Carnosinemia

Infobox_Disease
Name = PAGENAME

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Caption = Carnosine
DiseasesDB = 29672
ICD10 = ICD10|E|70|8|e|70
ICD9 = ICD9|270.5
ICDO =
OMIM = 212200
MedlinePlus =
eMedicineSubj =
eMedicineTopic =
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Carnosinemia, also called carnosinase deficiencyOMIM|212200] or aminoacyl-histidine dipeptidase deficiency, [DiseasesDB|29672] is a rare autosomal recessivecite journal |author=Willi SM, Zhang Y, Hill JB, Phelan MC, Michaelis RC, Holden KR |title=A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency |journal=Pediatr Res. |volume=41 |issue=2 |pages=210–213 |year=1997 |pmid=9029640 |doi=10.1203/00006450-199702000-00009 ] metabolic disordercite journal |author=Perry TL, Hansens S, Tischler B, Bunting R, Perry K |title=Carnosinemia. A new metabolic disorder associated with neurological disease and mental defect |journal=New Engl J Med. |volume=277 |issue=23 |pages=1219–1227 |year=1967 |pmid=6058610 ] caused by a deficiency of "carnosinase", a dipeptidase (a type of enzyme that splits dipeptides into their two amino acid constituents).cite journal |author=Sauerheifer S, Yuan G, Braun GS, Deiner RM, Neumaier M, Gretz N, Floege J, Kriz R, van der Woude F, Moeller MJ|title=L-carnosine, a substrate of carnosinase-1, influences glucose metabolism |journal=Diabetes |volume=56 |issue=10 |pages=2425–2432 |year=2007 |pmid=17601992 |doi=10.2337/db07-0177 ]

Carnosine is a dipeptide composed of beta-alanine and histidine, and is found in skeletal muscle and cells of the nervous system.cite journal |author=Rashid I, van Reyk DM, Davies MJ |title=Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro |journal=FEBS Lett. |volume=581 |issue=5 |pages=1067–1070 |year=2007 |pmid=17316626 |doi=10.1016/j.febslet.2007.01.082 ] This disorder results in an excess of carnosine in the urine, cerebrospinal fluid (CSF), blood and nervous tissue.cite journal |author=Gjessing LR, Lunde HA, Morkrid L, Lenney JF, Sjaastad O |title=Inborn errors of carnosine and homocarnosine metabolism |journal=J Neurol Transm Suppl. |volume=29 |issue= |pages=91–106 |year=1990 |pmid=2358806 ] Neurological disorders associated with a deficiency of carnosinase, and the resulting carnosinemia ("carnosine in the blood") are common.cite journal |author=Terplan KL, Cares HL |title=Histopathology of the nervous system in carnosinase enzyme deficiency with mental retardation |journal=Neurology |volume=22 |issue=6 |pages=644–655 |year=1972 |pmid=4673339 ] cite journal |author=Wisniewski K, Fleisher L, Rassin D, Lassmann H |title=Neurological diseases in a child with carnosinase deficiency |journal=Neuropediatrics |volume=12 |issue=2 |pages=143–151 |year=1981 |pmid=7266778 ]

Enzymology

Carnosinase in humans has two forms:cite journal |author=Jackson MC, Kucera CM, Lenney JF |title=Purification and properties of human serum carnosinase |journal=Clin Chim Acta. |volume=196 |issue=2-3 |pages=193–205 |year=1991 |pmid=1903095 |doi=10.1016/0009-8981(91)90073-L ] cite journal |author=Lenney JF, Peppers SC, Kucera-Orallo CM, George RP |title=Characterization of human tissue carnosinase |journal=Biochem J. |volume=228 |issue=3 |pages=653–660 |year=1985 |pmid=4026801 ] cite journal |author=Lenney JF |title=Separation and characterization of two carnosine-splitting cytosolic dipeptides from hog kidney (carnosinase and non-specific dipeptidase) |journal=Biol Chem Hoppe Seyler |volume=371 |issue=5 |pages=433–440 |year=1990 |pmid=2378680 ] cite journal |author=Lenney JF, George RP, Weiss AM, Kucera CM, Chan PW, Rinz GS |title=Human serum carnosinase: characterization, distinction from cellular carnosinase and activation by cadmium |journal=Clin Chim Acta. |volume=123 |issue=3 |pages=221–231 |year=1982 |pmid=7116644 |doi=10.1016/0009-8981(82)90166-8 ]

1. Cellular, or tissue carnosinase. 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. Tissue carnosinase is often considered a "non-specific dipeptidase",cite journal |author=Peppers SC, Lenney JF |title=Bestatin inhibition of human tissue carnosinase, a non-specific cytosolic dipeptidase |journal=Biol Chem Hoppe Seyler. |volume=369 |issue=12 |pages=1281–1286 |year=1988 |pmid=3242551 ] based in part on its ability to hydrolyze a range of dipeptide substrates, including those belonging to prolinase.cite journal |author=Lenney JF |title=Human cytosolic carnosinase: evidence of identity with prolinase, a non-specific dipeptidase |journal=Biol Chem Hoppe Seyler. |volume=371 |issue=2 |pages=167–171 |year=1990 |pmid=2334521 ]

2. Serum carnosinase. 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.cite journal |author=van Heeswijk PJ, Trijbels JM, Schretlen ED, van Munster PJ, Monnens LA |title=A patient with a deficiency of serum-carnosinase activity |journal=Acta Paediatr Scand. |volume=58 |issue=6 |pages=584–592 |year=1969 |pmid=5378348 |doi=10.1111/j.1651-2227.1969.tb04766.x ] Serum carnosinase is a glycoprotein, and splits free carnosine and anserine in the blood. This form of the dipeptidase is not found in human blood until late infancy, slowly rising to adult levels by age 15. Unlike tissue carnosinase, serum carnosinase also hydrolyzes the GABA metabolite homocarnosine. 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.cite journal |author=Lenney JF, Peppers SC, Kucera CM, Sjaastad O |title=Homocarnosinosis: lack of serum carnosinase is the deficiency probably responsible for elevated brain and CSF homocarnosine |journal=Clin Chim Acta. |volume=132 |issue=2 |pages=157–165 |year=1983 |pmid=6616870 |doi=10.1016/0009-8981(83)90243-7 ]

A deficiency of tissue and serum carnosinase, with serum being an indicator, is the underlying metabolic cause of carnosinemia.

ymptoms

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.

Genetics

The gene for carnosinase is located on chromosome 18, an autosome. The "carnosine dipeptidase-1" gene ("CNDP1") controls tissue and serum carnosinase.cite journal |author=Zschocke J, Nebel A, Wicks K, Peters V, El Mokhtari NE, Krawczak M, van der Woude F, Janssen B, Schreiber S |title=Allelic variation in the CNDP1 gene and its lack of association with longevity and coronary heart disease |journal=Mech Ageing Dev. |volume=127 |issue=11 |pages=817–820 |year=2006 |pmid=16965804 |doi=10.1016/j.mad.2006.08.002 ] Mutations in "CNDP1" are responsible for carnosinase deficiency, resulting in carnosinemia.

Carnosinemia is an autosomal recessive disorder, 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.

References

ee also

*Hyperprolinemia
*Histidinemia
*Proline
*Inborn errors of metabolism