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Arginine:glycine amidinotransferase deficiency(L-Arginine)

MedGen UID:
436367
Concept ID:
C2675179
Disease or Syndrome
Synonyms: AGAT deficiency; CEREBRAL CREATINE DEFICIENCY SYNDROME 3; CREATINE DEFICIENCY SYNDROME DUE TO AGAT DEFICIENCY; Creatine Deficiency Syndromes; GATM DEFICIENCY; L-Arginine; L-arginine:glycine amidinotransferase deficiency; L-Arginine:Glycine Amidinotransferase Deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
SNOMED CT: Cerebral creatine deficiency syndrome 3 (702440000); Arginine:glycine amidinotransferase deficiency (702440000); L-arginine:glycine amidinotransferase deficiency (702440000); Creatine deficiency syndrome due to arginine:glycine amidinotransferase deficiency (702440000)
 
Gene (location): GATM (15q21.1)
OMIM®: 612718
Orphanet: ORPHA35704

Disease characteristics

Excerpted from the GeneReview: Creatine Deficiency Syndromes
The cerebral creatine deficiency syndromes (CCDS), inborn errors of creatine metabolism, include the two creatine biosynthesis disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency, and the creatine transporter (CRTR) deficiency. Intellectual disability and seizures are common to all three CCDS. The majority of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; about 40% have movement disorder. Onset is between ages three months and three years. Only 14 individuals with AGAT deficiency have been reported. The phenotype of CRTR deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, movement disorder and behavior disorder; age at diagnosis ranges from two to 66 years. Clinical phenotype of females heterozygous for CRTR deficiency ranges from asymptomatic to severe phenotype resembling male phenotype. [from GeneReviews]
Authors:
Saadet Mercimek-Mahmutoglu  |  Gajja S Salomons   view full author information

Additional descriptions

From OMIM
Cerebral creatine deficiency syndrome-3 is an autosomal recessive disorder characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain (Schulze, 2003). Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. Oral creatine supplementation can offer symptom improvement (summary by Edvardson et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of cerebral creatine deficiency syndrome, see CCDS1 (300352).  http://www.omim.org/entry/612718
From GHR
Arginine:glycine amidinotransferase deficiency is an inherited disorder that primarily affects the brain. People with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected individuals develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever.Children with arginine:glycine amidinotransferase deficiency may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily.  http://ghr.nlm.nih.gov/condition/arginineglycine-amidinotransferase-deficiency

Clinical features

Organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Autistic disorder of childhood onset
MedGen UID:
13966
Concept ID:
C0004352
Mental or Behavioral Dysfunction
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS5 (606053), which maps to chromosome 2q; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; and AUTS18 (615032), associated with mutation in the CHD8 gene (610528). (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with mutation in the TMLHE gene (300777). Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
Delayed language development
MedGen UID:
9676
Concept ID:
C0023012
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Abnormality of creatine metabolism
MedGen UID:
866482
Concept ID:
C4020731
Finding
An anomaly of the concentration or homeostasis of creatine. Creatine is a derivative of glycine having methyl and amidino groups attached to the nitrogen. Creatine is naturally produced from amino acids, primarily in liver and kidney, and acts as an energy source for cells, primarly for muscle cells.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Arginine:glycine amidinotransferase deficiency in Orphanet.

Recent clinical studies

Etiology

Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. [Epub ahead of print] PMID: 25521922
Atzler D, Schwedhelm E, Choe CU
Curr Opin Clin Nutr Metab Care 2015 Jan;18(1):83-8. doi: 10.1097/MCO.0000000000000123. PMID: 25474016
Comeaux MS, Wang J, Wang G, Kleppe S, Zhang VW, Schmitt ES, Craigen WJ, Renaud D, Sun Q, Wong LJ
Mol Genet Metab 2013 Jul;109(3):260-8. Epub 2013 Apr 17 doi: 10.1016/j.ymgme.2013.04.006. [Epub ahead of print] PMID: 23660394
Davids M, Ndika JD, Salomons GS, Blom HJ, Teerlink T
FEBS Lett 2012 Oct 19;586(20):3653-7. Epub 2012 Aug 29 doi: 10.1016/j.febslet.2012.08.020. [Epub ahead of print] PMID: 23010440
Nasrallah F, Feki M, Kaabachi N
Pediatr Neurol 2010 Mar;42(3):163-71. doi: 10.1016/j.pediatrneurol.2009.07.015. PMID: 20159424

Diagnosis

Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. [Epub ahead of print] PMID: 25521922
Tran C, Yazdanpanah M, Kyriakopoulou L, Levandovskiy V, Zahid H, Naufer A, Isbrandt D, Schulze A
Clin Chim Acta 2014 Sep 25;436:160-8. Epub 2014 May 28 doi: 10.1016/j.cca.2014.05.007. [Epub ahead of print] PMID: 24877651
Nouioua S, Cheillan D, Zaouidi S, Salomons GS, Amedjout N, Kessaci F, Boulahdour N, Hamadouche T, Tazir M
Neuromuscul Disord 2013 Aug;23(8):670-4. Epub 2013 Jun 14 doi: 10.1016/j.nmd.2013.04.011. [Epub ahead of print] PMID: 23770102
Ndika JD, Johnston K, Barkovich JA, Wirt MD, O'Neill P, Betsalel OT, Jakobs C, Salomons GS
Mol Genet Metab 2012 May;106(1):48-54. Epub 2012 Jan 27 doi: 10.1016/j.ymgme.2012.01.017. [Epub ahead of print] PMID: 22386973
Verhoeven NM, Schor DS, Roos B, Battini R, Stöckler-Ipsiroglu S, Salomons GS, Jakobs C
Clin Chem 2003 May;49(5):803-5. PMID: 12709373

Therapy

Ndika JD, Johnston K, Barkovich JA, Wirt MD, O'Neill P, Betsalel OT, Jakobs C, Salomons GS
Mol Genet Metab 2012 May;106(1):48-54. Epub 2012 Jan 27 doi: 10.1016/j.ymgme.2012.01.017. [Epub ahead of print] PMID: 22386973
Verma A
Neurology 2010 Jul 13;75(2):186-8. doi: 10.1212/WNL.0b013e3181e7cabd. PMID: 20625172
Battini R, Alessandrì MG, Leuzzi V, Moro F, Tosetti M, Bianchi MC, Cioni G
J Pediatr 2006 Jun;148(6):828-30. doi: 10.1016/j.jpeds.2006.01.043. PMID: 16769397
Leuzzi V
J Child Neurol 2002 Dec;17 Suppl 3:3S89-97; discussion 3S97. PMID: 12597058
Item CB, Stöckler-Ipsiroglu S, Stromberger C, Mühl A, Alessandrì MG, Bianchi MC, Tosetti M, Fornai F, Cioni G
Am J Hum Genet 2001 Nov;69(5):1127-33. Epub 2001 Sep 10 doi: 10.1086/323765. [Epub ahead of print] PMID: 11555793Free PMC Article

Prognosis

Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. [Epub ahead of print] PMID: 25521922
Braissant O, Henry H
J Inherit Metab Dis 2008 Apr;31(2):230-9. Epub 2008 Apr 4 doi: 10.1007/s10545-008-0826-9. [Epub ahead of print] PMID: 18392746

Clinical prediction guides

Tran C, Yazdanpanah M, Kyriakopoulou L, Levandovskiy V, Zahid H, Naufer A, Isbrandt D, Schulze A
Clin Chim Acta 2014 Sep 25;436:160-8. Epub 2014 May 28 doi: 10.1016/j.cca.2014.05.007. [Epub ahead of print] PMID: 24877651
Braissant O, Henry H
J Inherit Metab Dis 2008 Apr;31(2):230-9. Epub 2008 Apr 4 doi: 10.1007/s10545-008-0826-9. [Epub ahead of print] PMID: 18392746

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