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Arginine:glycine amidinotransferase deficiency(CCDS3)

MedGen UID:
436367
Concept ID:
C2675179
Disease or Syndrome
Synonyms: AGAT deficiency; CCDS3; Cerebral creatine deficiency syndrome 3; Creatine deficiency syndrome due to AGAT deficiency; GATM deficiency; L-Arginine:Glycine Amidinotransferase Deficiency
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)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): GATM (15q21.1)
 
Monarch Initiative: MONDO:0012996
OMIM®: 612718
Orphanet: ORPHA35704

Disease characteristics

Excerpted from the GeneReview: Creatine Deficiency Disorders
The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported. [from GeneReviews]
Authors:
Saadet Mercimek-Andrews  |  Gajja S Salomons   view full author information

Additional descriptions

From OMIM
Cerebral creatine deficiency syndrome-3 (CCDS3) 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 MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/arginineglycine-amidinotransferase-deficiency

Clinical features

From HPO
Inborn organic aciduria
MedGen UID:
66037
Concept ID:
C0241775
Finding
Excretion of non-amino organic acids in urine.
Decreased urinary creatine level
MedGen UID:
1053013
Concept ID:
CN377897
Finding
The amount of creatine in the urine, normalized for urine concentration, is below the lower limit of normal.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Autism
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; 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; AUTS18 (615032), associated with mutation in the CHD8 gene (610528) on chromosome 14q11; AUTS19 (615091), associated with mutation in the EIF4E gene (133440) on chromosome 4q23; and AUTS20 (618830), associated with mutation in the NLGN1 gene (600568) on chromosome 3q26. (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). A locus on chromosome 2q (606053) associated with a phenotype including intellectual disability and speech deficits was formerly designated AUTS5. Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Reduced brain creatine level by MRS
MedGen UID:
1369880
Concept ID:
C4476570
Finding
A decrease in the level of creatine in the brain identified by magnetic resonance spectroscopy (MRS).
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.
Reduced tissue arginine:glycine amidinotransferase activity
MedGen UID:
1053259
Concept ID:
CN377404
Finding
Activity of L-arginine:glycine amidinotransferase (GATM; EC 2.1.4.1) in the tissues below the lower limit of normal. GATM activity can be measured in multiple tissues including leukocytes and cultured fibroblasts.

Term Hierarchy

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

Professional guidelines

PubMed

Stockler S, Schutz PW, Salomons GS
Subcell Biochem 2007;46:149-66. doi: 10.1007/978-1-4020-6486-9_8. PMID: 18652076

Recent clinical studies

Etiology

Goldstein J, Thomas-Wilson A, Groopman E, Aggarwal V, Bianconi S, Fernandez R, Hart K, Longo N, Liang N, Reich D, Wallis H, Weaver M, Young S, Mercimek-Andrews S
Mol Genet Metab 2024 May;142(1):108362. Epub 2024 Mar 2 doi: 10.1016/j.ymgme.2024.108362. PMID: 38452609
Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, Vamecq J
Biochimie 2015 Dec;119:146-65. Epub 2015 Nov 2 doi: 10.1016/j.biochi.2015.10.022. PMID: 26542286
Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. 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
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

DesRoches CL, Bruun T, Wang P, Marshall CR, Mercimek-Mahmutoglu S
Hum Mutat 2016 Sep;37(9):926-32. Epub 2016 Jun 27 doi: 10.1002/humu.23018. PMID: 27233232
Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, Dobbelaere D, Soto-Ares G, Cheillan D, Vamecq J
Biochimie 2015 Dec;119:146-65. Epub 2015 Nov 2 doi: 10.1016/j.biochi.2015.10.022. PMID: 26542286
Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, Dessoffy K, Edvardson S, Eichler F, Johnston K, Koeller DM, Nouioua S, Tazir M, Verma A, Dowling MD, Wierenga KJ, Wierenga AM, Zhang V, Wong LJ
Mol Genet Metab 2015 Dec;116(4):252-9. Epub 2015 Oct 17 doi: 10.1016/j.ymgme.2015.10.003. PMID: 26490222
Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. PMID: 25521922
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. PMID: 23660394

Therapy

Ostojic SM
Nutr Neurosci 2019 May;22(5):302-305. Epub 2017 Oct 3 doi: 10.1080/1028415X.2017.1385176. PMID: 28971744
Battini R, Alessandrì MG, Casalini C, Casarano M, Tosetti M, Cioni G
Orphanet J Rare Dis 2017 Feb 2;12(1):21. doi: 10.1186/s13023-017-0577-5. PMID: 28148286Free PMC Article
Stockler-Ipsiroglu S, Apatean D, Battini R, DeBrosse S, Dessoffy K, Edvardson S, Eichler F, Johnston K, Koeller DM, Nouioua S, Tazir M, Verma A, Dowling MD, Wierenga KJ, Wierenga AM, Zhang V, Wong LJ
Mol Genet Metab 2015 Dec;116(4):252-9. Epub 2015 Oct 17 doi: 10.1016/j.ymgme.2015.10.003. PMID: 26490222
Kayacelebi AA, Langen J, Weigt-Usinger K, Chobanyan-Jürgens K, Mariotti F, Schneider JY, Rothmann S, Frölich JC, Atzler D, Choe CU, Schwedhelm E, Huneau JF, Lücke T, Tsikas D
Amino Acids 2015 Sep;47(9):1893-908. Epub 2015 Jun 2 doi: 10.1007/s00726-015-2012-3. PMID: 26031828
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. PMID: 11555793Free PMC Article

Prognosis

DesRoches CL, Bruun T, Wang P, Marshall CR, Mercimek-Mahmutoglu S
Hum Mutat 2016 Sep;37(9):926-32. Epub 2016 Jun 27 doi: 10.1002/humu.23018. PMID: 27233232
Clark JF, Cecil KM
Pediatr Res 2015 Mar;77(3):398-405. Epub 2014 Dec 18 doi: 10.1038/pr.2014.203. 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. PMID: 18392746

Clinical prediction guides

DesRoches CL, Bruun T, Wang P, Marshall CR, Mercimek-Mahmutoglu S
Hum Mutat 2016 Sep;37(9):926-32. Epub 2016 Jun 27 doi: 10.1002/humu.23018. PMID: 27233232
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. 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. PMID: 18392746

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