ref name=histop/><ref name=neurp/>

Genetics

Carnosinemia has an autosomal recessive pattern of inheritance.

The gene for carnosinase is located on chromosome 18,<ref name=chroc/> an autosome. The carnosine dipeptidase-1 gene (CNDP1) controls tissue and serum carnosinase.<ref name=cndp1>,

 Allelic variation in the CNDP1 gene and its lack of association with longevity and coronary heart disease, 
 Mech Ageing Dev., 
 2006,
 Vol. 127(Issue: 11),
 pp. 817–820,
 DOI: 10.1016/j.mad.2006.08.002,
 PMID: 16965804,</ref> Mutations in CNDP1 are  responsible for carnosinase deficiency, resulting in carnosinemia.<ref name=chroc/>

Carnosinemia is an autosomal recessive disorder,<ref name=chroc/> which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.

Diagnosis

Types

Carnosinase in humans has two forms:<ref name=purc>,

 Purification and properties of human serum carnosinase, 
 Clin Chim Acta, 
 1991,
 Vol. 196(Issue: 2–3),
 pp. 193–205,
 DOI: 10.1016/0009-8981(91)90073-L,
 PMID: 1903095,</ref><ref name=charc>, 
 Characterization of human tissue carnosinase, 
 Biochem. J., 
 1985,
 Vol. 228(Issue: 3),
 pp. 653–660,
 DOI: 10.1042/bj2280653,
 PMID: 4026801,
 PMC: 1145034,</ref><ref name=sepc>Lenney JF, 
 Separation and characterization of two carnosine-splitting cytosolic dipeptides from hog kidney (carnosinase and non-specific dipeptidase), 
 Biol Chem Hoppe-Seyler, 
 1990,
 Vol. 371(Issue: 5),
 pp. 433–440,
 DOI: 10.1515/bchm3.1990.371.1.433,
 PMID: 2378680,</ref><ref name=humc>, 
 Human serum carnosinase: characterization, distinction from cellular carnosinase and activation by cadmium, 
 Clin Chim Acta, 
 1982,
 Vol. 123(Issue: 3),
 pp. 221–231,
 DOI: 10.1016/0009-8981(82)90166-8,
 PMID: 7116644,</ref>

1. Cellular, or tissue carnosinase:<ref name=charc/> This form of the enzyme is found in every bodily tissue. It is a dimer, and hydrolyzes both carnosine and anserine, preferring dipeptides that have a histidine monomer in the C-terminus position.<ref name=purc/><ref name=charc/> Tissue carnosinase is often considered a "nonspecific dipeptidase",<ref name=sepc/><ref name=besti>,

 Bestatin inhibition of human tissue carnosinase, a non-specific cytosolic dipeptidase, 
 Biol Chem Hoppe-Seyler, 
 1988,
 Vol. 369(Issue: 12),
 pp. 1281–1286,
 DOI: 10.1515/bchm3.1988.369.2.1281,
 PMID: 3242551,</ref> based in part on its ability to hydrolyze a range of dipeptide substrates, including those belonging to prolinase.<ref name=cpro>Lenney JF, 
 Human cytosolic carnosinase: evidence of identity with prolinase, a non-specific dipeptidase, 
 Biol Chem Hoppe-Seyler, 
 1990,
 Vol. 371(Issue: 2),
 pp. 167–171,
 DOI: 10.1515/bchm3.1990.371.1.167,
 PMID: 2334521,</ref>

2. Serum carnosinase:<ref name=humc/> This is the carnosinase found in the blood plasma. Deficiency of this form of carnosinase, along with carnosinuria ("carnosine in the urine"), is the usual metabolic indicator of systemic carnosinase deficiency.<ref name=chroc/><ref name=histop/><ref name=c69>,

 A patient with a deficiency of serum-carnosinase activity, 
 Acta Paediatr. Scand., 
 1969,
 Vol. 58(Issue: 6),
 pp. 584–592,
 DOI: 10.1111/j.1651-2227.1969.tb04766.x,
 PMID: 5378348,</ref> Serum carnosinase is a glycoprotein, and splits free carnosine and anserine in the blood.<ref name=purc/> This form of the dipeptidase is not found in human blood until late infancy, slowly rising to adult levels by age 15.<ref name=humc/> Unlike tissue carnosinase, serum carnosinase also hydrolyzes the GABA metabolite homocarnosine.<ref name=purc/> Homocarnosinosis, a neurological disorder resulting in an excess of homocarnosine in the brain, though unaffected by tissue carnosinase, is caused by a deficiency of serum carnosinase in its ability to hydrolyze homocarnosine.<ref name=hco>, 
 Homocarnosinosis: lack of serum carnosinase is the deficiency probably responsible for elevated brain and CSF homocarnosine, 
 Clin Chim Acta, 
 1983,
 Vol. 132(Issue: 2),
 pp. 157–165,
 DOI: 10.1016/0009-8981(83)90243-7,
 PMID: 6616870,</ref>

A deficiency of tissue and serum carnosinase, with serum being an indicator, is the underlying metabolic cause of carnosinemia.<ref name=iech/><ref name=neurp/>

See also

• Histidinemia
• Hyperprolinemia
• Inborn errors of metabolism
• Proline

External links

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