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| {{Infobox medical condition (new) | | {{Short description|A rare metabolic disorder}} |
| | name = Carnosinemia
| | {{Medical resources}} |
| | synonyms = '''Carnosinase deficiency'''<ref name=omim>{{OMIM|212200}}</ref> or '''Aminoacyl-histidine dipeptidase deficiency''',<ref>{{DiseasesDB|29672}}</ref> | |
| | image = Carnosine.svg
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| | caption = [[Carnosine]]
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| '''Carnosinemia''', is a rare [[autosome|autosomal]] [[dominance (genetics)|recessive]]<ref name=chroc>{{cite journal |vauthors=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 |doi-access=free }}</ref> [[metabolic disorder]]<ref name=ce>{{cite journal |doi=10.1056/NEJM196712072772302 |vauthors=Perry TL, Hansens S, Tischler B, Bunting R, Perry K |title=Carnosinemia. A new metabolic disorder associated with neurological disease and mental defect |journal=N. Engl. J. Med. |volume=277 |issue=23 |pages=1219–1227 |year=1967 |pmid=6058610 }}</ref> caused by a deficiency of [[carnosinase]]', a [[dipeptidase]] (a type of [[enzyme]] that splits [[dipeptide]]s into their two [[amino acid]] constituents).<ref name=lcarn>{{cite journal |vauthors=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 |doi-access=free }}</ref> | | '''Carnosinemia''' is a rare [[metabolic disorder]] characterized by elevated levels of [[carnosine]] in the blood and urine. This condition is caused by a deficiency of the enzyme carnosinase, which is responsible for breaking down carnosine into its constituent amino acids, [[beta-alanine]] and [[histidine]]. |
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| [[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>{{cite journal |vauthors=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 }}</ref> This disorder results in an excess of carnosine in the [[urine]], [[cerebrospinal fluid]], [[blood]], and [[nervous system|nervous tissue]].<ref name=iech>{{cite journal |vauthors=Gjessing LR, Lunde HA, Morkrid L, Lenney JF, Sjaastad O |title=Inborn errors of carnosine and homocarnosine metabolism |journal=J Neural Transm Suppl |volume=29 |issue= |pages=91–106 |year=1990 |pmid=2358806 |doi=10.1007/978-3-7091-9050-0_10|isbn=978-3-211-82142-8 }}</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>{{cite journal |vauthors=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 |doi=10.1212/wnl.22.6.644}}</ref><ref name=neurp>{{cite journal |vauthors=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 |doi=10.1055/s-2008-1059647 }}</ref>
| | ==Pathophysiology== |
| | Carnosinemia results from a deficiency in the enzyme carnosinase, specifically the cytosolic form known as CNDP1. Carnosinase is responsible for the hydrolysis of carnosine, a dipeptide composed of beta-alanine and histidine. In individuals with carnosinemia, the lack of functional carnosinase leads to the accumulation of carnosine in the blood and urine. |
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| ==Symptoms==
| | Carnosine is found in high concentrations in muscle and brain tissues, where it plays a role in buffering pH and acting as an antioxidant. However, its accumulation in the bloodstream due to carnosinase deficiency can lead to various neurological and developmental symptoms. |
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| A variety of neurological symptoms have been associated with carnosinemia. They include: [[hypotonia]], developmental delay, [[mental retardation]], [[distal axonopathy|degeneration of axons]], [[peripheral neuropathy|sensory neuropathy]], [[tremor]]s, [[myelin|demyelinization]], [[grey matter|gray matter]] anomalies, [[myoclonus|myoclonic seizures]], and loss of [[purkinje fibers]].<ref name=chroc/><ref name=ce/><ref name=histop/><ref name=neurp/>
| | ==Clinical Features== |
| | The clinical presentation of carnosinemia can vary, but common symptoms include: |
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| ==Genetics==
| | * Developmental delay |
| | * Intellectual disability |
| | * Seizures |
| | * Hypotonia (reduced muscle tone) |
| | * Ataxia (lack of voluntary coordination of muscle movements) |
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| [[Image:Autorecessive.svg|thumb|right|Carnosinemia has an autosomal recessive pattern of [[inheritance]].]]
| | The severity of symptoms can vary widely among affected individuals, and some may present with only mild symptoms. |
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| 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>{{cite journal |vauthors=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 }}</ref> Mutations in ''CNDP1'' are responsible for carnosinase deficiency, resulting in carnosinemia.<ref name=chroc/>
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| 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.
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| ==Diagnosis== | | ==Diagnosis== |
| ===Types===
| | Diagnosis of carnosinemia is typically made through biochemical analysis of blood and urine, revealing elevated levels of carnosine. Genetic testing can confirm mutations in the CNDP1 gene, which encodes the carnosinase enzyme. |
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| Carnosinase in humans has two forms:<ref name=purc>{{cite journal |vauthors=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 }}</ref><ref name=charc>{{cite journal |vauthors=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 |pmc=1145034 |doi=10.1042/bj2280653 }}</ref><ref name=sepc>{{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 |doi=10.1515/bchm3.1990.371.1.433 }}</ref><ref name=humc>{{cite journal |vauthors=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 }}</ref>
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| 1. '''Cellular''', or '''tissue carnosinase''':<ref name=charc/> This form of the enzyme is found in every bodily tissue. It is a [[protein dimer|dimer]], and [[hydrolysis|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>{{cite journal |vauthors=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 |doi=10.1515/bchm3.1988.369.2.1281 }}</ref> based in part on its ability to hydrolyze a range of dipeptide [[Substrate (biochemistry)|substrate]]s, including those belonging to [[prolinase]].<ref name=cpro>{{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 |doi=10.1515/bchm3.1990.371.1.167 }}</ref>
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| 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>{{cite journal |vauthors=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 }}</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>{{cite journal |vauthors=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 }}</ref>
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| 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/>
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| | ==Treatment== |
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| | There is currently no specific treatment for carnosinemia. Management of the condition is primarily supportive and symptomatic. This may include: |
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| ==See also==
| | * Anticonvulsant medications to control seizures |
| *[[Histidinemia]]
| | * Physical therapy to improve motor skills and muscle tone |
| *[[Hyperprolinemia]] | | * Special education programs to address developmental delays |
| *[[Inborn errors of metabolism]] | |
| *[[Proline]] | |
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| ==References== | | ==Prognosis== |
| {{Reflist}}
| | The prognosis for individuals with carnosinemia varies depending on the severity of the symptoms. Early intervention and supportive therapies can improve quality of life and developmental outcomes. |
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| == External links == | | ==Related pages== |
| {{Medical resources
| | * [[Metabolic disorder]] |
| | DiseasesDB = 29672
| | * [[Amino acid]] |
| | ICD10 = {{ICD10|E|70|8|e|70}}
| | * [[Enzyme deficiency]] |
| | ICD9 = {{ICD9|270.5}}
| | * [[Neurological disorder]] |
| | ICDO =
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| | OMIM = 212200
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| | MedlinePlus =
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| | eMedicineSubj =
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| | MeshID =
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| | SNOMED CT = 410052008
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| }}
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| {{Amino acid metabolic pathology}}
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| [[Category:Amino acid metabolism disorders]] | | [[Category:Metabolic disorders]] |
| [[Category:Autosomal recessive disorders]]
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| [[Category:Rare diseases]] | | [[Category:Rare diseases]] |
| {{dictionary-stub1}}
| | [[Category:Genetic disorders]] |
A rare metabolic disorder
Carnosinemia is a rare metabolic disorder characterized by elevated levels of carnosine in the blood and urine. This condition is caused by a deficiency of the enzyme carnosinase, which is responsible for breaking down carnosine into its constituent amino acids, beta-alanine and histidine.
Pathophysiology
Carnosinemia results from a deficiency in the enzyme carnosinase, specifically the cytosolic form known as CNDP1. Carnosinase is responsible for the hydrolysis of carnosine, a dipeptide composed of beta-alanine and histidine. In individuals with carnosinemia, the lack of functional carnosinase leads to the accumulation of carnosine in the blood and urine.
Carnosine is found in high concentrations in muscle and brain tissues, where it plays a role in buffering pH and acting as an antioxidant. However, its accumulation in the bloodstream due to carnosinase deficiency can lead to various neurological and developmental symptoms.
Clinical Features
The clinical presentation of carnosinemia can vary, but common symptoms include:
- Developmental delay
- Intellectual disability
- Seizures
- Hypotonia (reduced muscle tone)
- Ataxia (lack of voluntary coordination of muscle movements)
The severity of symptoms can vary widely among affected individuals, and some may present with only mild symptoms.
Diagnosis
Diagnosis of carnosinemia is typically made through biochemical analysis of blood and urine, revealing elevated levels of carnosine. Genetic testing can confirm mutations in the CNDP1 gene, which encodes the carnosinase enzyme.
Treatment
There is currently no specific treatment for carnosinemia. Management of the condition is primarily supportive and symptomatic. This may include:
- Anticonvulsant medications to control seizures
- Physical therapy to improve motor skills and muscle tone
- Special education programs to address developmental delays
Prognosis
The prognosis for individuals with carnosinemia varies depending on the severity of the symptoms. Early intervention and supportive therapies can improve quality of life and developmental outcomes.
Related pages
