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| {{Infobox medical condition (new) | | {{Short description|A rare metabolic disorder affecting creatine synthesis}} |
| | name = {{PAGENAME}} | | {{Medical condition (new)}} |
| | synonyms = '''GAMT deficiency'''
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| | image = Creatine neutral.png
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| | field = [[Medical genetics]]
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| | causes = deficiency of guanidinoacetate methyltransferase
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| | treatment = dietary adjustment and creatine supplementation
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| '''Guanidinoacetate methyltransferase deficiency''' (GAMT deficiency), is an [[autosomal]] [[recessive]]<ref name="Schulze2003">{{cite journal|last1=Schulze|first1=Andreas|journal=Molecular and Cellular Biochemistry|volume=244|issue=1/2|year=2003|pages=143–150|issn=03008177|doi=10.1023/A:1022443503883|title=Creatine deficiency syndromes|pmid=12701824}}</ref> [[cerebral creatine deficiency]] that primarily affects the [[nervous system]] and [[muscle]]s. It is the first described disorder of [[creatine]] metabolism, and results from deficient activity of [[guanidinoacetate methyltransferase]], an enzyme involved in the synthesis of creatine.<ref>{{cite journal |pmid=8651275 |date=1 May 1996|author1=Stöckler, S |author2=Isbrandt, D |author3=Hanefeld, F |author4=Schmidt, B |author5=Von Figura, K |title=Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man |volume=58 |issue=5 |pages=914–22 |issn=0002-9297 |pmc=1914613 |journal=American Journal of Human Genetics |format=Free full text }}</ref> Clinically, affected individuals often present with [[hypotonia]], seizures and developmental delay. Diagnosis can be suspected on clinical findings, and confirmed by specific biochemical tests, brain [[magnetic resonance spectroscopy]], or genetic testing. Biallelic pathogenic variants in ''[[GAMT (gene)|GAMT]]'' are the underlying cause of the disorder. After GAMT deficiency is diagnosed, it can be treated by dietary adjustments, including supplementation with [[creatine]]. Treatment is highly effective if started early in life. If treatment is started late, it cannot reverse brain damage which has already taken place.
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| ==Signs and symptoms==
| | '''Guanidinoacetate methyltransferase deficiency''' (GAMT deficiency) is a rare [[autosomal recessive]] [[metabolic disorder]] that affects the body's ability to synthesize [[creatine]], an essential compound for energy storage and utilization in [[muscle]] and [[brain]] tissues. This condition is characterized by a deficiency in the enzyme guanidinoacetate methyltransferase, which is crucial for the conversion of [[guanidinoacetate]] to [[creatine]]. |
| Individuals with GAMT deficiency appear normal at birth. Shortly after birth, infants may start to show signs, as the consequences of decreased [[creatine]] levels in their body become more apparent. These clinical findings are relatively non-specific, and do not immediately suggest a disorder of creatine metabolism. Common clinical findings, as with other cerebral creatine deficiencies, include developmental delay (both intellectual and motor), seizures and hypotonia.<ref name=omim>{{cite web|title=612736 CEREBRAL CREATINE DEFICIENCY SYNDROME 2; CCDS2 | url= https://omim.org/entry/612736 | publisher = Johns Hopkins University |accessdate = 2019-01-05}}</ref><ref name=pedsendo /> Speech delay, [[autism]], and self-injurious behaviour have also been described.<ref name="BraissantHenry2011">{{cite journal|last1=Braissant|first1=Olivier|last2=Henry|first2=Hugues|last3=Béard|first3=Elidie|last4=Uldry|first4=Joséphine|title=Creatine deficiency syndromes and the importance of creatine synthesis in the brain|journal=Amino Acids|volume=40|issue=5|year=2011|pages=1315–1324|issn=0939-4451|doi=10.1007/s00726-011-0852-z|url=https://serval.unil.ch/resource/serval:BIB_CE3937F9A69E.P001/REF.pdf|pmid=21390529}}</ref>
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| ==Genetics== | | ==Pathophysiology== |
| [[Image:CreatineSynthesis(en).png|thumb|300px|left|GAMT (EC 2.1.1.2) catalyzes the second step in the creatine biosynthetic pathway]]Biallelic pathogenic [[mutation|variants]] in ''[[GAMT]]'' are associated with guanidinoacetate methyltransferase deficiency. This gene codes for the enzyme [[guanidinoacetate methyltransferase]] (GAMT), which participates in the two-step synthesis of the compound [[creatine]] from amino acids [[glycine]], [[arginine]] and [[methionine]]. Specifically, GAMT controls the second step of the sequence, in which creatine is produced from another compound called [[guanidinoacetate]].<ref name="ClarkCecil2014">{{cite journal|last1=Clark|first1=Joseph F.|last2=Cecil|first2=Kim M.|title=Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes|journal=Pediatric Research|volume=77|issue=3|year=2014|pages=398–405|issn=0031-3998|doi=10.1038/pr.2014.203}}</ref> The effects of GAMT deficiency are most severe in organs and tissues that require large amounts of energy, such as the brain and muscles.
| | Guanidinoacetate methyltransferase deficiency results from mutations in the [[GAMT gene]], which encodes the enzyme responsible for the methylation of guanidinoacetate to form creatine. This enzymatic step is the final stage in the [[creatine synthesis]] pathway. The deficiency leads to an accumulation of guanidinoacetate and a depletion of creatine in the body. Elevated levels of guanidinoacetate are neurotoxic and contribute to the neurological symptoms observed in affected individuals. |
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| This disorder is inherited in an autosomal recessive manner, which means the causative gene is located on an [[autosome]], and two defective copies of the gene - one from each parent - are required to inherit the disorder. The parents both carry one pathogenic variant, however they are not affected by the disorder. As carriers, the residual activity of approximately 50% is enough to avoid clinical complications.<ref name=omim /> Unaffected siblings of an affected individual have a 2/3 chance of being carriers.<ref name=omim />
| | ==Clinical Presentation== |
| | The clinical manifestations of GAMT deficiency typically appear in infancy or early childhood. Common symptoms include: |
| | * [[Developmental delay]] |
| | * [[Intellectual disability]] |
| | * [[Seizures]] |
| | * [[Hypotonia]] |
| | * [[Movement disorders]] |
| | * Behavioral problems such as [[autism spectrum disorder]]-like features |
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| ==Diagnosis== | | ==Diagnosis== |
| GAMT deficiency can be suspected from clinical findings, although clinical findings are not suggestive of a specific diagnosis. Laboratory testing of [[Blood plasma|plasma]] and [[urine]] will show decreased levels of [[creatine]] and increased levels of [[guanidinoacetate]]. Non-specific elevations of metabolites on urine testing, such as organic acid analysis, that are normalized to [[creatinine]] may be observed. For these tests, the excretion of urine metabolites is not elevated, but appears elevated due to unusually low creatinine values.<ref name=pedsendo>{{cite book |last1=Schulze |first1=Andreas |editor1-first=Kiriakie |editor1-last=Sarafoglou |editor2-first=Georg F. |editor2-last=Hoffmann |editor3-first=Karl S. |editor3-last=Roth |others= |title=Pediatric Endocrinology and Inborn Errors of Metabolism |edition=1st |year=2009 |publisher=McGraw-Hill Medical |location=New York |language=English |isbn= 978-0-07-143915-2 |pages=153–161|chapter=Creatine Deficiency Syndromes}}</ref> Specific diagnostic testing for GAMT deficiency relies on the measurement of guanidinoacetate and creatine in urine and plasma. Increased levels of guanidinoacetate and decreased levels of creatine can suggest a diagnosis.<ref name=pedsendo /> Confirmatory testing can include enzyme assays to directly measure guanidinoacetate methyltransferase activity or molecular testing of ''GAMT''. Brain [[magnetic resonance spectroscopy]] will show decreased levels of creatine, in affected individuals, however this finding is seen in all three [[cerebral creatine deficiency|cerebral creatine deficiencies]], and needs to be followed up to identify the specific defect.<ref name = pedsendo />
| | Diagnosis of guanidinoacetate methyltransferase deficiency is based on clinical evaluation, biochemical testing, and genetic analysis. Key diagnostic tests include: |
| | * Measurement of guanidinoacetate and creatine levels in [[urine]] and [[blood]] |
| | * [[Magnetic resonance spectroscopy]] (MRS) to assess brain creatine levels |
| | * Genetic testing to identify mutations in the GAMT gene |
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| Treatment is most effective for GAMT deficiency with early diagnosis, however the non-specific clinical findings mean there is often a delay in diagnosis. Due to the efficacy of treatment and the delay in diagnosis, GAMT deficiency has been a candidate for [[newborn screening]] programs.<ref name=msreview>{{cite journal |vauthors=Ombrone D, Giocaliere E, Forni G, Malvagia S, la Marca G |title=Expanded newborn screening by mass spectrometry: New tests, future perspectives |journal=Mass Spectrom Rev |volume=35 |issue=1 |pages=71–84 |date=2016 |pmid=25952022 |doi=10.1002/mas.21463 |url=https://flore.unifi.it/bitstream/2158/1010572/5/MSR%20NBS.pdf|bibcode=2016MSRv...35...71O |hdl=2158/1010572 }}</ref><ref name=newsstory>{{cite web|title=Creatine deficiency among disorders underdiagnosed, researchers say | url = https://abc7chicago.com/health/creatine-deficiency-underdiagnosed-researchers-say/98061/ | accessdate = 2019-02-18 | date = 2014-06-07 | publisher = ABC 7; WLS-TV}}</ref> Newborn screening assays measure the amount of guanidinoacetate in a [[dried blood spot]] using [[tandem mass spectrometry]]. Abnormal results from a newborn screening test still need to be confirmed by testing in plasma or urine.<ref name=msreview /> GAMT deficiency was nominated to be included in the list of disorders recommended for screening in the United States in 2016. It was not recommended for inclusion, as studies completed at the time could not demonstrate that a case could be reliably identified in a newborn screening setting.<ref name=rusp>{{cite web|title=Utah mom, doctors push to add rare disorder to national newborn screening panel | url=https://www.deseretnews.com/article/865666296/Utah-mom-doctors-push-to-add-rare-disorder-to-national-newborn-screening-panel.html | accessdate = 2019-02-18 |date = 2016-11-02 | publisher=Deseret News, Utah | author = Chen, Daphne }}</ref> Utah started screening for GAMT deficiency in all newborns in 2015. New York started screening newborns in late 2018, and Michigan planned to start in 2019.<ref name=gamtnbs>{{cite web|url=https://creatineinfo.org/newborn-screening-program/|title=Newborn Screening Program | publisher=Association for Creatine Deficiencies|accessdate = 2019-05-05}}</ref> | | ==Treatment== |
| | The primary treatment for GAMT deficiency involves dietary supplementation to restore creatine levels and reduce guanidinoacetate accumulation. Treatment strategies include: |
| | * [[Creatine monohydrate]] supplementation |
| | * [[Ornithine]] supplementation to reduce guanidinoacetate production |
| | * Dietary restriction of [[arginine]] and [[protein]] to lower guanidinoacetate levels |
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| ==Treatment==
| | Early diagnosis and treatment are crucial to improving outcomes and preventing irreversible neurological damage. |
| Treatment of GAMT deficiency focuses on restoration of depleted brain creatine with creatine supplementation in pharmacologic doses, and removal of toxic intermediates via ornithine supplementation.<ref name=rusp /> All patients are reported to benefit by this treatment, with improvements in muscular hypotonia, dyskinesia, social contact, alertness and behavior. Seizures appear to reduce more with dietary arginine restriction and ornithine supplementation. Despite treatment, none of the patients have been reported to return to completely normal developmental level, if significant damage had taken place before treatment. Prior to the addition of GAMT deficiency to newborn screening panels, younger siblings of affected individuals may have been tested at birth and treated early. This early treatment can result in outcomes that are very close to normal.<ref name=rusp />
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| ==References== | | ==Prognosis== |
| {{Reflist}}
| | With early and appropriate treatment, individuals with GAMT deficiency can experience significant improvements in symptoms and quality of life. However, untreated or late-diagnosed cases may result in severe intellectual disability and persistent neurological issues. |
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| ==Further reading== | | ==Related pages== |
| *National Library of Medicine. [http://ghr.nlm.nih.gov/condition=guanidinoacetatemethyltransferasedeficiency Genetics Home Reference - Guanidinoacetate methyltransferase deficiency] | | * [[Creatine deficiency syndromes]] |
| *[https://www.ncbi.nlm.nih.gov/books/NBK3794/ GeneReview/NIH/UW entry on Cerebral Creatine Deficiency syndromes] | | * [[Metabolic disorders]] |
| == External links ==
| | * [[Inborn errors of metabolism]] |
| {{Medical resources
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| | DiseasesDB = 5461
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| | ICD10 = {{ICD10|E72.8}}
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| | ICD9 =
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| | ICDO =
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| | OMIM = 601240
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| | MedlinePlus =
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| | eMedicineSubj =
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| | eMedicineTopic =
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| | MeshID = C537622
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| | GeneReviewsNBK = NBK3794
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| | GeneReviewsName = Creatine Deficiency Syndromes
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| | Orphanet = 382
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| }}
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| {{DEFAULTSORT:Guanidinoacetate Methyltransferase Deficiency}}
| | [[Category:Metabolic disorders]] |
| [[Category:Amino acid metabolism disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Autosomal recessive disorders]] | |
| [[Category:Rare diseases]] | | [[Category:Rare diseases]] |
| {{dictionary-stub1}}
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A rare metabolic disorder affecting creatine synthesis
Template:Medical condition (new)
Guanidinoacetate methyltransferase deficiency (GAMT deficiency) is a rare autosomal recessive metabolic disorder that affects the body's ability to synthesize creatine, an essential compound for energy storage and utilization in muscle and brain tissues. This condition is characterized by a deficiency in the enzyme guanidinoacetate methyltransferase, which is crucial for the conversion of guanidinoacetate to creatine.
Pathophysiology
Guanidinoacetate methyltransferase deficiency results from mutations in the GAMT gene, which encodes the enzyme responsible for the methylation of guanidinoacetate to form creatine. This enzymatic step is the final stage in the creatine synthesis pathway. The deficiency leads to an accumulation of guanidinoacetate and a depletion of creatine in the body. Elevated levels of guanidinoacetate are neurotoxic and contribute to the neurological symptoms observed in affected individuals.
Clinical Presentation
The clinical manifestations of GAMT deficiency typically appear in infancy or early childhood. Common symptoms include:
Diagnosis
Diagnosis of guanidinoacetate methyltransferase deficiency is based on clinical evaluation, biochemical testing, and genetic analysis. Key diagnostic tests include:
Treatment
The primary treatment for GAMT deficiency involves dietary supplementation to restore creatine levels and reduce guanidinoacetate accumulation. Treatment strategies include:
Early diagnosis and treatment are crucial to improving outcomes and preventing irreversible neurological damage.
Prognosis
With early and appropriate treatment, individuals with GAMT deficiency can experience significant improvements in symptoms and quality of life. However, untreated or late-diagnosed cases may result in severe intellectual disability and persistent neurological issues.
Related pages
