Carnosinemia
| Carnosinemia | |
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| Carnosine | |
| ICD-10 | E70.8 |
| ICD-9 | 270.5 |
| OMIM | 212200 |
| DiseasesDB | 29672 |
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Carnosinemia, also called carnosinase deficiency[1] or aminoacyl-histidine dipeptidase deficiency,[2] is a rare autosomal recessive[3] metabolic disorder[4] caused by a deficiency of carnosinase, a dipeptidase (a type of enzyme that splits dipeptides into their two amino acid constituents).[5]
Carnosine is a dipeptide composed of beta-alanine and histidine, and is found in skeletal muscle and cells of the nervous system.[6] This disorder results in an excess of carnosine in the urine, cerebrospinal fluid (CSF), blood and nervous tissue.[7] Neurological disorders associated with a deficiency of carnosinase, and the resulting carnosinemia ("carnosine in the blood") are common.[8][9][3]
Enzymology
Carnosinase in humans has two forms:[10][11][12][13]
1. Cellular, or tissue carnosinase.[11] 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.[10][11] Tissue carnosinase is often considered a "non-specific dipeptidase",[12][14] based in part on its ability to hydrolyze a range of dipeptide substrates, including those belonging to prolinase.[15]
2. Serum carnosinase.[13] 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.[16][3][8] Serum carnosinase is a glycoprotein, and splits free carnosine and anserine in the blood.[10] This form of the dipeptidase is not found in human blood until late infancy, slowly rising to adult levels by age 15.[13] Unlike tissue carnosinase, serum carnosinase also hydrolyzes the GABA metabolite homocarnosine.[10] 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.[17]
A deficiency of tissue and serum carnosinase, with serum being an indicator, is the underlying metabolic cause of carnosinemia.[7][9]
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.[3][4][8][9]
Genetics
The gene for carnosinase is located on chromosome 18,[3] an autosome. The carnosine dipeptidase-1 gene (CNDP1) controls tissue and serum carnosinase.[18] Mutations in CNDP1 are responsible for carnosinase deficiency, resulting in carnosinemia.[3]
Carnosinemia is an autosomal recessive disorder,[3] 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
- ↑ Online Mendelian Inheritance in Man (OMIM) 212200
- ↑ Template:DiseasesDB
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Willi SM, Zhang Y, Hill JB, Phelan MC, Michaelis RC, Holden KR (1997). "A deletion in the long arm of chromosome 18 in a child with serum carnosinase deficiency". Pediatr Res. 41 (2): 210–213. PMID 9029640.
- ↑ 4.0 4.1 Perry TL, Hansens S, Tischler B, Bunting R, Perry K (1967). "Carnosinemia. A new metabolic disorder associated with neurological disease and mental defect". New Engl J Med. 277 (23): 1219–1227. PMID 6058610.
- ↑ Sauerheifer S, Yuan G, Braun GS, Deiner RM, Neumaier M, Gretz N, Floege J, Kriz R, van der Woude F, Moeller MJ (2007). "L-carnosine, a substrate of carnosinase-1, influences glucose metabolism". Diabetes. 56 (10): 2425–2432. PMID 17601992.
- ↑ Rashid I, van Reyk DM, Davies MJ (2007). "Carnosine and its constituents inhibit glycation of low-density lipoproteins that promotes foam cell formation in vitro". FEBS Lett. 581 (5): 1067–1070. PMID 17316626.
- ↑ 7.0 7.1 Gjessing LR, Lunde HA, Morkrid L, Lenney JF, Sjaastad O (1990). "Inborn errors of carnosine and homocarnosine metabolism". J Neurol Transm Suppl. 29: 91–106. PMID 2358806.
- ↑ 8.0 8.1 8.2 Terplan KL, Cares HL (1972). "Histopathology of the nervous system in carnosinase enzyme deficiency with mental retardation". Neurology. 22 (6): 644–655. PMID 4673339.
- ↑ 9.0 9.1 9.2 Wisniewski K, Fleisher L, Rassin D, Lassmann H (1981). "Neurological diseases in a child with carnosinase deficiency". Neuropediatrics. 12 (2): 143–151. PMID 7266778.
- ↑ 10.0 10.1 10.2 10.3 Jackson MC, Kucera CM, Lenney JF (1991). "Purification and properties of human serum carnosinase". Clin Chim Acta. 196 (2–3): 193–205. PMID 1903095.
- ↑ 11.0 11.1 11.2 Lenney JF, Peppers SC, Kucera-Orallo CM, George RP (1985). "Characterization of human tissue carnosinase". Biochem J. 228 (3): 653–660. PMID 4026801.
- ↑ 12.0 12.1 Lenney JF (1990). "Separation and characterization of two carnosine-splitting cytosolic dipeptides from hog kidney (carnosinase and non-specific dipeptidase)". Biol Chem Hoppe Seyler. 371 (5): 433–440. PMID 2378680.
- ↑ 13.0 13.1 13.2 Lenney JF, George RP, Weiss AM, Kucera CM, Chan PW, Rinz GS (1982). "Human serum carnosinase: characterization, distinction from cellular carnosinase and activation by cadmium". Clin Chim Acta. 123 (3): 221–231. PMID 7116644.
- ↑ Peppers SC, Lenney JF (1988). "Bestatin inhibition of human tissue carnosinase, a non-specific cytosolic dipeptidase". Biol Chem Hoppe Seyler. 369 (12): 1281–1286. PMID 3242551.
- ↑ Lenney JF (1990). "Human cytosolic carnosinase: evidence of identity with prolinase, a non-specific dipeptidase". Biol Chem Hoppe Seyler. 371 (2): 167–171. PMID 2334521.
- ↑ van Heeswijk PJ, Trijbels JM, Schretlen ED, van Munster PJ, Monnens LA (1969). "A patient with a deficiency of serum-carnosinase activity". Acta Paediatr Scand. 58 (6): 584–592. PMID 5378348.
- ↑ Lenney JF, Peppers SC, Kucera CM, Sjaastad O (1983). "Homocarnosinosis: lack of serum carnosinase is the deficiency probably responsible for elevated brain and CSF homocarnosine". Clin Chim Acta. 132 (2): 157–165. PMID 6616870.
- ↑ Zschocke J, Nebel A, Wicks K, Peters V, El Mokhtari NE, Krawczak M, van der Woude F, Janssen B, Schreiber S (2006). "Allelic variation in the CNDP1 gene and its lack of association with longevity and coronary heart disease". Mech Ageing Dev. 127 (11): 817–820. PMID 16965804.