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Deficiency of guanidinoacetate methyltransferase(CCDS2)

MedGen UID:
154356
Concept ID:
C0574080
Disease or Syndrome
Synonyms: CCDS2; CEREBRAL CREATINE DEFICIENCY SYNDROME 2; Guanidinoacetate Methyltransferase Deficiency
SNOMED CT: Deficiency of guanidinoacetate methyltransferase (124239003); Guanidinoacetate methyltransferase deficiency (124239003)
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): GAMT (19p13.3)
 
Monarch Initiative: MONDO:0012999
OMIM®: 612736
Orphanet: ORPHA382

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
Guanidinoacetate methyltransferase deficiency, an autosomal recessive inborn error of creatine synthesis, is characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, intractable seizures and movement disturbances, severe depletion of creatine/phosphocreatine in the brain, and accumulation of guanidinoacetic acid (GAA) in brain and body fluids (summary by Schulze, 2003). For a general phenotypic description and a discussion of genetic heterogeneity of CCDS, see CCDS1 (300352).  http://www.omim.org/entry/612736
From MedlinePlus Genetics
Guanidinoacetate methyltransferase deficiency is an inherited disorder that primarily affects the brain and muscles. Without early treatment, people with this disorder have neurological problems that are usually severe. These problems include intellectual disability, speech development limited to a few words, and recurrent seizures (epilepsy). Affected individuals may also exhibit autistic behaviors that affect communication and social interaction or self-injurious behaviors such as head-banging. Other features of this disorder can include involuntary movements (extrapyramidal dysfunction) such as tremors or facial tics.

People with guanidinoacetate methyltransferase deficiency may have weak muscle tone and delayed development of motor skills such as sitting or walking. In severe cases they may lose previously acquired skills such as the ability to support their head or to sit unsupported.  https://medlineplus.gov/genetics/condition/guanidinoacetate-methyltransferase-deficiency

Clinical features

From HPO
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Febrile seizure (within the age range of 3 months to 6 years)
MedGen UID:
3232
Concept ID:
C0009952
Disease or Syndrome
A febrile seizure is any type of seizure (most often a generalized tonic-clonic seizure) occurring with fever (at least 38 degrees Celsius) but in the absence of central nervous system infection, severe metabolic disturbance or other alternative precipitant in children between the ages of 3 months and 6 years.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Paraparesis
MedGen UID:
113150
Concept ID:
C0221166
Sign or Symptom
Weakness or partial paralysis in the lower limbs.
Atonic seizure
MedGen UID:
78735
Concept ID:
C0270846
Disease or Syndrome
Atonic seizure is a type of motor seizure characterized by a sudden loss or diminution of muscle tone without apparent preceding myoclonic or tonic event lasting about 1 to 2 seconds, involving head, trunk, jaw, or limb musculature.
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.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Progressive extrapyramidal movement disorder
MedGen UID:
411258
Concept ID:
C2748610
Finding
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).
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Infantile muscular hypotonia
MedGen UID:
395993
Concept ID:
C1860834
Finding
Muscular hypotonia (abnormally low muscle tone) manifesting in infancy.
Decreased serum creatinine
MedGen UID:
488901
Concept ID:
C0428282
Finding
An abnormally reduced amount of creatinine in the blood.
Elevated circulating guanidinoacetic acid concentration
MedGen UID:
1815073
Concept ID:
C5706167
Finding
Concentration of guanidinoacetic acid in the blood circulation is above the upper limit of normal.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Deficiency of guanidinoacetate methyltransferase in Orphanet.

Professional guidelines

PubMed

Wojcik M, Morrissey M, Borden K, Teta B, Sicko R, Showers A, Sunny S, Caggana M
Mol Genet Metab 2022 Mar;135(3):186-192. Epub 2022 Jan 26 doi: 10.1016/j.ymgme.2022.01.101. PMID: 35120844
Cheillan D, Salomons GS, Acquaviva C, Boisson C, Roth P, Cordier MP, François L, Jakobs C, Vianey-Saban C
Clin Chem 2006 Apr;52(4):775-7. doi: 10.1373/clinchem.2005.065185. PMID: 16595836

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Guanidinoacetate, Guanidinoacetate Methyltransferase Deficiency, 2022

American College of Medical Genetics and Genomics Algorithm, GAMT Deficiency: Elevated Guanidinoacetate, 2022

Recent clinical studies

Diagnosis

Ensenauer R, Thiel T, Schwab KO, Tacke U, Stöckler-Ipsiroglu S, Schulze A, Hennig J, Lehnert W
Mol Genet Metab 2004 Jul;82(3):208-13. doi: 10.1016/j.ymgme.2004.04.005. PMID: 15234333

Therapy

Ensenauer R, Thiel T, Schwab KO, Tacke U, Stöckler-Ipsiroglu S, Schulze A, Hennig J, Lehnert W
Mol Genet Metab 2004 Jul;82(3):208-13. doi: 10.1016/j.ymgme.2004.04.005. PMID: 15234333
Stöckler S, Hanefeld F, Frahm J
Lancet 1996 Sep 21;348(9030):789-90. doi: 10.1016/s0140-6736(96)04116-5. PMID: 8813986

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Guanidinoacetate, Guanidinoacetate Methyltransferase Deficiency, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics Algorithm, GAMT Deficiency: Elevated Guanidinoacetate, 2022

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