AGAT Deficiency

Mendelian MONDO:0012996 Pathograph 24 Show in embeddings browser Cerebral Creatine Deficiency Syndrome Inborn Error of Metabolism

AGAT deficiency is an autosomal recessive cerebral creatine biosynthesis disorder caused by biallelic loss-of-function pathogenic variants in GATM, which encodes L-arginine:glycine amidinotransferase. Reduced AGAT activity lowers guanidinoacetate and endogenous creatine synthesis, producing low guanidinoacetate and creatine in body fluids and reduced cerebral creatine on proton magnetic resonance spectroscopy. The clinical spectrum is dominated by developmental, cognitive, speech-language, and skeletal-muscle manifestations. AGAT deficiency is highly responsive to oral creatine monohydrate, particularly when treatment begins early.

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1
Inheritance
3
Pathophys.
18
Phenotypes
4
Hypotheses
2
Gaps
24
Pathograph
1
Genes
6
Medical Actions
3
Differentials
1
Models
14
References
2
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
AGAT deficiency results from biallelic pathogenic GATM variants and follows autosomal recessive inheritance.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20301745 SUPPORT Other
"GAMT deficiency (caused by pathogenic variants in GAMT) and AGAT deficiency (caused by pathogenic variants in GATM) are inherited in an autosomal recessive manner."
GeneReviews directly states the inheritance pattern.
CGGV:assertion_d63bfeff-882d-400f-af17-277a702fd09b-2019-03-08T170000.000Z SUPPORT Other
"GATM | HGNC:4175 | AGAT deficiency | MONDO:0012996 | AR | Definitive"
ClinGen reports a definitive autosomal recessive GATM–AGAT deficiency relationship.
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Mechanistic Hypotheses

4
GATM Loss and Creatine Biosynthesis Failure Model
agat_creatine_biosynthesis_model CANONICAL
Evidence balance 2 support
Biallelic loss-of-function GATM variants reduce AGAT catalytic activity, lowering production of guanidinoacetate and endogenous creatine and thereby depleting cerebral creatine.
Pathograph links
GATM Loss and Reduced AGAT Activity -> Reduced Guanidinoacetate and Endogenous Creatine Synthesis DIRECT AGAT loss blocks guanidinoacetate formation, the first reaction in endogenous creatine synthesis.
GATM Loss and Reduced AGAT Activity -> Reduced tissue arginine:glycine amidinotransferase activity DIRECT The loss-of-function mechanism is directly measurable as reduced tissue or cultured-cell AGAT activity.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Decreased urine guanidinoacetic acid level DIRECT Reduced formation of the AGAT product lowers guanidinoacetate in urine and plasma.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Reduced circulating creatine concentration DIRECT Impaired endogenous synthesis lowers creatine in body fluids.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Decreased urinary creatine level DIRECT Impaired endogenous synthesis lowers urinary creatine.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Cerebral Creatine Depletion INDIRECT KNOWN INTERMEDIATES Reduced endogenous synthesis produces low or undetectable cerebral creatine. Intermediates: reduced creatine availability across body-fluid and brain compartments; reduced local and imported cerebral creatine supply
Cerebral Creatine Depletion -> Reduced brain creatine level by MRS DIRECT Reduced brain creatine is directly observed as a diminished proton-MRS creatine signal.
Show evidence (2 references)
PMID:27233232 SUPPORT In Vitro
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
Variant functional assays establish loss of AGAT activity.
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
Human cohort biochemistry establishes the characteristic downstream metabolite pattern.
Cerebral Creatine Depletion and Energy-Buffering Model
cerebral_creatine_energy_buffering_model EMERGING
Evidence balance 2 support
Cerebral creatine depletion is directly measured, and creatine is central to phosphocreatine-mediated ATP buffering. Treatment timing and response support a contribution to neurodevelopmental impairment, but the proposed energy-buffering intermediate has not been directly measured in human AGAT brain tissue.
Pathograph links
Cerebral Creatine Depletion -> Global developmental delay UNKNOWN Cerebral creatine depletion is treatment-associated with developmental outcome, but the human intermediate is not directly demonstrated.
Cerebral Creatine Depletion -> Cognitive impairment UNKNOWN Cerebral creatine depletion may contribute to cognitive impairment through incompletely measured mechanisms.
Cerebral Creatine Depletion -> Delayed speech and language development UNKNOWN Speech-language impairment is associated with cerebral creatine deficiency, but its specific causal route remains unresolved.
Show evidence (2 references)
PMID:32883247 SUPPORT Other
"Cr, an amino acid derivative, is one of the most important sources of energy due to its primary function as both a spatial and temporal energy buffer. By way of the phosphorylated analogue phosphocreatine (PCr) and creatine kinase (CK) it transfers high energy groups from mitochondria to sites..."
This supports the general biochemical interpretation, not direct demonstration in affected human brain.
PMID:28148286 SUPPORT Human Clinical
"Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation."
Treatment-linked MRS recovery supports relevance of the measured depletion without proving the inferred intermediate.
Systemic Creatine Deficiency and Myopathy Model
systemic_creatine_myopathy_model EMERGING
Evidence balance 1 support
Proximal weakness and myopathy co-occur with the low-creatine biochemical state and improve with oral creatine. Human studies did not directly measure restoration of a skeletal-muscle creatine pool, so that intermediate is not asserted as established.
Pathograph links
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Muscle weakness UNKNOWN Low systemic creatine is associated with proximal weakness, but the intervening human muscle mechanism was not directly measured.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Myopathy UNKNOWN Low systemic creatine is associated with myopathy, but no human muscle-creatine intermediate was directly measured.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis -> Gait disturbance UNKNOWN Proximal weakness may contribute to gait disturbance, but this mediation has not been directly quantified.
Show evidence (1 reference)
PMID:23770102 SUPPORT Human Clinical
"Thirteen months after beginning the treatment with oral creatine monohydrate 200mg/kg/day, then 400mg/kg/day, there was a dramatic improvement in muscle strength with Gowers sign disappearance in both patients, and a mild improvement in language and cognitive functions."
Clinical treatment response supports a creatine-responsive muscle branch.
Emerging AGAT-Associated Epilepsy Model
agat_epilepsy_model EMERGING
Evidence balance 1 support
Focal and temperature-related seizures were reported in small 2025 series. Low brain creatine and altered inhibitory neurotransmission are proposed, but the mechanism and any seizure-specific effect of creatine treatment remain unresolved.
Pathograph links
Cerebral Creatine Depletion -> Seizure UNKNOWN Recent small series suggest an association, but seizure causality and the role of low brain creatine remain uncertain.
Show evidence (1 reference)
PMID:40674085 SUPPORT Human Clinical
"Definitive conclusions on the role of creatine supplementation in epilepsy associated with AGAT deficiency cannot be drawn, as it was not modified after seizure onset in the first proband and introduced only after seizure control in the second."
The clinical report explicitly preserves uncertainty about treatment and causal mechanism.
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Discussions and Knowledge Gaps

2
Is epilepsy a reproducible AGAT deficiency manifestation, and if so, how do low cerebral creatine, structural brain changes, and inhibitory neurotransmission contribute?
KNOWLEDGE GAP OPEN gap_agat_epilepsy_spectrum
Attached to
pathophysiology#Cerebral Creatine Depletion phenotypes#Seizure
GeneReviews summarized the original 16 reported individuals as having no epilepsy, whereas two 2025 studies reported focal, sensory, febrile, and temperature-related seizures. The new series are small and do not establish prevalence, a causal mechanism, or a seizure-specific creatine response.
Show evidence (2 references)
PMID:20301745 SUPPORT Other
"AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders."
The historical cohort boundary did not include epilepsy.
PMID:40674085 SUPPORT Human Clinical
"This study presents the first cases of epilepsy in AGAT deficiency, suggesting its prevalence may be underestimated."
New cases support spectrum expansion while leaving prevalence and mechanism unresolved.
How should creatine dose and biochemical targets be adjusted during pregnancy in people with AGAT deficiency?
KNOWLEDGE GAP OPEN gap_agat_pregnancy_creatine_requirements
Attached to
treatments#Pregnancy-specific creatine monitoring
The only detailed pregnancy report found declining maternal creatine and adjusted the dose, but a single case cannot define universal targets or prove that earlier or higher dosing changes fetal growth.
Show evidence (1 reference)
PMID:32883247 SUPPORT Human Clinical
"From these data, however, it cannot be stated if a higher Cr dose or an earlier supplementation would have avoided the slight growth delay observed in the fetus."
The authors explicitly identify the limits of the single-case dosing inference.
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Pathophysiology

3
GATM Loss and Reduced AGAT Activity
Biallelic loss-of-function GATM variants reduce or abolish AGAT activity, blocking the first reaction of creatine biosynthesis.
GATM Loss and Creatine Biosynthesis Failure Model
GATM hgnc:4175 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATM (hgnc:4175). hgnc:4175 is a gene from the HUGO Gene Nomenclature Committee.
creatine biosynthetic process GO:0006601 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine biosynthetic process (GO:0006601). GO:0006601 is a biological process from the Gene Ontology. ↓ DECREASED
glycine amidinotransferase activity GO:0015068 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glycine amidinotransferase activity (GO:0015068). GO:0015068 is a molecular function from the Gene Ontology. ↓ DECREASED
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in mitochondrion (GO:0005739). GO:0005739 is an anatomical location from the Gene Ontology.
Experimental models
GATM missense-variant enzyme activity assay CELL LINE The expression assay measures variant-specific loss of GATM catalytic activity.
Downstream
Reduced Guanidinoacetate and Endogenous Creatine Synthesis AGAT loss blocks guanidinoacetate formation, the first reaction in endogenous creatine synthesis. GATM Loss and Creatine Biosynthesis Failure Model
Reduced tissue arginine:glycine amidinotransferase activity The loss-of-function mechanism is directly measurable as reduced tissue or cultured-cell AGAT activity. GATM Loss and Creatine Biosynthesis Failure Model
Show evidence (2 references)
PMID:22386973 SUPPORT In Vitro
"AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay."
Patient-derived cultured cells directly demonstrate absent activity and transcript loss.
PMID:27233232 SUPPORT In Vitro
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
Independent missense-variant assays demonstrate loss of catalytic activity.
Reduced Guanidinoacetate and Endogenous Creatine Synthesis
The AGAT block lowers guanidinoacetate, the substrate for GAMT, and reduces endogenous creatine production in body fluids and tissues.
GATM Loss and Creatine Biosynthesis Failure Model Systemic Creatine Deficiency and Myopathy Model
creatine metabolism GO:0006600 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine metabolism, annotated with creatine metabolic process (GO:0006600). GO:0006600 is a biological process from the Gene Ontology. ↓ DECREASED
glycine amidinotransferase activity GO:0015068 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased glycine amidinotransferase activity (GO:0015068). GO:0015068 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Decreased urine guanidinoacetic acid level Reduced formation of the AGAT product lowers guanidinoacetate in urine and plasma. GATM Loss and Creatine Biosynthesis Failure Model
Reduced circulating creatine concentration Impaired endogenous synthesis lowers creatine in body fluids. GATM Loss and Creatine Biosynthesis Failure Model
Decreased urinary creatine level Impaired endogenous synthesis lowers urinary creatine. GATM Loss and Creatine Biosynthesis Failure Model
Cerebral Creatine Depletion Reduced endogenous synthesis produces low or undetectable cerebral creatine. GATM Loss and Creatine Biosynthesis Failure Model
Muscle weakness Low systemic creatine is associated with proximal weakness, but the intervening human muscle mechanism was not directly measured. Systemic Creatine Deficiency and Myopathy Model
Myopathy Low systemic creatine is associated with myopathy, but no human muscle-creatine intermediate was directly measured. Systemic Creatine Deficiency and Myopathy Model
Gait disturbance Proximal weakness may contribute to gait disturbance, but this mediation has not been directly quantified. Systemic Creatine Deficiency and Myopathy Model
Show evidence (2 references)
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
The international cohort defines the characteristic biochemical lesion.
PMID:23770102 SUPPORT Human Clinical
"Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome."
Affected sisters had the expected low guanidinoacetate and creatine pattern.
Cerebral Creatine Depletion
Brain proton magnetic resonance spectroscopy shows low, absent, or markedly reduced cerebral creatine. This measured lesion is kept separate from the inferred phosphocreatine energy-buffering consequences.
Cerebral Creatine Depletion and Energy-Buffering Model Emerging AGAT-Associated Epilepsy Model GATM Loss and Creatine Biosynthesis Failure Model
creatine metabolism GO:0006600 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine metabolism, annotated with creatine metabolic process (GO:0006600). GO:0006600 is a biological process from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced brain creatine level by MRS Reduced brain creatine is directly observed as a diminished proton-MRS creatine signal. GATM Loss and Creatine Biosynthesis Failure Model
Global developmental delay Cerebral creatine depletion is treatment-associated with developmental outcome, but the human intermediate is not directly demonstrated. Cerebral Creatine Depletion and Energy-Buffering Model
Cognitive impairment Cerebral creatine depletion may contribute to cognitive impairment through incompletely measured mechanisms. Cerebral Creatine Depletion and Energy-Buffering Model
Delayed speech and language development Speech-language impairment is associated with cerebral creatine deficiency, but its specific causal route remains unresolved. Cerebral Creatine Depletion and Energy-Buffering Model
Seizure Recent small series suggest an association, but seizure causality and the role of low brain creatine remain uncertain. Emerging AGAT-Associated Epilepsy Model
Show evidence (2 references)
PMID:23770102 SUPPORT Human Clinical
"Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine."
Proton MRS directly measures cerebral creatine depletion.
PMID:28148286 SUPPORT Human Clinical
"Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation."
Serial MRS confirms the measured lesion and its treatment responsiveness.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for AGAT Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

18
Musculoskeletal 3
Muscle weakness FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:35704 SUPPORT Other
"HP:0001324 | Muscle weakness | Frequent (79-30%)"
Orphanet reports muscle weakness as frequent.
PMID:23770102 SUPPORT Human Clinical
"weakness in the lower limbs with Gowers sign and myopathic electromyography."
Directly documents progressive proximal muscle weakness.
Myopathy FREQUENT HP:0003198 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:35704 SUPPORT Other
"HP:0003198 | Myopathy | Frequent (79-30%)"
Orphanet reports myopathy as frequent.
PMID:26490222 SUPPORT Human Clinical
"8 patients also had myopathy/proximal"
The international cohort documents myopathy or proximal muscle weakness in half of reported patients.
Hypotonia OCCASIONAL HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0001252 | Hypotonia | Occasional (29-5%)"
Orphanet reports hypotonia as occasional.
Nervous System 7
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0001263 | Global developmental delay | Very frequent (99-80%)"
Orphanet reports global developmental delay as very frequent.
Cognitive impairment VERY_FREQUENT HP:0100543 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0100543 | Cognitive impairment | Very frequent (99-80%)"
Orphanet reports cognitive impairment as very frequent.
Delayed speech and language development FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:35704 SUPPORT Other
"HP:0000750 | Delayed speech and language development | Frequent (79-30%)"
Orphanet reports delayed speech and language development as frequent.
PMID:23770102 SUPPORT Human Clinical
"Examination showed an important language delay, a progressive proximal muscular"
Case report documents prominent language delay in affected sisters.
Atypical behavior OCCASIONAL HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0000708 | Atypical behavior | Occasional (29-5%)"
Orphanet reports atypical behavior as occasional.
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
ORPHA:35704 SUPPORT Other
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet reports seizure as occasional.
PMID:40323733 SUPPORT Human Clinical
"Our findings suggest that focal epilepsy with sensory seizures and temperature-related seizures may be part of the AGAT deficiency spectrum."
A 2025 four-person family study supports an emerging seizure phenotype.
PMID:40674085 SUPPORT Human Clinical
"This study presents the first cases of epilepsy in AGAT deficiency, suggesting its prevalence may be underestimated."
Two probands in a separate 2025 report expand the spectrum but do not establish a stable frequency estimate.
Gait disturbance OCCASIONAL HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0001288 | Gait disturbance | Occasional (29-5%)"
Orphanet reports gait disturbance as occasional.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40323733 SUPPORT Human Clinical
"Despite creatine supplementation, cortical thickness was significantly reduced across multiple brain regions compared to controls, as indicated by Z-scores."
This is a single-family imaging observation and is not generalized to all AGAT deficiency.
Other 8
Reduced brain creatine level by MRS FREQUENT HP:0025051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced brain creatine level by MRS (HP:0025051). HP:0025051 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:35704 SUPPORT Other
"HP:0025051 | Reduced brain creatine level by MRS | Frequent (79-30%)"
Orphanet reports reduced brain creatine by MRS as frequent.
PMID:23770102 SUPPORT Human Clinical
"magnetic resonance spectroscopy showed a markedly reduced level of creatine"
Case report directly documents reduced brain creatine by MRS.
Reduced tissue arginine:glycine amidinotransferase activity VERY_FREQUENT HP:6000572 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced tissue arginine:glycine amidinotransferase activity (HP:6000572). HP:6000572 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:6000572 | Reduced tissue arginine:glycine amidinotransferase activity | Very frequent (99-80%)"
Orphanet reports reduced tissue AGAT activity as very frequent.
Reduced circulating creatine concentration FREQUENT HP:0034292 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced circulating creatine concentration (HP:0034292). HP:0034292 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0034292 | Reduced circulating creatine concentration | Frequent (79-30%)"
Orphanet reports reduced circulating creatine concentration as frequent.
Decreased urine guanidinoacetic acid level FREQUENT HP:0034888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased urine guanidinoacetic acid level (HP:0034888). HP:0034888 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0034888 | Decreased urine guanidinoacetic acid level | Frequent (79-30%)"
Orphanet reports decreased urinary guanidinoacetic acid as frequent.
Decreased serum creatinine FREQUENT HP:0012101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased serum creatinine (HP:0012101). HP:0012101 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0012101 | Decreased serum creatinine | Frequent (79-30%)"
Orphanet reports decreased serum creatinine as frequent.
Decreased CSF creatinine concentration FREQUENT HP:0034597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased CSF creatinine concentration (HP:0034597). HP:0034597 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:0034597 | Decreased CSF creatinine concentration | Frequent (79-30%)"
Orphanet reports decreased CSF creatinine concentration as frequent.
Decreased urinary creatine level FREQUENT HP:6000748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased urinary creatine level (HP:6000748). HP:6000748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:6000748 | Decreased urinary creatine level | Frequent (79-30%)"
Orphanet reports decreased urinary creatine level as frequent.
Decreased urine creatinine level FREQUENT HP:6000115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased urine creatinine level (HP:6000115). HP:6000115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"HP:6000115 | Decreased urine creatinine level | Frequent (79-30%)"
Orphanet reports decreased urine creatinine level as frequent.
🧬

Genetic Associations

1
Biallelic loss-of-function GATM variants (Loss of AGAT catalytic activity)
Gene: GATM hgnc:4175 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GATM (hgnc:4175). hgnc:4175 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:36856349 SUPPORT Other
"Biallelic pathogenic variants in GAMT result in guanidinoacetate methyltransferase deficiency and biallelic pathogenic variants in GATM result in l-arginine:glycine amidinotransferase deficiency."
The review directly defines the biallelic GATM disease mechanism.
CGGV:assertion_d63bfeff-882d-400f-af17-277a702fd09b-2019-03-08T170000.000Z SUPPORT Other
"GATM | HGNC:4175 | AGAT deficiency | MONDO:0012996 | AR | Definitive"
ClinGen classifies the gene-disease relationship as definitive and autosomal recessive.
💊

Medical Actions

6
Oral creatine monohydrate supplementation
Category: Therapeutic Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Agent: creatine CHEBI:16919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses creatine (CHEBI:16919). CHEBI:16919 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral creatine monohydrate bypasses impaired endogenous synthesis and is the disease-directed therapy. Published cohorts used 100–800 mg/kg/day, but this is an observed range rather than a universal prescription; dosing should be individualized by a metabolic specialist. Early treatment can prevent adverse developmental outcome, while later treatment can restore cerebral creatine, improve myopathy, and yield partial adaptive or cognitive gains.
Mechanism Target:
RESTORES Cerebral Creatine Depletion — Oral creatine replenishes the measured cerebral creatine pool.
Show evidence (1 reference)
PMID:28148286 SUPPORT Human Clinical
"Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation."
Serial MRS directly supports restoration of cerebral creatine.
Target Phenotypes: Reduced brain creatine level by MRS HP:0025051 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Reduced brain creatine level by MRS (HP:0025051). HP:0025051 is a phenotype from the Human Phenotype Ontology. Muscle weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology. Myopathy HP:0003198 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Myopathy (HP:0003198). HP:0003198 is a phenotype from the Human Phenotype Ontology. Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology. Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:20301745 SUPPORT Other
"GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to replenish cerebral creatine levels."
GeneReviews identifies oral creatine as disease-directed treatment.
PMID:26490222 SUPPORT Human Clinical
"Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy."
Cohort data support the published dosing range and major biochemical and muscle responses.
PMID:28148286 SUPPORT Human Clinical
"Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning."
Long-term follow-up supports the importance of timing and residual benefit after later treatment.
Developmental and neurologic supportive care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Individualized education and developmental therapies address developmental, language, cognitive, and behavioral needs. Neurology specialists manage seizures by standard approaches when they occur. These actions address consequences and do not alter the biochemical lesion.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology. Cognitive impairment HP:0100543 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cognitive impairment (HP:0100543). HP:0100543 is a phenotype from the Human Phenotype Ontology. Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology. Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology. Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Other
"The developmental delay, intellectual disability, and behavior problems are managed with an individualized education and therapy program; epilepsy and movement disorder are treated by the appropriate specialist in a standard manner."
GeneReviews supports consequence-directed developmental and neurologic care.
Creatine treatment surveillance
Category: Monitoring
Periodically assess cerebral creatine by in vivo proton MRS, measure kidney function annually, and perform developmental and neurologic assessment at each clinic visit. Monitor weight and symptoms of nephrolithiasis during high-dose creatine treatment.
Show evidence (2 references)
PMID:20301745 SUPPORT Other
"In those treated with creatine monohydrate, periodic determination of cerebral creatine level by in vivo 1H-MRS and annual measurement of kidney function to detect possible creatine-associated nephropathy is warranted. Developmental and neurologic assessments are recommended at each clinic visit."
GeneReviews defines longitudinal MRS, renal, developmental, and neurologic surveillance.
PMID:28148286 SUPPORT Human Clinical
"Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported."
Long-term follow-up supports monitoring for weight gain and nephrolithiasis.
Testing of at-risk newborn relatives
Category: Screening
Biochemical or familial-variant testing of at-risk neonates enables presymptomatic diagnosis and early treatment.
Show evidence (1 reference)
PMID:20301745 SUPPORT Other
"Early diagnosis of neonates at risk for a CDD by biochemical or molecular genetic testing allows for early diagnosis and treatment."
GeneReviews supports prompt testing of at-risk neonates.
Genetic counseling and reproductive planning
Category: Counseling / Informational Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counsel families about autosomal recessive recurrence, carrier testing, and prenatal or preimplantation testing after familial variants are known.
Show evidence (1 reference)
PMID:20301745 SUPPORT Other
"If both parents are known to be heterozygous for a GAMT or GATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
GeneReviews provides the autosomal recessive recurrence risks used in counseling.
Pregnancy-specific creatine monitoring
Category: Monitoring
A single reported pregnancy showed falling maternal urine and plasma creatine and dose adjustment. Pregnancy may increase creatine requirements; maternal metabolites and fetal growth should be followed with metabolic and obstetric specialist input, without assuming that every pregnancy requires dose escalation.
Show evidence (1 reference)
PMID:32883247 SUPPORT Human Clinical
"Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations, in particular in the urine sample, requiring prompt correction of the Cr dose."
One case supports individualized biochemical monitoring and dose review during pregnancy.
🔬

Biochemical Markers

4
AGAT enzyme activity in cultured cells (DECREASED)
Context: Absent or markedly reduced AGAT activity in a validated cultured-cell assay can functionally confirm the GATM defect.
Pathograph Readouts
Readout Of GATM Loss and Reduced AGAT Activity Negative Diagnostic
Reduced enzyme activity directly reports the proximal molecular defect.
Show evidence (1 reference)
PMID:22386973 SUPPORT In Vitro
"AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay."
Patient lymphoblasts directly demonstrate the diagnostic enzyme-activity readout.
Show evidence (1 reference)
PMID:22386973 SUPPORT In Vitro
"AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay."
The patient-derived cultured-cell assay found no detectable AGAT activity.
Urine and plasma guanidinoacetate (DECREASED)
Context: Low or undetectable guanidinoacetate in urine and plasma is the most direct metabolite signature of the blocked AGAT reaction.
Pathograph Readouts
Readout Of Reduced Guanidinoacetate and Endogenous Creatine Synthesis Negative Diagnostic
Low guanidinoacetate reports loss of the immediate AGAT reaction product.
Show evidence (1 reference)
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
The international cohort directly supports this product-level readout.
Show evidence (2 references)
PMID:23770102 SUPPORT Human Clinical
"Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome."
This directly supports the combined low-guanidinoacetate and low-creatine body-fluid pattern.
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
The cohort establishes low urine and plasma guanidinoacetate.
Urine and plasma creatine (DECREASED)
Context: Low creatine in body fluids accompanies low guanidinoacetate; the combined pattern is more discriminating than low creatine alone.
Pathograph Readouts
Readout Of Reduced Guanidinoacetate and Endogenous Creatine Synthesis Negative Diagnostic
Low body-fluid creatine reports reduced endogenous creatine synthesis.
Show evidence (1 reference)
PMID:23770102 SUPPORT Human Clinical
"Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome."
Patient testing directly supports the combined low-metabolite pattern.
Show evidence (1 reference)
PMID:23770102 SUPPORT Human Clinical
"Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome."
The report documents low creatine in both plasma and urine.
Cerebral creatine by proton magnetic resonance spectroscopy (DECREASED)
Context: Absent or markedly reduced cerebral creatine on proton MRS supports a cerebral creatine deficiency syndrome but is interpreted with metabolite and molecular findings because it is not specific to AGAT deficiency.
Pathograph Readouts
Readout Of Cerebral Creatine Depletion Negative Diagnostic
A reduced brain creatine peak directly reports cerebral creatine depletion.
Show evidence (1 reference)
PMID:23770102 SUPPORT Human Clinical
"Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine."
Proton MRS directly measures the cerebral-depletion node.
Show evidence (1 reference)
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
The international cohort identifies cerebral creatine depletion as a common biochemical denominator.
🔬

Diagnosis

4
Urine and plasma guanidinoacetate and creatine measurement
Measure guanidinoacetate and creatine in urine and plasma. The characteristic AGAT pattern is low or undetectable guanidinoacetate together with low creatine; low creatine alone is not disease-specific.
Markers: Guanidinoacetate and creatine in urine and plasma
Results: Low or undetectable guanidinoacetate with low creatine supports AGAT deficiency.
Show evidence (3 references)
PMID:23770102 SUPPORT Human Clinical
"Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome."
This directly supports the combined low-guanidinoacetate and low-creatine body-fluid pattern.
PMID:26490222 SUPPORT Human Clinical
"Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels."
The international cohort directly establishes the diagnostic metabolite pattern.
PMID:28055022 SUPPORT Other
"Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in..."
The ACMG laboratory guideline supports metabolite testing as part of preliminary and confirmatory diagnosis.
Brain proton magnetic resonance spectroscopy
Proton MRS evaluates the cerebral creatine peak. An absent or markedly reduced peak supports a cerebral creatine deficiency syndrome but must be interpreted with metabolite and molecular results.
Markers: Cerebral creatine peak
Results: Absent or markedly reduced cerebral creatine supports a cerebral creatine deficiency syndrome.
Show evidence (1 reference)
PMID:36856349 SUPPORT Other
"Genetic investigations such as targeted next-generation sequencing panel or exome sequencing can also identify these disorders; however, metabolite measurements and creatine in proton magnetic resonance spectroscopy are crucial to confirm the diagnosis."
The review supports MRS as a key confirmatory component when combined with metabolite testing.
Molecular confirmation of biallelic GATM variants
Targeted next-generation sequencing panels or exome sequencing can identify biallelic pathogenic GATM variants.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic GATM variants establish the molecular diagnosis in a compatible phenotype.
Show evidence (2 references)
PMID:20301745 SUPPORT Other
"The diagnosis of a CDD is established in a proband with suggestive findings and biallelic pathogenic variants in GAMT or GATM or a hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular genetic testing."
GeneReviews directly supports molecular confirmation with biallelic GATM variants.
PMID:36856349 SUPPORT Other
"Genetic investigations such as targeted next-generation sequencing panel or exome sequencing can also identify these disorders; however, metabolite measurements and creatine in proton magnetic resonance spectroscopy are crucial to confirm the diagnosis."
The review supports panel or exome sequencing while retaining biochemical and MRS confirmation.
AGAT enzyme activity assay in cultured cells
A validated cultured-cell enzyme assay can provide functional confirmation when molecular findings require clarification.
Markers: AGAT enzymatic activity
Results: Absent or markedly reduced AGAT activity supports a functional GATM defect.
Show evidence (1 reference)
PMID:22386973 SUPPORT In Vitro
"AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay."
Patient lymphoblasts provide direct functional confirmation.
📈

Progression

3
Infancy presentation
Onset is generally in infancy. In the international cohort, the post-neonatally diagnosed patients had intellectual disability or developmental delay, and half also had myopathy or proximal weakness.
Show evidence (2 references)
ORPHA:35704 SUPPORT Other
"Age of onset: Infancy"
Orphanet records infancy as the age of onset.
PMID:26490222 SUPPORT Human Clinical
"16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness."
The largest published cohort defines the observed untreated or later-diagnosed presentation.
Early-treated or presymptomatic course
Diagnosis in the neonatal period or early infancy permits treatment before fixed neurodevelopmental impairment. The small published cohort supports normal later development in two children treated from infancy.
Show evidence (1 reference)
PMID:26490222 SUPPORT Human Clinical
"The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years."
Two early-treated children had normal cognitive and behavioral development at long follow-up.
Later-treated course
Creatine treatment can restore cerebral creatine and improve myopathy after later diagnosis, while cognitive recovery is generally incomplete.
Show evidence (1 reference)
PMID:28148286 SUPPORT Human Clinical
"Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning."
Long-term follow-up separates prevention with early treatment from partial recovery after later treatment.
📊

Prevalence

1
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet classifies AGAT deficiency below one per million worldwide; the evidence base otherwise consists of published cases and families.
Show evidence (1 reference)
ORPHA:35704 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
Orphanet reports worldwide point prevalence below one per million.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from AGAT Deficiency:

Guanidinoacetate methyltransferase deficiency MONDO:0012999
Overlapping Features GAMT deficiency also causes low cerebral and body-fluid creatine, but guanidinoacetate is elevated rather than low and epilepsy is much more characteristic.
Distinguishing Features
  • Elevated guanidinoacetate with low creatine in GAMT deficiency
  • Low guanidinoacetate with low creatine in AGAT deficiency
Show evidence (1 reference)
PMID:36856349 SUPPORT Other
"The diagnosis can be suspected by elevated guanidinoacetate and low creatine levels in body fluids in guanidinoacetate methyltransferase deficiency, low guanidinoacetate and low creatine levels in body fluids in l-arginine:glycine amidinotransferase deficiency, and elevated..."
The review directly contrasts the biochemical patterns.
Creatine transporter deficiency MONDO:0010305
Overlapping Features SLC6A8-related creatine transporter deficiency shares low cerebral creatine and neurodevelopmental features but typically shows an elevated urinary creatine-to-creatinine ratio in affected males rather than low guanidinoacetate.
Distinguishing Features
  • X-linked SLC6A8 inheritance
  • Elevated urinary creatine-to-creatinine ratio in affected males
  • Low guanidinoacetate is characteristic of AGAT deficiency
Show evidence (2 references)
PMID:36856349 SUPPORT Other
"Hemizygous pathogenic variant in males and heterozygous pathogenic variant in females in SLC6A8 result in creatine transporter deficiency."
This supports the X-linked molecular distinction.
PMID:36856349 SUPPORT Other
"The diagnosis can be suspected by elevated guanidinoacetate and low creatine levels in body fluids in guanidinoacetate methyltransferase deficiency, low guanidinoacetate and low creatine levels in body fluids in l-arginine:glycine amidinotransferase deficiency, and elevated..."
The biochemical comparison distinguishes the transporter disorder from AGAT deficiency.
Autosomal dominant GATM-associated renal Fanconi syndrome
Overlapping Features Monoallelic GATM variants cause a distinct renal tubular and kidney failure disorder. This must not be conflated with biallelic loss-of-function AGAT deficiency.
Distinguishing Features
  • Autosomal dominant monoallelic GATM missense variants
  • Renal Fanconi syndrome and progressive kidney failure
Show evidence (1 reference)
PMID:29654216 SUPPORT Human Clinical
"The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency."
The renal study directly separates the monoallelic renal disorder from recessive creatine deficiency.
🧫

Experimental Models

1
GATM missense-variant enzyme activity assay CELL_LINE
Rare GATM missense variants were expressed and assayed for retained wild-type catalytic activity to support functional variant interpretation.
Wild-type GATM Rare GATM missense variants
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Human cell-line expression assay for rare GATM missense variants
Pathograph links
GATM Loss and Reduced AGAT Activity The expression assay measures variant-specific loss of GATM catalytic activity.
Show evidence (1 reference)
PMID:27233232 SUPPORT In Vitro
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
The functional assay directly measures the modeled loss-of-activity mechanism.
Findings
Seven assayed missense variants retained no wild-type GATM activity.
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
Show evidence (1 reference)
PMID:27233232 SUPPORT In Vitro
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
The functional assay directly supports the finding statement.
Show evidence (1 reference)
PMID:27233232 SUPPORT In Vitro
"We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity."
The functional assay directly demonstrates complete activity loss for seven variants.
{ }

Source YAML

click to show 
name: AGAT Deficiency
category: Mendelian
creation_date: '2026-05-03T00:00:00Z'
synonyms:
- L-arginine:glycine amidinotransferase deficiency
- Arginine:glycine amidinotransferase deficiency
- GATM deficiency
- Cerebral creatine deficiency syndrome type 3
- CCDS3
description: >-
  AGAT deficiency is an autosomal recessive cerebral creatine biosynthesis
  disorder caused by biallelic loss-of-function pathogenic variants in GATM,
  which encodes L-arginine:glycine amidinotransferase. Reduced AGAT activity
  lowers guanidinoacetate and endogenous creatine synthesis, producing low
  guanidinoacetate and creatine in body fluids and reduced cerebral creatine on
  proton magnetic resonance spectroscopy. The clinical spectrum is dominated
  by developmental, cognitive, speech-language, and skeletal-muscle
  manifestations. AGAT deficiency is highly responsive to oral creatine
  monohydrate, particularly when treatment begins early.
disease_term:
  preferred_term: AGAT deficiency
  term:
    id: MONDO:0012996
    label: AGAT deficiency
parents:
- Cerebral Creatine Deficiency Syndrome
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    AGAT deficiency results from biallelic pathogenic GATM variants and follows
    autosomal recessive inheritance.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GAMT deficiency (caused by pathogenic variants in GAMT) and AGAT deficiency (caused by pathogenic variants in GATM) are inherited in an autosomal recessive manner.
    explanation: GeneReviews directly states the inheritance pattern.
  - reference: CGGV:assertion_d63bfeff-882d-400f-af17-277a702fd09b-2019-03-08T170000.000Z
    reference_title: GATM / AGAT deficiency (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GATM | HGNC:4175 | AGAT deficiency | MONDO:0012996 | AR | Definitive
    explanation: ClinGen reports a definitive autosomal recessive GATM–AGAT deficiency relationship.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: >-
    Orphanet classifies AGAT deficiency below one per million worldwide; the
    evidence base otherwise consists of published cases and families.
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet reports worldwide point prevalence below one per million.
progression:
- phase: Infancy presentation
  notes: >-
    Onset is generally in infancy. In the international cohort, the
    post-neonatally diagnosed patients had intellectual disability or
    developmental delay, and half also had myopathy or proximal weakness.
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infancy as the age of onset.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness.
    explanation: The largest published cohort defines the observed untreated or later-diagnosed presentation.
- phase: Early-treated or presymptomatic course
  notes: >-
    Diagnosis in the neonatal period or early infancy permits treatment before
    fixed neurodevelopmental impairment. The small published cohort supports
    normal later development in two children treated from infancy.
  evidence:
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years.
    explanation: Two early-treated children had normal cognitive and behavioral development at long follow-up.
- phase: Later-treated course
  notes: >-
    Creatine treatment can restore cerebral creatine and improve myopathy after
    later diagnosis, while cognitive recovery is generally incomplete.
  evidence:
  - reference: PMID:28148286
    reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning.
    explanation: Long-term follow-up separates prevention with early treatment from partial recovery after later treatment.
mechanistic_hypotheses:
- hypothesis_group_id: agat_creatine_biosynthesis_model
  hypothesis_label: GATM Loss and Creatine Biosynthesis Failure Model
  status: CANONICAL
  description: >-
    Biallelic loss-of-function GATM variants reduce AGAT catalytic activity,
    lowering production of guanidinoacetate and endogenous creatine and thereby
    depleting cerebral creatine.
  evidence:
  - reference: PMID:27233232
    reference_title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
    explanation: Variant functional assays establish loss of AGAT activity.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
    explanation: Human cohort biochemistry establishes the characteristic downstream metabolite pattern.
- hypothesis_group_id: cerebral_creatine_energy_buffering_model
  hypothesis_label: Cerebral Creatine Depletion and Energy-Buffering Model
  status: EMERGING
  description: >-
    Cerebral creatine depletion is directly measured, and creatine is central
    to phosphocreatine-mediated ATP buffering. Treatment timing and response
    support a contribution to neurodevelopmental impairment, but the proposed
    energy-buffering intermediate has not been directly measured in human AGAT
    brain tissue.
  evidence:
  - reference: PMID:32883247
    reference_title: "Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cr, an amino acid derivative, is one of the most important sources of energy due to its primary function as both a spatial and temporal energy buffer. By way of the phosphorylated analogue phosphocreatine (PCr) and creatine kinase (CK) it transfers high energy groups from mitochondria to sites of consumption and regenerates ATP from ADP.
    explanation: This supports the general biochemical interpretation, not direct demonstration in affected human brain.
  - reference: PMID:28148286
    reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation.
    explanation: Treatment-linked MRS recovery supports relevance of the measured depletion without proving the inferred intermediate.
- hypothesis_group_id: systemic_creatine_myopathy_model
  hypothesis_label: Systemic Creatine Deficiency and Myopathy Model
  status: EMERGING
  description: >-
    Proximal weakness and myopathy co-occur with the low-creatine biochemical
    state and improve with oral creatine. Human studies did not directly measure
    restoration of a skeletal-muscle creatine pool, so that intermediate is not
    asserted as established.
  evidence:
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirteen months after beginning the treatment with oral creatine monohydrate 200mg/kg/day, then 400mg/kg/day, there was a dramatic improvement in muscle strength with Gowers sign disappearance in both patients, and a mild improvement in language and cognitive functions.
    explanation: Clinical treatment response supports a creatine-responsive muscle branch.
- hypothesis_group_id: agat_epilepsy_model
  hypothesis_label: Emerging AGAT-Associated Epilepsy Model
  status: EMERGING
  description: >-
    Focal and temperature-related seizures were reported in small 2025 series.
    Low brain creatine and altered inhibitory neurotransmission are proposed,
    but the mechanism and any seizure-specific effect of creatine treatment
    remain unresolved.
  evidence:
  - reference: PMID:40674085
    reference_title: "Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Definitive conclusions on the role of creatine supplementation in epilepsy associated with AGAT deficiency cannot be drawn, as it was not modified after seizure onset in the first proband and introduced only after seizure control in the second.
    explanation: The clinical report explicitly preserves uncertainty about treatment and causal mechanism.
pathophysiology:
- name: GATM Loss and Reduced AGAT Activity
  description: >-
    Biallelic loss-of-function GATM variants reduce or abolish AGAT activity,
    blocking the first reaction of creatine biosynthesis.
  genes:
  - preferred_term: GATM
    term:
      id: hgnc:4175
      label: GATM
  molecular_functions:
  - preferred_term: glycine amidinotransferase activity
    term:
      id: GO:0015068
      label: glycine amidinotransferase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: creatine biosynthetic process
    term:
      id: GO:0006601
      label: creatine biosynthetic process
    modifier: DECREASED
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:22386973
    reference_title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay.
    explanation: Patient-derived cultured cells directly demonstrate absent activity and transcript loss.
  - reference: PMID:27233232
    reference_title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
    explanation: Independent missense-variant assays demonstrate loss of catalytic activity.
  downstream:
  - target: Reduced Guanidinoacetate and Endogenous Creatine Synthesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: AGAT loss blocks guanidinoacetate formation, the first reaction in endogenous creatine synthesis.
    evidence:
    - reference: PMID:32883247
      reference_title: "Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Cr is synthesized in a two-step reaction, where the rate-limiting step is the Arginine: Glycine Amidino-Transferase (AGAT) reaction to form guanidinoacetic acid (GAA) from arginine and glycine; GAA is quickly converted to Cr by guanidinoacetate methyltransferase (GAMT).
      explanation: The pathway description directly links AGAT loss to reduced guanidinoacetate and creatine synthesis.
  - target: Reduced tissue arginine:glycine amidinotransferase activity
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: The loss-of-function mechanism is directly measurable as reduced tissue or cultured-cell AGAT activity.
    evidence:
    - reference: PMID:22386973
      reference_title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay.
      explanation: Patient lymphoblasts directly demonstrate the enzyme-activity readout.
- name: Reduced Guanidinoacetate and Endogenous Creatine Synthesis
  description: >-
    The AGAT block lowers guanidinoacetate, the substrate for GAMT, and reduces
    endogenous creatine production in body fluids and tissues.
  biological_processes:
  - preferred_term: creatine metabolism
    term:
      id: GO:0006600
      label: creatine metabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: glycine amidinotransferase activity
    term:
      id: GO:0015068
      label: glycine amidinotransferase activity
    modifier: DECREASED
  chemical_entities:
  - preferred_term: guanidinoacetic acid
    term:
      id: CHEBI:16344
      label: guanidinoacetic acid
    modifier: DECREASED
  - preferred_term: creatine
    term:
      id: CHEBI:16919
      label: creatine
    modifier: DECREASED
  evidence:
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
    explanation: The international cohort defines the characteristic biochemical lesion.
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
    explanation: Affected sisters had the expected low guanidinoacetate and creatine pattern.
  downstream:
  - target: Decreased urine guanidinoacetic acid level
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: Reduced formation of the AGAT product lowers guanidinoacetate in urine and plasma.
    evidence:
    - reference: PMID:26490222
      reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
      explanation: Human cohort testing demonstrates the predicted low product concentration.
  - target: Reduced circulating creatine concentration
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: Impaired endogenous synthesis lowers creatine in body fluids.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
      explanation: Plasma and urine testing directly supports the low-creatine readout.
  - target: Decreased urinary creatine level
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: Impaired endogenous synthesis lowers urinary creatine.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
      explanation: Urine testing directly supports this biochemical consequence.
  - target: Cerebral Creatine Depletion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced creatine availability across body-fluid and brain compartments
    - reduced local and imported cerebral creatine supply
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: Reduced endogenous synthesis produces low or undetectable cerebral creatine.
    evidence:
    - reference: PMID:26490222
      reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
      explanation: The cohort directly establishes cerebral depletion with the biochemical block.
  - target: Muscle weakness
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - systemic_creatine_myopathy_model
    description: Low systemic creatine is associated with proximal weakness, but the intervening human muscle mechanism was not directly measured.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Examination showed an important language delay, a progressive proximal muscular weakness in the lower limbs with Gowers sign and myopathic electromyography.
      explanation: The phenotype is directly observed, while the upstream creatine-to-muscle mechanism remains unresolved.
  - target: Myopathy
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - systemic_creatine_myopathy_model
    description: Low systemic creatine is associated with myopathy, but no human muscle-creatine intermediate was directly measured.
    evidence:
    - reference: PMID:26490222
      reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy.
      explanation: Treatment response supports the branch without establishing a measured skeletal-muscle creatine pool.
  - target: Gait disturbance
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - systemic_creatine_myopathy_model
    description: Proximal weakness may contribute to gait disturbance, but this mediation has not been directly quantified.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Examination showed an important language delay, a progressive proximal muscular weakness in the lower limbs with Gowers sign and myopathic electromyography.
      explanation: Proximal weakness makes the gait link plausible, while the cited report does not separately quantify gait.
- name: Cerebral Creatine Depletion
  description: >-
    Brain proton magnetic resonance spectroscopy shows low, absent, or markedly
    reduced cerebral creatine. This measured lesion is kept separate from the
    inferred phosphocreatine energy-buffering consequences.
  biological_processes:
  - preferred_term: creatine metabolism
    term:
      id: GO:0006600
      label: creatine metabolic process
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  chemical_entities:
  - preferred_term: creatine
    term:
      id: CHEBI:16919
      label: creatine
    modifier: DECREASED
  evidence:
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine.
    explanation: Proton MRS directly measures cerebral creatine depletion.
  - reference: PMID:28148286
    reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation.
    explanation: Serial MRS confirms the measured lesion and its treatment responsiveness.
  downstream:
  - target: Reduced brain creatine level by MRS
    causal_link_type: DIRECT
    hypothesis_groups:
    - agat_creatine_biosynthesis_model
    description: Reduced brain creatine is directly observed as a diminished proton-MRS creatine signal.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine.
      explanation: The imaging result is a direct readout of the mechanism node.
  - target: Global developmental delay
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - cerebral_creatine_energy_buffering_model
    description: Cerebral creatine depletion is treatment-associated with developmental outcome, but the human intermediate is not directly demonstrated.
    evidence:
    - reference: PMID:26490222
      reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions.
      explanation: Timing and response support relevance while not proving a causal cellular intermediate.
  - target: Cognitive impairment
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - cerebral_creatine_energy_buffering_model
    description: Cerebral creatine depletion may contribute to cognitive impairment through incompletely measured mechanisms.
    evidence:
    - reference: PMID:28148286
      reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning.
      explanation: Treatment timing supports association but does not establish the intervening brain mechanism.
  - target: Delayed speech and language development
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - cerebral_creatine_energy_buffering_model
    description: Speech-language impairment is associated with cerebral creatine deficiency, but its specific causal route remains unresolved.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thirteen months after beginning the treatment with oral creatine monohydrate 200mg/kg/day, then 400mg/kg/day, there was a dramatic improvement in muscle strength with Gowers sign disappearance in both patients, and a mild improvement in language and cognitive functions.
      explanation: Treatment response supports a relationship but not a defined molecular intermediate.
  - target: Seizure
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - agat_epilepsy_model
    description: Recent small series suggest an association, but seizure causality and the role of low brain creatine remain uncertain.
    evidence:
    - reference: PMID:40674085
      reference_title: "Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In AGAT deficiency, epilepsy is not linked to GAA accumulation as in other creatine deficiency disorders but rather to low brain creatine levels, which may affect γ-aminobutyric acidergic neurotransmission and seizure thresholds. The role of creatine supplementation in seizure control warrants further investigation.
      explanation: The authors explicitly present the pathway as a possibility requiring further study.
phenotypes:
- name: Global developmental delay
  frequency: VERY_FREQUENT
  description: Global developmental delay is a core clinical feature of AGAT deficiency.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001263 | Global developmental delay | Very frequent (99-80%)"
    explanation: Orphanet reports global developmental delay as very frequent.
- name: Cognitive impairment
  frequency: VERY_FREQUENT
  description: Cognitive impairment is very frequent in AGAT deficiency.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100543 | Cognitive impairment | Very frequent (99-80%)"
    explanation: Orphanet reports cognitive impairment as very frequent.
- name: Delayed speech and language development
  frequency: FREQUENT
  description: Speech-language delay is a frequent neurodevelopmental manifestation.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000750 | Delayed speech and language development | Frequent (79-30%)"
    explanation: Orphanet reports delayed speech and language development as frequent.
  - reference: PMID:23770102
    reference_title: "Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination showed an important language delay, a progressive proximal muscular"
    explanation: Case report documents prominent language delay in affected sisters.
- name: Muscle weakness
  frequency: FREQUENT
  description: Progressive proximal muscle weakness and myopathy are frequent in AGAT deficiency.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001324 | Muscle weakness | Frequent (79-30%)"
    explanation: Orphanet reports muscle weakness as frequent.
  - reference: PMID:23770102
    reference_title: "Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "weakness in the lower limbs with Gowers sign and myopathic electromyography."
    explanation: Directly documents progressive proximal muscle weakness.
- name: Myopathy
  frequency: FREQUENT
  description: Myopathy is a frequent skeletal-muscle manifestation and can improve with creatine supplementation.
  phenotype_term:
    preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003198 | Myopathy | Frequent (79-30%)"
    explanation: Orphanet reports myopathy as frequent.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "8 patients also had myopathy/proximal"
    explanation: The international cohort documents myopathy or proximal muscle weakness in half of reported patients.
- name: Atypical behavior
  frequency: OCCASIONAL
  description: Behavioral abnormalities are occasional manifestations within the neurodevelopmental AGAT deficiency spectrum.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000708 | Atypical behavior | Occasional (29-5%)"
    explanation: Orphanet reports atypical behavior as occasional.
- name: Hypotonia
  frequency: OCCASIONAL
  description: Hypotonia is an occasional motor manifestation of AGAT deficiency.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001252 | Hypotonia | Occasional (29-5%)"
    explanation: Orphanet reports hypotonia as occasional.
- name: Reduced brain creatine level by MRS
  frequency: FREQUENT
  description: Brain magnetic resonance spectroscopy demonstrates reduced creatine stores.
  phenotype_term:
    preferred_term: Reduced brain creatine level by MRS
    term:
      id: HP:0025051
      label: Reduced brain creatine level by MRS
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025051 | Reduced brain creatine level by MRS | Frequent (79-30%)"
    explanation: Orphanet reports reduced brain creatine by MRS as frequent.
  - reference: PMID:23770102
    reference_title: "Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "magnetic resonance spectroscopy showed a markedly reduced level of creatine"
    explanation: Case report directly documents reduced brain creatine by MRS.
- name: Seizure
  frequency: OCCASIONAL
  description: >-
    Seizures are an emerging expanded-spectrum finding reported in a small
    number of families rather than a classical feature of the original cohort.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet reports seizure as occasional.
  - reference: PMID:40323733
    reference_title: "Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings suggest that focal epilepsy with sensory seizures and temperature-related seizures may be part of the AGAT deficiency spectrum.
    explanation: A 2025 four-person family study supports an emerging seizure phenotype.
  - reference: PMID:40674085
    reference_title: "Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study presents the first cases of epilepsy in AGAT deficiency, suggesting its prevalence may be underestimated.
    explanation: Two probands in a separate 2025 report expand the spectrum but do not establish a stable frequency estimate.
- name: Reduced tissue arginine:glycine amidinotransferase activity
  frequency: VERY_FREQUENT
  description: Reduced tissue AGAT enzyme activity is the primary biochemical lesion.
  phenotype_term:
    preferred_term: Reduced tissue arginine:glycine amidinotransferase activity
    term:
      id: HP:6000572
      label: Reduced tissue arginine:glycine amidinotransferase activity
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000572 | Reduced tissue arginine:glycine amidinotransferase activity | Very frequent (99-80%)"
    explanation: Orphanet reports reduced tissue AGAT activity as very frequent.
- name: Reduced circulating creatine concentration
  frequency: FREQUENT
  description: Circulating creatine is reduced because AGAT deficiency blocks endogenous creatine synthesis.
  phenotype_term:
    preferred_term: Reduced circulating creatine concentration
    term:
      id: HP:0034292
      label: Reduced circulating creatine concentration
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0034292 | Reduced circulating creatine concentration | Frequent (79-30%)"
    explanation: Orphanet reports reduced circulating creatine concentration as frequent.
- name: Decreased urine guanidinoacetic acid level
  frequency: FREQUENT
  description: Urinary guanidinoacetic acid is reduced because guanidinoacetate is the AGAT reaction product.
  phenotype_term:
    preferred_term: Decreased urine guanidinoacetic acid level
    term:
      id: HP:0034888
      label: Decreased urine guanidinoacetic acid level
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0034888 | Decreased urine guanidinoacetic acid level | Frequent (79-30%)"
    explanation: Orphanet reports decreased urinary guanidinoacetic acid as frequent.
- name: Decreased serum creatinine
  frequency: FREQUENT
  description: Serum creatinine is reduced as part of the creatine-deficiency biochemical profile.
  phenotype_term:
    preferred_term: Decreased serum creatinine
    term:
      id: HP:0012101
      label: Decreased serum creatinine
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012101 | Decreased serum creatinine | Frequent (79-30%)"
    explanation: Orphanet reports decreased serum creatinine as frequent.
- name: Decreased CSF creatinine concentration
  frequency: FREQUENT
  description: CSF creatinine is reduced within the central creatine-deficiency biochemical pattern.
  phenotype_term:
    preferred_term: Decreased CSF creatinine concentration
    term:
      id: HP:0034597
      label: Decreased CSF creatinine concentration
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0034597 | Decreased CSF creatinine concentration | Frequent (79-30%)"
    explanation: Orphanet reports decreased CSF creatinine concentration as frequent.
- name: Decreased urinary creatine level
  frequency: FREQUENT
  description: Urinary creatine is reduced because endogenous creatine synthesis is impaired.
  phenotype_term:
    preferred_term: Decreased urinary creatine level
    term:
      id: HP:6000748
      label: Decreased urinary creatine level
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000748 | Decreased urinary creatine level | Frequent (79-30%)"
    explanation: Orphanet reports decreased urinary creatine level as frequent.
- name: Decreased urine creatinine level
  frequency: FREQUENT
  description: Urinary creatinine is reduced as part of the low-creatine biochemical profile.
  phenotype_term:
    preferred_term: Decreased urine creatinine level
    term:
      id: HP:6000115
      label: Decreased urine creatinine level
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:6000115 | Decreased urine creatinine level | Frequent (79-30%)"
    explanation: Orphanet reports decreased urine creatinine level as frequent.
- name: Gait disturbance
  frequency: OCCASIONAL
  description: Gait disturbance is an occasional motor manifestation.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:35704
    reference_title: L-Arginine:glycine amidinotransferase deficiency
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Occasional (29-5%)"
    explanation: Orphanet reports gait disturbance as occasional.
- name: Cerebral atrophy
  description: >-
    Reduced cortical thickness and other structural abnormalities were reported
    in one 2025 family and remain an emerging, family-level observation.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:40323733
    reference_title: "Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite creatine supplementation, cortical thickness was significantly reduced across multiple brain regions compared to controls, as indicated by Z-scores.
    explanation: This is a single-family imaging observation and is not generalized to all AGAT deficiency.

biochemical:
- name: AGAT enzyme activity in cultured cells
  presence: DECREASED
  context: >-
    Absent or markedly reduced AGAT activity in a validated cultured-cell assay
    can functionally confirm the GATM defect.
  readouts:
  - target: GATM Loss and Reduced AGAT Activity
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reduced enzyme activity directly reports the proximal molecular defect.
    evidence:
    - reference: PMID:22386973
      reference_title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay.
      explanation: Patient lymphoblasts directly demonstrate the diagnostic enzyme-activity readout.
  evidence:
  - reference: PMID:22386973
    reference_title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay.
    explanation: The patient-derived cultured-cell assay found no detectable AGAT activity.
- name: Urine and plasma guanidinoacetate
  presence: DECREASED
  context: >-
    Low or undetectable guanidinoacetate in urine and plasma is the most direct
    metabolite signature of the blocked AGAT reaction.
  biomarker_term:
    preferred_term: guanidinoacetic acid
    term:
      id: CHEBI:16344
      label: guanidinoacetic acid
  readouts:
  - target: Reduced Guanidinoacetate and Endogenous Creatine Synthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low guanidinoacetate reports loss of the immediate AGAT reaction product.
    evidence:
    - reference: PMID:26490222
      reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
      explanation: The international cohort directly supports this product-level readout.
  evidence:
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
    explanation: This directly supports the combined low-guanidinoacetate and low-creatine body-fluid pattern.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
    explanation: The cohort establishes low urine and plasma guanidinoacetate.
- name: Urine and plasma creatine
  presence: DECREASED
  context: >-
    Low creatine in body fluids accompanies low guanidinoacetate; the combined
    pattern is more discriminating than low creatine alone.
  biomarker_term:
    preferred_term: creatine
    term:
      id: CHEBI:16919
      label: creatine
  readouts:
  - target: Reduced Guanidinoacetate and Endogenous Creatine Synthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Low body-fluid creatine reports reduced endogenous creatine synthesis.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
      explanation: Patient testing directly supports the combined low-metabolite pattern.
  evidence:
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
    explanation: The report documents low creatine in both plasma and urine.
- name: Cerebral creatine by proton magnetic resonance spectroscopy
  presence: DECREASED
  context: >-
    Absent or markedly reduced cerebral creatine on proton MRS supports a
    cerebral creatine deficiency syndrome but is interpreted with metabolite and
    molecular findings because it is not specific to AGAT deficiency.
  readouts:
  - target: Cerebral Creatine Depletion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A reduced brain creatine peak directly reports cerebral creatine depletion.
    evidence:
    - reference: PMID:23770102
      reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine.
      explanation: Proton MRS directly measures the cerebral-depletion node.
  evidence:
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
    explanation: The international cohort identifies cerebral creatine depletion as a common biochemical denominator.
genetic:
- name: Biallelic loss-of-function GATM variants
  association: Loss of AGAT catalytic activity
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: GATM
    term:
      id: hgnc:4175
      label: GATM
  features: >-
    Biallelic loss-of-function pathogenic variants in GATM cause autosomal
    recessive AGAT deficiency. This allelic mechanism is distinct from
    monoallelic GATM missense variants that cause autosomal dominant renal
    Fanconi syndrome.
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Biallelic pathogenic variants in GAMT result in guanidinoacetate methyltransferase deficiency and biallelic pathogenic variants in GATM result in l-arginine:glycine amidinotransferase deficiency.
    explanation: The review directly defines the biallelic GATM disease mechanism.
  - reference: CGGV:assertion_d63bfeff-882d-400f-af17-277a702fd09b-2019-03-08T170000.000Z
    reference_title: GATM / AGAT deficiency (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GATM | HGNC:4175 | AGAT deficiency | MONDO:0012996 | AR | Definitive
    explanation: ClinGen classifies the gene-disease relationship as definitive and autosomal recessive.
treatments:
- name: Oral creatine monohydrate supplementation
  action_category: THERAPEUTIC
  description: >-
    Oral creatine monohydrate bypasses impaired endogenous synthesis and is the
    disease-directed therapy. Published cohorts used 100–800 mg/kg/day, but this
    is an observed range rather than a universal prescription; dosing should be
    individualized by a metabolic specialist. Early treatment can prevent
    adverse developmental outcome, while later treatment can restore cerebral
    creatine, improve myopathy, and yield partial adaptive or cognitive gains.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    therapeutic_agent:
    - preferred_term: creatine
      term:
        id: CHEBI:16919
        label: creatine
  target_mechanisms:
  - target: Cerebral Creatine Depletion
    treatment_effect: RESTORES
    description: Oral creatine replenishes the measured cerebral creatine pool.
    evidence:
    - reference: PMID:28148286
      reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation.
      explanation: Serial MRS directly supports restoration of cerebral creatine.
  target_phenotypes:
  - preferred_term: Reduced brain creatine level by MRS
    term:
      id: HP:0025051
      label: Reduced brain creatine level by MRS
  - preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Myopathy
    term:
      id: HP:0003198
      label: Myopathy
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to replenish cerebral creatine levels.
    explanation: GeneReviews identifies oral creatine as disease-directed treatment.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy.
    explanation: Cohort data support the published dosing range and major biochemical and muscle responses.
  - reference: PMID:28148286
    reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but significant cognitive recovery with clear improvements in adaptive functioning.
    explanation: Long-term follow-up supports the importance of timing and residual benefit after later treatment.
- name: Developmental and neurologic supportive care
  action_category: THERAPEUTIC
  description: >-
    Individualized education and developmental therapies address developmental,
    language, cognitive, and behavioral needs. Neurology specialists manage
    seizures by standard approaches when they occur. These actions address
    consequences and do not alter the biochemical lesion.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  - preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The developmental delay, intellectual disability, and behavior problems are managed with an individualized education and therapy program; epilepsy and movement disorder are treated by the appropriate specialist in a standard manner.
    explanation: GeneReviews supports consequence-directed developmental and neurologic care.
- name: Creatine treatment surveillance
  action_category: MONITORING
  description: >-
    Periodically assess cerebral creatine by in vivo proton MRS, measure kidney
    function annually, and perform developmental and neurologic assessment at
    each clinic visit. Monitor weight and symptoms of nephrolithiasis during
    high-dose creatine treatment.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In those treated with creatine monohydrate, periodic determination of cerebral creatine level by in vivo 1H-MRS and annual measurement of kidney function to detect possible creatine-associated nephropathy is warranted. Developmental and neurologic assessments are recommended at each clinic visit.
    explanation: GeneReviews defines longitudinal MRS, renal, developmental, and neurologic surveillance.
  - reference: PMID:28148286
    reference_title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported.
    explanation: Long-term follow-up supports monitoring for weight gain and nephrolithiasis.
- name: Testing of at-risk newborn relatives
  action_category: SCREENING
  description: >-
    Biochemical or familial-variant testing of at-risk neonates enables
    presymptomatic diagnosis and early treatment.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Early diagnosis of neonates at risk for a CDD by biochemical or molecular genetic testing allows for early diagnosis and treatment.
    explanation: GeneReviews supports prompt testing of at-risk neonates.
- name: Genetic counseling and reproductive planning
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counsel families about autosomal recessive recurrence, carrier testing, and
    prenatal or preimplantation testing after familial variants are known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      If both parents are known to be heterozygous for a GAMT or GATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
    explanation: GeneReviews provides the autosomal recessive recurrence risks used in counseling.
- name: Pregnancy-specific creatine monitoring
  action_category: MONITORING
  description: >-
    A single reported pregnancy showed falling maternal urine and plasma
    creatine and dose adjustment. Pregnancy may increase creatine requirements;
    maternal metabolites and fetal growth should be followed with metabolic and
    obstetric specialist input, without assuming that every pregnancy requires
    dose escalation.
  evidence:
  - reference: PMID:32883247
    reference_title: "Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations, in particular in the urine sample, requiring prompt correction of the Cr dose.
    explanation: One case supports individualized biochemical monitoring and dose review during pregnancy.
diagnosis:
- name: Urine and plasma guanidinoacetate and creatine measurement
  description: >-
    Measure guanidinoacetate and creatine in urine and plasma. The characteristic
    AGAT pattern is low or undetectable guanidinoacetate together with low
    creatine; low creatine alone is not disease-specific.
  markers: Guanidinoacetate and creatine in urine and plasma
  results: Low or undetectable guanidinoacetate with low creatine supports AGAT deficiency.
  evidence:
  - reference: PMID:23770102
    reference_title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome.
    explanation: This directly supports the combined low-guanidinoacetate and low-creatine body-fluid pattern.
  - reference: PMID:26490222
    reference_title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels.
    explanation: The international cohort directly establishes the diagnostic metabolite pattern.
  - reference: PMID:28055022
    reference_title: "Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Several laboratory methods are available for preliminary and confirmatory diagnosis of these conditions, including measurement of creatine and related metabolites in biofluids using liquid chromatography-tandem mass spectrometry or gas chromatography-mass spectrometry, enzyme activity assays in cultured cells, and DNA sequence analysis.
    explanation: The ACMG laboratory guideline supports metabolite testing as part of preliminary and confirmatory diagnosis.
- name: Brain proton magnetic resonance spectroscopy
  description: >-
    Proton MRS evaluates the cerebral creatine peak. An absent or markedly
    reduced peak supports a cerebral creatine deficiency syndrome but must be
    interpreted with metabolite and molecular results.
  markers: Cerebral creatine peak
  results: Absent or markedly reduced cerebral creatine supports a cerebral creatine deficiency syndrome.
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic investigations such as targeted next-generation sequencing panel or exome sequencing can also identify these disorders; however, metabolite measurements and creatine in proton magnetic resonance spectroscopy are crucial to confirm the diagnosis.
    explanation: The review supports MRS as a key confirmatory component when combined with metabolite testing.
- name: Molecular confirmation of biallelic GATM variants
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Targeted next-generation sequencing panels or exome sequencing can identify
    biallelic pathogenic GATM variants.
  results: Biallelic pathogenic GATM variants establish the molecular diagnosis in a compatible phenotype.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of a CDD is established in a proband with suggestive findings and biallelic pathogenic variants in GAMT or GATM or a hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular genetic testing.
    explanation: GeneReviews directly supports molecular confirmation with biallelic GATM variants.
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic investigations such as targeted next-generation sequencing panel or exome sequencing can also identify these disorders; however, metabolite measurements and creatine in proton magnetic resonance spectroscopy are crucial to confirm the diagnosis.
    explanation: The review supports panel or exome sequencing while retaining biochemical and MRS confirmation.
- name: AGAT enzyme activity assay in cultured cells
  description: >-
    A validated cultured-cell enzyme assay can provide functional confirmation
    when molecular findings require clarification.
  markers: AGAT enzymatic activity
  results: Absent or markedly reduced AGAT activity supports a functional GATM defect.
  evidence:
  - reference: PMID:22386973
    reference_title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay.
    explanation: Patient lymphoblasts provide direct functional confirmation.
differential_diagnoses:
- name: Guanidinoacetate methyltransferase deficiency
  disease_term:
    preferred_term: guanidinoacetate methyltransferase deficiency
    term:
      id: MONDO:0012999
      label: guanidinoacetate methyltransferase deficiency
  description: >-
    GAMT deficiency also causes low cerebral and body-fluid creatine, but
    guanidinoacetate is elevated rather than low and epilepsy is much more
    characteristic.
  distinguishing_features:
  - Elevated guanidinoacetate with low creatine in GAMT deficiency
  - Low guanidinoacetate with low creatine in AGAT deficiency
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis can be suspected by elevated guanidinoacetate and low creatine levels in body fluids in guanidinoacetate methyltransferase deficiency, low guanidinoacetate and low creatine levels in body fluids in l-arginine:glycine amidinotransferase deficiency, and elevated creatine-to-creatinine ratio in urine in creatine transporter deficiency in males as well as absent or significantly decreased creatine level in brain proton magnetic resonance spectroscopy.
    explanation: The review directly contrasts the biochemical patterns.
- name: Creatine transporter deficiency
  disease_term:
    preferred_term: creatine transporter deficiency
    term:
      id: MONDO:0010305
      label: creatine transporter deficiency
  description: >-
    SLC6A8-related creatine transporter deficiency shares low cerebral creatine
    and neurodevelopmental features but typically shows an elevated urinary
    creatine-to-creatinine ratio in affected males rather than low
    guanidinoacetate.
  distinguishing_features:
  - X-linked SLC6A8 inheritance
  - Elevated urinary creatine-to-creatinine ratio in affected males
  - Low guanidinoacetate is characteristic of AGAT deficiency
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hemizygous pathogenic variant in males and heterozygous pathogenic variant in females in SLC6A8 result in creatine transporter deficiency.
    explanation: This supports the X-linked molecular distinction.
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis can be suspected by elevated guanidinoacetate and low creatine levels in body fluids in guanidinoacetate methyltransferase deficiency, low guanidinoacetate and low creatine levels in body fluids in l-arginine:glycine amidinotransferase deficiency, and elevated creatine-to-creatinine ratio in urine in creatine transporter deficiency in males as well as absent or significantly decreased creatine level in brain proton magnetic resonance spectroscopy.
    explanation: The biochemical comparison distinguishes the transporter disorder from AGAT deficiency.
- name: Autosomal dominant GATM-associated renal Fanconi syndrome
  description: >-
    Monoallelic GATM variants cause a distinct renal tubular and kidney failure
    disorder. This must not be conflated with biallelic loss-of-function AGAT
    deficiency.
  distinguishing_features:
  - Autosomal dominant monoallelic GATM missense variants
  - Renal Fanconi syndrome and progressive kidney failure
  evidence:
  - reference: PMID:29654216
    reference_title: Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency.
    explanation: The renal study directly separates the monoallelic renal disorder from recessive creatine deficiency.
experimental_models:
- name: GATM missense-variant enzyme activity assay
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Human cell-line expression assay for rare GATM missense variants
  description: >-
    Rare GATM missense variants were expressed and assayed for retained
    wild-type catalytic activity to support functional variant interpretation.
  conditions:
  - Wild-type GATM
  - Rare GATM missense variants
  modeled_mechanisms:
  - target: GATM Loss and Reduced AGAT Activity
    description: The expression assay measures variant-specific loss of GATM catalytic activity.
    evidence:
    - reference: PMID:27233232
      reference_title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
      explanation: The functional assay directly measures the modeled loss-of-activity mechanism.
  findings:
  - statement: Seven assayed missense variants retained no wild-type GATM activity.
    supporting_text: >-
      We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
    evidence:
    - reference: PMID:27233232
      reference_title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
      explanation: The functional assay directly supports the finding statement.
  evidence:
  - reference: PMID:27233232
    reference_title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found seven missense variants retaining 0% of wild-type GATM activity indicating putative pathogenicity.
    explanation: The functional assay directly demonstrates complete activity loss for seven variants.
discussions:
- discussion_id: gap_agat_epilepsy_spectrum
  prompt: >-
    Is epilepsy a reproducible AGAT deficiency manifestation, and if so, how do
    low cerebral creatine, structural brain changes, and inhibitory
    neurotransmission contribute?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Cerebral Creatine Depletion
  - phenotypes#Seizure
  rationale: >-
    GeneReviews summarized the original 16 reported individuals as having no
    epilepsy, whereas two 2025 studies reported focal, sensory, febrile, and
    temperature-related seizures. The new series are small and do not establish
    prevalence, a causal mechanism, or a seizure-specific creatine response.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders.
    explanation: The historical cohort boundary did not include epilepsy.
  - reference: PMID:40674085
    reference_title: "Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study presents the first cases of epilepsy in AGAT deficiency, suggesting its prevalence may be underestimated.
    explanation: New cases support spectrum expansion while leaving prevalence and mechanism unresolved.
- discussion_id: gap_agat_pregnancy_creatine_requirements
  prompt: >-
    How should creatine dose and biochemical targets be adjusted during
    pregnancy in people with AGAT deficiency?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Pregnancy-specific creatine monitoring
  rationale: >-
    The only detailed pregnancy report found declining maternal creatine and
    adjusted the dose, but a single case cannot define universal targets or
    prove that earlier or higher dosing changes fetal growth.
  evidence:
  - reference: PMID:32883247
    reference_title: "Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      From these data, however, it cannot be stated if a higher Cr dose or an earlier supplementation would have avoided the slight growth delay observed in the fetus.
    explanation: The authors explicitly identify the limits of the single-case dosing inference.
references:
- reference: ORPHA:35704
  title: L-Arginine:glycine amidinotransferase deficiency
- reference: PMID:20301745
  title: Creatine Deficiency Disorders.
  tags:
  - GeneReviews
- reference: PMID:22386973
  title: Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
- reference: PMID:23770102
  title: Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
- reference: PMID:26490222
  title: "Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide."
- reference: PMID:27233232
  title: Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
- reference: PMID:28055022
  title: "Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics."
- reference: PMID:28148286
  title: Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
- reference: PMID:29654216
  title: Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.
- reference: PMID:32883247
  title: "Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report."
- reference: PMID:36856349
  title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
- reference: PMID:40323733
  title: "Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study."
- reference: PMID:40674085
  title: "Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency."
- reference: CGGV:assertion_d63bfeff-882d-400f-af17-277a702fd09b-2019-03-08T170000.000Z
  title: GATM / AGAT deficiency (Definitive)
📚

References & Deep Research

References

14
ORPHA:35704
L-Arginine:glycine amidinotransferase deficiency
No top-level findings curated for this source.
PMID:20301745
Creatine Deficiency Disorders.
No top-level findings curated for this source.
PMID:22386973
Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.
No top-level findings curated for this source.
PMID:23770102
Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.
No top-level findings curated for this source.
PMID:26490222
Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide.
No top-level findings curated for this source.
PMID:27233232
Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM.
No top-level findings curated for this source.
PMID:28055022
Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.
No top-level findings curated for this source.
PMID:28148286
Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency.
No top-level findings curated for this source.
PMID:29654216
Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure.
No top-level findings curated for this source.
PMID:32883247
Increased creatine demand during pregnancy in Arginine: Glycine Amidino-Transferase deficiency: a case report.
No top-level findings curated for this source.
PMID:36856349
Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes.
No top-level findings curated for this source.
PMID:40323733
Focal epilepsy with sensory seizures associated with arginine:glycine amidinotransferase deficiency: A clinical and advanced magnetic resonance imaging study.
No top-level findings curated for this source.
PMID:40674085
Epilepsy expands the phenotype of L-arginine:glycine amidinotransferase deficiency.
No top-level findings curated for this source.
No top-level findings curated for this source.

Deep Research

2
Falcon ▸
AGAT Deficiency (GATM-related creatine synthesis defect) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 52 citations 2026-05-02T23:48:43.874766

AGAT Deficiency (GATM-related creatine synthesis defect) — Comprehensive Disease Characteristics Report

Target disease: AGAT Deficiency (autosomal recessive creatine biosynthesis disorder; a cerebral creatine deficiency disorder). (mulik2023creatinedeficiencydisorders pages 2-3, longo2011disordersofcreatine pages 2-3)

Key recent sources prioritized: - ClinGen CCDS Variant Curation Expert Panel (VCEP) specifications for GATM variant interpretation (May 2024). (goldstein2024clingenvariantcuration pages 3-4) - Review of creatine deficiency disorders (Mar 2023). (mulik2023creatinedeficiencydisorders pages 2-3) - CCDS diagnostic implementation statistics (Swiss laboratory study, Jan 2025). (kaufman2025diagnosticdelayin pages 1-2) - MRS case report demonstrating treatment response (Dec 2024). (garg2024magneticresonancespectroscopy pages 2-4)

1. Disease Information

1.1 Definition / overview

AGAT deficiency is an ultrarare inborn error of creatine biosynthesis caused by biallelic loss-of-function variants in GATM, encoding L-arginine:glycine amidinotransferase (AGAT), the first step in creatine synthesis. It causes cerebral creatine deficiency detectable by proton magnetic resonance spectroscopy (1H-MRS) and a neurodevelopmental phenotype (developmental delay/intellectual disability with prominent speech-language impairment), often with myopathy/proximal weakness. (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, longo2011disordersofcreatine pages 2-3)

1.2 Key identifiers and ontologies

  • MONDO: MONDO:0012996 (AGAT deficiency) (from Open Targets disease-target association output). (ndika2012developmentalprogressand pages 1-2)
  • OMIM (disease): 612718 (AGAT deficiency) (longo2011disordersofcreatine pages 2-3)
  • OMIM (gene): GATM 602360 (mulik2023creatinedeficiencydisorders pages 2-3)

Not retrieved in this tool run (needs external lookup to complete): Orphanet ID, MeSH ID, ICD-10/ICD-11 codes.

1.3 Synonyms / alternative names

  • L-arginine:glycine amidinotransferase deficiency (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)
  • GATM-related creatine deficiency / creatine synthesis defect (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)
  • Cerebral creatine deficiency disorder/syndrome (CCDD/CCDS), enzyme-defect subgroup (kaufman2025diagnosticdelayin pages 1-2)

Note: The synonym “cerebral creatine deficiency syndrome 3” appears in a CCDS case-report context (garg2024magneticresonancespectroscopy pages 2-4) but was not consistently used across the core genetics/biochemical literature retrieved here.

1.4 Evidence sources (patient-level vs aggregated)

Most clinical knowledge is derived from individual case reports and small case series (e.g., 16 patients worldwide in a 2015 cohort) and synthesized in reviews and expert-consensus variant interpretation guidance (ClinGen VCEP). (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, goldstein2024clingenvariantcuration pages 3-4)

2. Etiology

2.1 Disease causal factors

Primary cause: biallelic pathogenic variants in GATM leading to deficient AGAT enzyme activity (loss of function), impairing endogenous creatine synthesis. (mulik2023creatinedeficiencydisorders pages 2-3, goldstein2024clingenvariantcuration pages 3-4)

Authoritative expert consensus (ClinGen VCEP, 2024): the panel “determined loss-of-function is the disease mechanism” for GATM and applies the ACMG/AMP PVS1 framework to null variants expected to undergo NMD. (goldstein2024clingenvariantcuration pages 3-4)

2.2 Risk factors

  • Genetic risk factor: inheriting two pathogenic GATM alleles (autosomal recessive). Heterozygous parents are typically asymptomatic. (mulik2023creatinedeficiencydisorders pages 2-3)
  • Consanguinity: reported in at least one adult case report family structure. (verma2010arginineglycineamidinotransferasedeficiency pages 1-3)

No specific environmental/exogenous risk factors were identified in the retrieved evidence; AGAT deficiency is primarily a Mendelian enzymatic disorder.

2.3 Protective factors

No validated protective genetic variants or environmental protective factors were identified in the retrieved human evidence.

Model-organism inference: systemic AGAT deficiency in mice was associated with protection from metabolic syndrome (a separate phenotype outside the core neurodevelopmental disorder), suggesting complex systemic metabolic consequences of creatine depletion. (ndika2012developmentalprogressand pages 1-2)

2.4 Gene–environment interactions

No direct gene–environment interaction evidence specific to AGAT deficiency was identified in the retrieved literature.

3. Phenotypes

3.1 Core clinical phenotype spectrum

Across the largest human cohort retrieved (n=16), the dominant presentation was neurodevelopmental impairment with frequent myopathy: - Intellectual disability/developmental delay: 15/16 patients. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Myopathy/proximal muscle weakness: 8/16 patients. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Language delay / severe speech-language disorder: commonly reported. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, pintilie2021ararebut pages 4-5) - Behavioral/psychiatric features (including autistic-like features): reported in multiple families/reviews. (pintilie2021ararebut pages 4-5, ndika2012developmentalprogressand pages 1-2) - Seizures: rare/variable; present in some reports. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, ndika2012developmentalprogressand pages 1-2)

3.2 Age of onset, severity, and progression

  • Age at diagnosis has ranged from 3 weeks to 23 years across early literature summarized in a case report review. (ndika2012developmentalprogressand pages 5-6)
  • Adult presentations emphasizing insidious proximal weakness beginning in late adolescence/early adulthood have been described. (verma2010arginineglycineamidinotransferasedeficiency pages 1-3)
  • Neurodevelopmental outcomes are strongly time-dependent with treatment initiation (see Treatment section). (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

3.3 Laboratory/biochemical phenotypes (laboratory abnormalities)

  • Low/undetectable guanidinoacetate (GAA) in urine and plasma is a hallmark. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, mulik2023creatinedeficiencydisorders pages 2-3)
  • Low (or low-normal) creatine in body fluids and absent/markedly reduced brain creatine peak by 1H-MRS. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3)

3.4 Suggested HPO terms (non-exhaustive)

Based on retrieved clinical descriptions: - Developmental delay — HP:0001263 (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Intellectual disability — HP:0001249 (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Speech delay / severe speech impairment — HP:0000750 (speech delay) / HP:0002463 (aphasia may be too specific) (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Hypotonia — HP:0001252 (ndika2012developmentalprogressand pages 1-2) - Proximal muscle weakness / myopathy — HP:0003701 (proximal muscle weakness) / HP:0003198 (myopathy) (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Seizures — HP:0001250 (ndika2012developmentalprogressand pages 1-2) - Autistic-like behavior / behavioral abnormality — HP:0000729 (autistic behavior) / HP:0000708 (behavioral abnormality) (pintilie2021ararebut pages 4-5)

Note: HPO IDs are standard ontology suggestions; the supporting evidence for the phenotype presence is from the cited papers above.

4. Genetic/Molecular Information

4.1 Causal gene

  • Gene: GATM (encodes AGAT; mitochondrial glycine amidinotransferase). (longo2011disordersofcreatine pages 2-3)

4.2 Inheritance

  • Autosomal recessive inheritance with biallelic pathogenic variants. (mulik2023creatinedeficiencydisorders pages 2-3, goldstein2024clingenvariantcuration pages 3-4)

4.3 Pathogenic variant spectrum and examples

Reported variant types include truncating/null variants, missense variants, and splice variants. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 5-7)

Examples explicitly mentioned in retrieved evidence: - c.484+1G>T (splice) in a long-term supplementation case series context. (ndika2012developmentalprogressand pages 1-2) - p.W149X (nonsense) reported in the Longo review excerpt and as a shared variant in an Italian family follow-up cohort (p.Trp149). (longo2011disordersofcreatine pages 2-3, battini2017fifteenyearfollowupof pages 2-4) - 1111_1112insA (frameshift insertion) in a two-patient report. (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2) - R169X* (nonsense) in an adult-onset myopathy report. (verma2010arginineglycineamidinotransferasedeficiency pages 1-3)

4.4 Variant interpretation guidance (expert consensus; 2024)

The ClinGen CCDS VCEP created gene- and disease-specific ACMG/AMP specifications for GATM, explicitly integrating disease biomarkers (GAA/creatine in body fluids and brain MRS creatine) into phenotype evidence (PP4) via a points-based system. (goldstein2024clingenvariantcuration pages 8-9, goldstein2024clingenvariantcuration pages 13-18)

Key quantitative thresholds reported for GATM by the VCEP include: - Estimated prevalence used for calculations: 1 in 3,450,000 (goldstein2024clingenvariantcuration pages 4-6) - Allele frequency thresholds: BA1 >0.0005, BS1 >0.0001, PM2_supporting <0.000055. (goldstein2024clingenvariantcuration pages 13-18)

4.5 Modifier genes / epigenetics / chromosomal abnormalities

No modifier genes, epigenetic mechanisms, or chromosomal abnormalities specific to AGAT deficiency were identified in the retrieved evidence.

5. Environmental Information

No disease-specific environmental toxins, lifestyle contributors, or infectious triggers were identified in the retrieved evidence. AGAT deficiency is primarily a genetic enzymatic deficiency. (mulik2023creatinedeficiencydisorders pages 2-3, goldstein2024clingenvariantcuration pages 3-4)

6. Mechanism / Pathophysiology

6.1 Core biochemical pathway defect

AGAT catalyzes the first and rate-limiting step of creatine biosynthesis: - Arginine + glycine → guanidinoacetate (GAA) + ornithine. (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2, verma2010arginineglycineamidinotransferasedeficiency pages 1-3)

Loss of AGAT activity causes: - Marked reduction of GAA production (low/undetectable GAA in urine/plasma). (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2) - Secondary creatine deficiency, including in brain, detectable as absent/markedly reduced creatine signal by 1H-MRS. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3)

6.2 Causal chain (upstream → downstream)

  • Upstream trigger: biallelic loss-of-function variants in GATM → reduced/absent AGAT enzyme function. (goldstein2024clingenvariantcuration pages 3-4)
  • Metabolic consequence: low GAA and deficient creatine synthesis → inadequate creatine/phosphocreatine availability, particularly in energy-demanding tissues (brain, muscle). (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)
  • Clinical consequence: neurodevelopmental impairment with major speech/language deficits and myopathy/proximal weakness; seizures variably. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

6.3 Key biochemical abnormalities (diagnostic biomarkers)

  • Low/undetectable GAA in plasma/urine and low creatine; absent or markedly decreased brain creatine peak on 1H-MRS. (mulik2023creatinedeficiencydisorders pages 2-3)

6.4 Suggested GO and CL terms (mechanism-oriented suggestions)

  • GO:0006600 creatine biosynthetic process (general) (supported conceptually by creatine synthesis defect described in multiple sources). (mulik2023creatinedeficiencydisorders pages 2-3, edvardson2010larginineglycineamidinotransferase(agat) pages 1-2)
  • GO:0003848 arginine:glycine amidinotransferase activity (enzyme function) (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2)
  • CL terms (likely impacted cell types):
  • Neurons (e.g., cortical neurons) and skeletal muscle myocytes as high-energy demand cell types implicated by clinical phenotype and MRS/myopathy findings. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

7. Anatomical Structures Affected

7.1 Organ/system level

  • Central nervous system: cerebral creatine deficiency on MRS, neurodevelopmental phenotype. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3, garg2024magneticresonancespectroscopy pages 2-4)
  • Skeletal muscle: proximal myopathy/weakness in many patients; adult myopathy presentations reported. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, verma2010arginineglycineamidinotransferasedeficiency pages 1-3)

7.2 Suggested UBERON terms (examples)

  • Brain — UBERON:0000955 (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3)
  • Skeletal muscle tissue — UBERON:0001134 (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

7.3 Subcellular localization (suggested)

AGAT is encoded by mitochondrial glycine amidinotransferase (gene-level description in review literature), suggesting mitochondrial relevance in creatine biosynthesis and cellular energy buffering. (longo2011disordersofcreatine pages 2-3)

8. Temporal Development

8.1 Onset

Common onset is in infancy/early childhood with developmental delay and speech delay, though diagnosis may occur later and adult-onset myopathy has been described. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, verma2010arginineglycineamidinotransferasedeficiency pages 1-3, ndika2012developmentalprogressand pages 5-6)

8.2 Progression/course

  • Without early treatment, persistent neurocognitive and language deficits may occur. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, battini2017fifteenyearfollowupof pages 7-8)
  • With treatment, cerebral creatine can be replenished over months (tracked by serial MRS), and muscle symptoms may improve relatively rapidly. (verma2010arginineglycineamidinotransferasedeficiency pages 1-3, battini2017fifteenyearfollowupof pages 4-7)

9. Inheritance and Population

9.1 Epidemiology (rarity)

AGAT deficiency is consistently described as ultrarare, with <20–25 individuals reported in the literature in recent summaries. (mulik2023creatinedeficiencydisorders pages 2-3, goldstein2024clingenvariantcuration pages 1-3)

9.2 Prevalence / carrier frequency estimates

  • A 2023 review reports an estimated carrier frequency of 0.077% (method not detailed in excerpt). (mulik2023creatinedeficiencydisorders pages 2-3)
  • ClinGen VCEP (for variant-frequency threshold setting) used an estimated prevalence of 1 in 3,450,000 for GATM-related disease. (goldstein2024clingenvariantcuration pages 4-6)

9.3 Penetrance/expressivity

ClinGen VCEP treated biallelic pathogenic variants in GATM as fully penetrant for purposes of allele-frequency calculations and variant interpretation (maximum genetic contribution and penetrance set to 100%). (goldstein2024clingenvariantcuration pages 4-6)

10. Diagnostics

10.1 Core diagnostic tests and biomarkers

Biochemical testing - Urine and plasma GAA and creatine measurements are central; low/undetectable GAA with low creatine supports AGAT deficiency. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

Neuroimaging - 1H-MRS: absent/markedly decreased brain creatine peak is a hallmark; MRI can be normal. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3, garg2024magneticresonancespectroscopy pages 2-4)

Genetic confirmation - GATM sequencing (single gene, panel, WES/WGS) to confirm biallelic pathogenic variants. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8)

Functional confirmation - In uncertain genetic cases, AGAT enzyme activity in fibroblasts may help resolve interpretation. (mulik2023creatinedeficiencydisorders pages 2-3, goldstein2024clingenvariantcuration pages 13-18)

10.2 Real-world diagnostic implementation and delays (statistics)

A Swiss cross-sectional/systems study (2015–2023) on cerebral creatine deficiency disorders reported: - Diagnostic/therapeutic delay 3–32 months (mean 13.8 months) in their cohort. (kaufman2025diagnosticdelayin pages 1-2) - Total 4,967 guanidinoacetate and creatine measurements performed (urine+plasma) across two Swiss centers (2015–2023). (kaufman2025diagnosticdelayin pages 4-5) - Testing volume increased from 312 analyses (2015) to 883 (2023). (kaufman2025diagnosticdelayin pages 2-4) - Urine is described as “the preferred sample for CCDD detection” and “clearly the best matrix for the initial selective screening.” (kaufman2025diagnosticdelayin pages 1-2, kaufman2025diagnosticdelayin pages 6-8)

10.3 Differential diagnosis (high-level)

AGAT deficiency should be differentiated from other cerebral creatine deficiency disorders: - GAMT deficiency (elevated GAA rather than low) and SLC6A8 creatine transporter deficiency (different urine creatine/creatinine patterns; often poor response to creatine). (mulik2023creatinedeficiencydisorders pages 1-2, kaufman2025diagnosticdelayin pages 1-2)

10.4 Screening

Newborn screening feasibility and challenges - The 2015 cohort argues AGAT deficiency is “an ideal candidate for newborn screening” because early treatment can prevent adverse outcomes, but notes it is “difficult to devise a sensitive screening algorithm based on GAA quantitation alone,” proposing multianalyte DBS algorithms or enzyme assay approaches. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8)

11. Outcome / Prognosis

11.1 Prognosis with treatment (long-term data)

A 15-year follow-up cohort (Italy; 4 patients) indicates: - Long-term oral creatine is generally safe and well tolerated; renal function was preserved with monitoring, though occasional kidney stones and other side effects occurred. (battini2017fifteenyearfollowupof pages 4-7) - Early treatment can prevent adverse developmental outcomes; later-treated patients often have persistent neurocognitive deficits, but adaptive functioning can improve. (battini2017fifteenyearfollowupof pages 1-2)

11.2 Prognostic factors

Age at treatment initiation is repeatedly highlighted as the dominant prognostic factor for neurocognitive outcomes. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)

12. Treatment

12.1 Standard-of-care pharmacotherapy

Creatine monohydrate supplementation is the main disease-specific therapy.

Dosing ranges reported across studies: - 100–800 mg/kg/day across cohorts and reviews. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, mulik2023creatinedeficiencydisorders pages 2-3) - A 2023 review states: “While all 3 disorders are currently treated with creatine supplementation,” and specifies for AGAT deficiency that oral creatine has been used and benefit depends on early initiation. (mulik2023creatinedeficiencydisorders pages 1-2)

Evidence for time-dependent neurocognitive benefit (review): - Cognitive restoration reported when treatment started <2 years, but not when started after age 10 in the 2023 review summary. (mulik2023creatinedeficiencydisorders pages 2-3)

Long-term treatment strategies / tapering (Italian follow-up cohort): - Symptomatic patients began at ~400 mg/kg/day, later reduced to 200–300 mg/kg/day, then 100 mg/kg/day guided by MRS and biochemical monitoring. (battini2017fifteenyearfollowupof pages 1-2)

12.2 Treatment outcomes

  • Creatine supplementation often increases cerebral creatine on MRS and improves myopathy; however, complete normalization of cerebral creatine is not universal even with very high doses. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8)
  • In an MRS-focused clinical case report (44-month-old), pretreatment MRS had no definable creatine peak at 3.0 ppm and follow-up MRS at 5 months showed reappearance of the creatine peak after supplementation. (garg2024magneticresonancespectroscopy pages 2-4)

12.3 Adverse effects and monitoring

Reported adverse events/side effects with chronic creatine therapy include: - Weight gain, polyuria/polydipsia, transient diarrhea with dose increases, urinary creatine crystals, and kidney stones (at least one asymptomatic). (battini2017fifteenyearfollowupof pages 4-7, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8)

Monitoring strategies include serial urine/plasma creatine and GAA and periodic MRS (1H/31P) to track brain replenishment and guide dosing. (battini2017fifteenyearfollowupof pages 4-7)

12.4 Pregnancy management (real-world implementation)

A pregnancy case report (2020) describes a woman with AGAT deficiency requiring close monitoring due to increased creatine demand: - Abstract quote: “Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations… requiring prompt correction of the Cr dose.” (Sep 2020). (alessandri2020increasedcreatinedemand pages 1-2) - The mother’s creatine dose was increased (e.g., to 3 g/day mid-pregnancy), and the infant had normal brain creatine and typical developmental milestones at one year. (alessandri2020increasedcreatinedemand pages 2-4, alessandri2020increasedcreatinedemand pages 1-2)

12.5 Suggested MAXO terms (treatment action ontology; suggestions)

  • Creatine supplementation therapy (oral) (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2)
  • Magnetic resonance spectroscopy monitoring (treatment-response monitoring) (battini2017fifteenyearfollowupof pages 4-7)
  • Genetic counseling (autosomal recessive disorder; prenatal testing possible when familial variants known) (mulik2023creatinedeficiencydisorders pages 2-3)

13. Prevention

13.1 Primary/secondary prevention

No primary prevention exists for a Mendelian enzymatic deficiency, but secondary prevention via early detection and early creatine supplementation is repeatedly emphasized.

Early treatment prevention concept: - A 2023 review notes the disorders are treatable with creatine, and early treatment in AGAT deficiency can prevent adverse outcomes. (mulik2023creatinedeficiencydisorders pages 2-3) - A 2015 cohort states: “Early treatment seems to prevent adverse developmental outcomes.” (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8)

13.2 Newborn screening implementation

  • Early Check expanded newborn screening program includes AGAT deficiency on its screening panel and operationalizes confirmatory testing and genetic counseling after positive screens (observational cohort; estimated enrollment 30,000 newborns). (NCT03655223 chunk 2)

14. Other Species / Natural Disease

No naturally occurring veterinary cases were retrievable in the accessible full texts for this run (a relevant 2026 dog paper was listed as unobtainable by the search tool). Therefore, no curated cross-species natural disease entry can be provided from the current evidence set.

15. Model Organisms

15.1 Mouse model evidence

An AGAT-deficient mouse model has been used to study systemic creatine depletion and metabolic consequences; one study reports that AGAT deficiency protects from metabolic syndrome (model-organism phenotype not directly equivalent to the human neurodevelopmental disorder but informative for systemic pathway biology). (ndika2012developmentalprogressand pages 1-2)

Key abstract quotes (supporting major claims)

  1. Creatine deficiency disorders review (Mar 2023):

  2. “Biallelic pathogenic variants in GATM result in l-arginine:glycine amidinotransferase deficiency.” (mulik2023creatinedeficiencydisorders pages 2-3)

  3. Pregnancy in AGAT deficiency (Sep 2020):

  4. “Biochemical monitoring of Cr in biological fluids of the mother revealed a decline of the Cr concentrations… requiring prompt correction of the Cr dose.” (alessandri2020increasedcreatinedemand pages 1-2)

  5. Long-term Italian follow-up (Feb 2017):

  6. “Consecutive MRS examinations have confirmed that Cr depletion in AGAT-d patients is reversible under Cr supplementation.” (ndika2012developmentalprogressand pages 1-2)

Summary artifact

The following table provides a compact disease knowledge-base-ready summary (identifiers, biomarkers, phenotypes, diagnostics, dosing, outcomes, screening):

Domain Key facts Key sources (citation ids) URLs/publication years when available
Disease/identifiers AGAT deficiency is a GATM-related cerebral creatine deficiency disorder, inherited in an autosomal recessive manner; reported as ultrarare with fewer than 20-25 patients/individuals described in the literature. OMIM identifiers reported in gathered evidence include AGAT deficiency OMIM #612718 and GATM gene OMIM #602360. MONDO association evidence supports MONDO:0012996 for AGAT deficiency. (mulik2023creatinedeficiencydisorders pages 2-3, mulik2023creatinedeficiencydisorders pages 1-2, longo2011disordersofcreatine pages 2-3) Mulik 2023: https://doi.org/10.5152/turkarchpediatr.2023.23022; Longo 2011: https://doi.org/10.1002/ajmg.c.30292; Open Targets evidence includes MONDO_0012996
Gene/mechanism GATM encodes AGAT, the first/rate-limiting enzyme of creatine biosynthesis, catalyzing arginine + glycine to guanidinoacetate (GAA) and ornithine. Disease mechanism is loss of function; ClinGen CCDS VCEP applies PVS1 to GATM and considers AGAT deficiency a fully penetrant autosomal recessive creatine synthesis disorder. (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2, goldstein2024clingenvariantcuration pages 3-4, goldstein2024clingenvariantcuration pages 4-6) Edvardson 2010: https://doi.org/10.1016/j.ymgme.2010.06.021; Goldstein 2024: https://doi.org/10.1016/j.ymgme.2024.108362
Biochemical signature Hallmark profile: very low/undetectable GAA in urine and plasma, low or low-normal creatine/creatinine in urine, plasma, and sometimes CSF, with absent or markedly decreased brain creatine peak on 1H-MRS. Pretreatment cerebral creatine is markedly reduced or absent in essentially all studied patients. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 5-7, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3) Mulik 2023: https://doi.org/10.5152/turkarchpediatr.2023.23022; Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003
Core phenotypes Most common manifestations are developmental delay/intellectual disability and severe speech/language delay; behavioral problems/autistic-like features are frequent. Myopathy/proximal muscle weakness occurs in about half of reported patients or 8/16 in the largest series; hypotonia, failure to thrive/low weight, and rare seizures have also been reported. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, pintilie2021ararebut pages 4-5, verma2010arginineglycineamidinotransferasedeficiency pages 1-3, ndika2012developmentalprogressand pages 5-6) Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; Pintilie 2021: https://doi.org/10.37897/rjp.2021.3.4; Verma 2010: https://doi.org/10.1212/wnl.0b013e3181e7cabd; Ndika 2012: https://doi.org/10.1016/j.ymgme.2012.01.017
Onset/natural history Age at diagnosis reported from 3 weeks to 23 years. Early infancy/childhood presentations predominate, but adult-onset or later-recognized myopathy has been described. Untreated disease can lead to persistent cognitive/language impairment; early-treated infants can remain asymptomatic or achieve normal neurodevelopment. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, verma2010arginineglycineamidinotransferasedeficiency pages 1-3, ndika2012developmentalprogressand pages 5-6, battini2017fifteenyearfollowupof pages 1-2) Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; Verma 2010: https://doi.org/10.1212/wnl.0b013e3181e7cabd; Ndika 2012: https://doi.org/10.1016/j.ymgme.2012.01.017; Battini 2017: https://doi.org/10.1186/s13023-017-0577-5
Diagnostics Recommended workup includes urine and plasma GAA/creatine testing, brain 1H-MRS to document absent or reduced creatine peak, and confirmatory GATM sequencing; WES/WGS are alternatives. Functional confirmation can include AGAT enzyme activity in fibroblasts when variants are uncertain. ClinGen 2024 formalized phenotype/biomarker-based PP4 scoring using low GAA, low creatine, MRS findings, and enzyme activity. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8, goldstein2024clingenvariantcuration pages 8-9, goldstein2024clingenvariantcuration pages 13-18) Mulik 2023: https://doi.org/10.5152/turkarchpediatr.2023.23022; Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; Goldstein 2024: https://doi.org/10.1016/j.ymgme.2024.108362
MRS implementation Brain MRI may be normal, but MRS is highly informative: absent/undefinable creatine peak at ~3.0 ppm is a characteristic finding, and follow-up MRS can document reappearance of the peak after treatment. (garg2024magneticresonancespectroscopy pages 4-5, garg2024magneticresonancespectroscopy pages 2-4, garg2024magneticresonancespectroscopy pages 1-2) Garg 2024: https://doi.org/10.25259/crcr_92_2024
Treatment Main disease-specific therapy is oral creatine monohydrate supplementation. Dosing reported across studies ranges from 100-800 mg/kg/day; common long-term regimens include ~400 mg/kg/day initially with later taper to 200-100 mg/kg/day based on MRS/biochemical monitoring. Adult case reports also used 5 g/day with later escalation to weight-based dosing. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 3-4, battini2017fifteenyearfollowupof pages 1-2, battini2017fifteenyearfollowupof pages 7-8) Mulik 2023: https://doi.org/10.5152/turkarchpediatr.2023.23022; Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; Battini 2017: https://doi.org/10.1186/s13023-017-0577-5
Treatment outcomes Creatine supplementation significantly improves or normalizes muscle function in most patients and increases cerebral creatine on MRS, but complete normalization is not universal even at high doses. Developmental/cognitive outcomes are strongly time-dependent: treatment begun in infancy (<2 years in review evidence; as early as 4-16 months in case series) can prevent adverse neurodevelopmental outcomes, whereas treatment started after ~10 years yields limited cognitive recovery. (mulik2023creatinedeficiencydisorders pages 2-3, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 1-2, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8, battini2017fifteenyearfollowupof pages 1-2, battini2017fifteenyearfollowupof pages 4-7) Mulik 2023: https://doi.org/10.5152/turkarchpediatr.2023.23022; Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; Battini 2017: https://doi.org/10.1186/s13023-017-0577-5
Monitoring/adverse effects Monitoring strategies include serial plasma/urine creatine and GAA, neuropsychological assessment, and repeat brain MRS. Reported adverse effects are generally mild but include weight gain, polyuria/polydipsia, transient diarrhea with dose increases, urinary creatine crystals, and occasional kidney stones; renal function was generally preserved in long-term follow-up. (battini2017fifteenyearfollowupof pages 1-2, battini2017fifteenyearfollowupof pages 4-7, battini2017fifteenyearfollowupof pages 7-8) Battini 2017: https://doi.org/10.1186/s13023-017-0577-5
Epidemiology/screening implementation AGAT deficiency is an extreme ultrarare disorder; ClinGen used an estimated prevalence of ~1 in 3,450,000 for GATM-related disease in variant-classification threshold setting. Newborn screening is considered attractive because early treatment can prevent disease, but AGAT is harder to detect than GAMT using GAA alone; proposed approaches include multianalyte dried-blood-spot algorithms or enzyme assays. Early Check (NCT03655223) explicitly includes AGAT deficiency in an expanded newborn screening program, while BioCDS (NCT02934854) aimed to develop DBS mass-spectrometry biomarkers but was withdrawn with enrollment 0. (goldstein2024clingenvariantcuration pages 4-6, stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8, NCT03655223 chunk 2, NCT02934854 chunk 1) Goldstein 2024: https://doi.org/10.1016/j.ymgme.2024.108362; Stockler-Ipsiroglu 2015: https://doi.org/10.1016/j.ymgme.2015.10.003; NCT03655223: https://clinicaltrials.gov/study/NCT03655223 (2018-ongoing); NCT02934854: https://clinicaltrials.gov/study/NCT02934854 (2018, withdrawn)

Table: This table condenses the most actionable disease-level facts for GATM-related AGAT deficiency, including identifiers, biochemical hallmarks, clinical presentation, diagnostics, and treatment evidence with dosing ranges. It is useful as a quick-reference artifact for a disease knowledge base entry.

Clinical trials / real-world studies relevant to AGAT deficiency

  1. Early Check: Expanded Screening in Newborns (ClinicalTrials.gov NCT03655223, posted 2018; observational; estimated enrollment 30,000)

  2. Explicitly lists Agat Deficiency on its screening panel and provides confirmatory testing and genetic counseling workflow. URL: https://clinicaltrials.gov/study/NCT03655223 (NCT03655223 chunk 2)

  3. Biomarker for Creatine Deficiency Syndromes (BioCDS) (ClinicalTrials.gov NCT02934854, posted 2018; observational; withdrawn, enrollment 0)

  4. Proposed DBS LC/MRM-MS biomarker discovery/validation with GATM sequencing; withdrawn due to “Transition into BioMetabol.” URL: https://clinicaltrials.gov/study/NCT02934854 (NCT02934854 chunk 1)

Important limitations of this report (data not retrieved in-tool)

  • Orphanet/MeSH/ICD codes were not retrieved via the available full texts and would require targeted database queries.
  • Variant-level allele frequencies in gnomAD and comprehensive ClinVar variant lists are not included beyond the ClinGen thresholds and exemplar variants available in the retrieved excerpts.
  • Many phenotype frequencies beyond IDD (15/16) and myopathy (8/16) were not extractable from the provided excerpts and would require full-table extraction from primary cohorts.

References

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  2. (longo2011disordersofcreatine pages 2-3): Nicola Longo, Orly Ardon, Rena Vanzo, Elizabeth Schwartz, and Marzia Pasquali. Disorders of creatine transport and metabolism. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 157:72-78, Feb 2011. URL: https://doi.org/10.1002/ajmg.c.30292, doi:10.1002/ajmg.c.30292. This article has 135 citations.

  3. (goldstein2024clingenvariantcuration pages 3-4): Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, and Saadet Mercimek-Andrews. Clingen variant curation expert panel recommendations for classification of variants in gamt, gatm and slc6a8 for cerebral creatine deficiency syndromes. Molecular Genetics and Metabolism, 142:108362, May 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108362, doi:10.1016/j.ymgme.2024.108362. This article has 12 citations and is from a peer-reviewed journal.

  4. (kaufman2025diagnosticdelayin pages 1-2): Christina Kaufman, Anaïs D’Andrea, Annette Hackenberg, Martin Poms, Olivier Braissant, and Johannes Häberle. Diagnostic delay in cerebral creatine deficiency disorders: lessons learned from a cross-sectional single center study, and guanidinoacetate and creatine measurements in switzerland between 2015 and 2023. Molecular and Cellular Pediatrics, Jan 2025. URL: https://doi.org/10.1186/s40348-024-00188-4, doi:10.1186/s40348-024-00188-4. This article has 2 citations.

  5. (garg2024magneticresonancespectroscopy pages 2-4): Ankita Garg, Rajiv Gupta, Jayesh Ashok Kumar Modi, and Debolina Kabiraj. Magnetic resonance spectroscopy as a diagnostic tool in cerebral creatine deficiency syndrome 3. Case Reports in Clinical Radiology, 0:1-5, Dec 2024. URL: https://doi.org/10.25259/crcr_92_2024, doi:10.25259/crcr_92_2024. This article has 0 citations.

  6. (edvardson2010larginineglycineamidinotransferase(agat) pages 1-2): Simon Edvardson, Stanley H. Korman, Amir Livne, Avraham Shaag, Ann Saada, Ruppen Nalbandian, Hyla Allouche-Arnon, J. Moshe Gomori, and Rachel Katz-Brull. L-arginine:glycine amidinotransferase (agat) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. Molecular Genetics and Metabolism, 101:228-232, Oct 2010. URL: https://doi.org/10.1016/j.ymgme.2010.06.021, doi:10.1016/j.ymgme.2010.06.021. This article has 72 citations and is from a peer-reviewed journal.

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  8. (ndika2012developmentalprogressand pages 1-2): Joseph D.T. Ndika, Kathreen Johnston, James A. Barkovich, Michael D. Wirt, Patricia O'Neill, Ofir T. Betsalel, Cornelis Jakobs, and Gajja S. Salomons. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Molecular Genetics and Metabolism, 106:48-54, May 2012. URL: https://doi.org/10.1016/j.ymgme.2012.01.017, doi:10.1016/j.ymgme.2012.01.017. This article has 48 citations and is from a peer-reviewed journal.

  9. (verma2010arginineglycineamidinotransferasedeficiency pages 1-3): Ashok Verma. Arginine:glycine amidinotransferase deficiency: a treatable metabolic encephalomyopathy. Neurology, 75:186-188, Jul 2010. URL: https://doi.org/10.1212/wnl.0b013e3181e7cabd, doi:10.1212/wnl.0b013e3181e7cabd. This article has 24 citations and is from a highest quality peer-reviewed journal.

  10. (pintilie2021ararebut pages 4-5): Sebastian Romeo Pintilie, Adriana Fodor, Marius Bembea, Codruța Diana Petchesi, Simona Grad, Laura Damian, and Romana Vulturar. A rare but treatable inborn error of metabolism: arginine glycine amidinotransferase (agat) deficiency. Romanian Journal of Pediatrics, 70:186-191, Sep 2021. URL: https://doi.org/10.37897/rjp.2021.3.4, doi:10.37897/rjp.2021.3.4. This article has 0 citations.

  11. (ndika2012developmentalprogressand pages 5-6): Joseph D.T. Ndika, Kathreen Johnston, James A. Barkovich, Michael D. Wirt, Patricia O'Neill, Ofir T. Betsalel, Cornelis Jakobs, and Gajja S. Salomons. Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency. Molecular Genetics and Metabolism, 106:48-54, May 2012. URL: https://doi.org/10.1016/j.ymgme.2012.01.017, doi:10.1016/j.ymgme.2012.01.017. This article has 48 citations and is from a peer-reviewed journal.

  12. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 2-3): Sylvia Stockler-Ipsiroglu, Delia Apatean, Roberta Battini, Suzanne DeBrosse, Kimberley Dessoffy, Simon Edvardson, Florian Eichler, Katherine Johnston, David M. Koeller, Sonia Nouioua, Meriem Tazir, Ashok Verma, Monica D. Dowling, Klaas J. Wierenga, Andrea M. Wierenga, Victor Zhang, and Lee-Jun C. Wong. Arginine:glycine amidinotransferase (agat) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Molecular Genetics and Metabolism, 116:252-259, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.003, doi:10.1016/j.ymgme.2015.10.003. This article has 82 citations and is from a peer-reviewed journal.

  13. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 5-7): Sylvia Stockler-Ipsiroglu, Delia Apatean, Roberta Battini, Suzanne DeBrosse, Kimberley Dessoffy, Simon Edvardson, Florian Eichler, Katherine Johnston, David M. Koeller, Sonia Nouioua, Meriem Tazir, Ashok Verma, Monica D. Dowling, Klaas J. Wierenga, Andrea M. Wierenga, Victor Zhang, and Lee-Jun C. Wong. Arginine:glycine amidinotransferase (agat) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Molecular Genetics and Metabolism, 116:252-259, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.003, doi:10.1016/j.ymgme.2015.10.003. This article has 82 citations and is from a peer-reviewed journal.

  14. (battini2017fifteenyearfollowupof pages 2-4): Roberta Battini, M. Grazia Alessandrì, Claudia Casalini, Manuela Casarano, Michela Tosetti, and Giovanni Cioni. Fifteen-year follow-up of italian families affected by arginine glycine amidinotransferase deficiency. Orphanet Journal of Rare Diseases, Feb 2017. URL: https://doi.org/10.1186/s13023-017-0577-5, doi:10.1186/s13023-017-0577-5. This article has 22 citations and is from a peer-reviewed journal.

  15. (goldstein2024clingenvariantcuration pages 8-9): Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, and Saadet Mercimek-Andrews. Clingen variant curation expert panel recommendations for classification of variants in gamt, gatm and slc6a8 for cerebral creatine deficiency syndromes. Molecular Genetics and Metabolism, 142:108362, May 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108362, doi:10.1016/j.ymgme.2024.108362. This article has 12 citations and is from a peer-reviewed journal.

  16. (goldstein2024clingenvariantcuration pages 13-18): Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, and Saadet Mercimek-Andrews. Clingen variant curation expert panel recommendations for classification of variants in gamt, gatm and slc6a8 for cerebral creatine deficiency syndromes. Molecular Genetics and Metabolism, 142:108362, May 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108362, doi:10.1016/j.ymgme.2024.108362. This article has 12 citations and is from a peer-reviewed journal.

  17. (goldstein2024clingenvariantcuration pages 4-6): Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, and Saadet Mercimek-Andrews. Clingen variant curation expert panel recommendations for classification of variants in gamt, gatm and slc6a8 for cerebral creatine deficiency syndromes. Molecular Genetics and Metabolism, 142:108362, May 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108362, doi:10.1016/j.ymgme.2024.108362. This article has 12 citations and is from a peer-reviewed journal.

  18. (battini2017fifteenyearfollowupof pages 7-8): Roberta Battini, M. Grazia Alessandrì, Claudia Casalini, Manuela Casarano, Michela Tosetti, and Giovanni Cioni. Fifteen-year follow-up of italian families affected by arginine glycine amidinotransferase deficiency. Orphanet Journal of Rare Diseases, Feb 2017. URL: https://doi.org/10.1186/s13023-017-0577-5, doi:10.1186/s13023-017-0577-5. This article has 22 citations and is from a peer-reviewed journal.

  19. (battini2017fifteenyearfollowupof pages 4-7): Roberta Battini, M. Grazia Alessandrì, Claudia Casalini, Manuela Casarano, Michela Tosetti, and Giovanni Cioni. Fifteen-year follow-up of italian families affected by arginine glycine amidinotransferase deficiency. Orphanet Journal of Rare Diseases, Feb 2017. URL: https://doi.org/10.1186/s13023-017-0577-5, doi:10.1186/s13023-017-0577-5. This article has 22 citations and is from a peer-reviewed journal.

  20. (goldstein2024clingenvariantcuration pages 1-3): Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, and Saadet Mercimek-Andrews. Clingen variant curation expert panel recommendations for classification of variants in gamt, gatm and slc6a8 for cerebral creatine deficiency syndromes. Molecular Genetics and Metabolism, 142:108362, May 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108362, doi:10.1016/j.ymgme.2024.108362. This article has 12 citations and is from a peer-reviewed journal.

  21. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 7-8): Sylvia Stockler-Ipsiroglu, Delia Apatean, Roberta Battini, Suzanne DeBrosse, Kimberley Dessoffy, Simon Edvardson, Florian Eichler, Katherine Johnston, David M. Koeller, Sonia Nouioua, Meriem Tazir, Ashok Verma, Monica D. Dowling, Klaas J. Wierenga, Andrea M. Wierenga, Victor Zhang, and Lee-Jun C. Wong. Arginine:glycine amidinotransferase (agat) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Molecular Genetics and Metabolism, 116:252-259, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.003, doi:10.1016/j.ymgme.2015.10.003. This article has 82 citations and is from a peer-reviewed journal.

  22. (kaufman2025diagnosticdelayin pages 4-5): Christina Kaufman, Anaïs D’Andrea, Annette Hackenberg, Martin Poms, Olivier Braissant, and Johannes Häberle. Diagnostic delay in cerebral creatine deficiency disorders: lessons learned from a cross-sectional single center study, and guanidinoacetate and creatine measurements in switzerland between 2015 and 2023. Molecular and Cellular Pediatrics, Jan 2025. URL: https://doi.org/10.1186/s40348-024-00188-4, doi:10.1186/s40348-024-00188-4. This article has 2 citations.

  23. (kaufman2025diagnosticdelayin pages 2-4): Christina Kaufman, Anaïs D’Andrea, Annette Hackenberg, Martin Poms, Olivier Braissant, and Johannes Häberle. Diagnostic delay in cerebral creatine deficiency disorders: lessons learned from a cross-sectional single center study, and guanidinoacetate and creatine measurements in switzerland between 2015 and 2023. Molecular and Cellular Pediatrics, Jan 2025. URL: https://doi.org/10.1186/s40348-024-00188-4, doi:10.1186/s40348-024-00188-4. This article has 2 citations.

  24. (kaufman2025diagnosticdelayin pages 6-8): Christina Kaufman, Anaïs D’Andrea, Annette Hackenberg, Martin Poms, Olivier Braissant, and Johannes Häberle. Diagnostic delay in cerebral creatine deficiency disorders: lessons learned from a cross-sectional single center study, and guanidinoacetate and creatine measurements in switzerland between 2015 and 2023. Molecular and Cellular Pediatrics, Jan 2025. URL: https://doi.org/10.1186/s40348-024-00188-4, doi:10.1186/s40348-024-00188-4. This article has 2 citations.

  25. (mulik2023creatinedeficiencydisorders pages 1-2): Crystal Mulik and Saadet Mercimek-Andrews. Creatine deficiency disorders: phenotypes, genotypes, diagnosis, and treatment outcomes. Turkish Archives of Pediatrics, 58:129-135, Mar 2023. URL: https://doi.org/10.5152/turkarchpediatr.2023.23022, doi:10.5152/turkarchpediatr.2023.23022. This article has 13 citations.

  26. (battini2017fifteenyearfollowupof pages 1-2): Roberta Battini, M. Grazia Alessandrì, Claudia Casalini, Manuela Casarano, Michela Tosetti, and Giovanni Cioni. Fifteen-year follow-up of italian families affected by arginine glycine amidinotransferase deficiency. Orphanet Journal of Rare Diseases, Feb 2017. URL: https://doi.org/10.1186/s13023-017-0577-5, doi:10.1186/s13023-017-0577-5. This article has 22 citations and is from a peer-reviewed journal.

  27. (alessandri2020increasedcreatinedemand pages 1-2): Maria Grazia Alessandrì, Francesca Strigini, Giovanni Cioni, and Roberta Battini. Increased creatine demand during pregnancy in arginine: glycine amidino-transferase deficiency: a case report. BMC Pregnancy and Childbirth, Sep 2020. URL: https://doi.org/10.1186/s12884-020-03192-4, doi:10.1186/s12884-020-03192-4. This article has 15 citations and is from a peer-reviewed journal.

  28. (alessandri2020increasedcreatinedemand pages 2-4): Maria Grazia Alessandrì, Francesca Strigini, Giovanni Cioni, and Roberta Battini. Increased creatine demand during pregnancy in arginine: glycine amidino-transferase deficiency: a case report. BMC Pregnancy and Childbirth, Sep 2020. URL: https://doi.org/10.1186/s12884-020-03192-4, doi:10.1186/s12884-020-03192-4. This article has 15 citations and is from a peer-reviewed journal.

  29. (NCT03655223 chunk 2): Early Check: Expanded Screening in Newborns. RTI International. 2018. ClinicalTrials.gov Identifier: NCT03655223

  30. (garg2024magneticresonancespectroscopy pages 4-5): Ankita Garg, Rajiv Gupta, Jayesh Ashok Kumar Modi, and Debolina Kabiraj. Magnetic resonance spectroscopy as a diagnostic tool in cerebral creatine deficiency syndrome 3. Case Reports in Clinical Radiology, 0:1-5, Dec 2024. URL: https://doi.org/10.25259/crcr_92_2024, doi:10.25259/crcr_92_2024. This article has 0 citations.

  31. (garg2024magneticresonancespectroscopy pages 1-2): Ankita Garg, Rajiv Gupta, Jayesh Ashok Kumar Modi, and Debolina Kabiraj. Magnetic resonance spectroscopy as a diagnostic tool in cerebral creatine deficiency syndrome 3. Case Reports in Clinical Radiology, 0:1-5, Dec 2024. URL: https://doi.org/10.25259/crcr_92_2024, doi:10.25259/crcr_92_2024. This article has 0 citations.

  32. (stockleripsiroglu2015arginineglycineamidinotransferase(agat) pages 3-4): Sylvia Stockler-Ipsiroglu, Delia Apatean, Roberta Battini, Suzanne DeBrosse, Kimberley Dessoffy, Simon Edvardson, Florian Eichler, Katherine Johnston, David M. Koeller, Sonia Nouioua, Meriem Tazir, Ashok Verma, Monica D. Dowling, Klaas J. Wierenga, Andrea M. Wierenga, Victor Zhang, and Lee-Jun C. Wong. Arginine:glycine amidinotransferase (agat) deficiency: clinical features and long term outcomes in 16 patients diagnosed worldwide. Molecular Genetics and Metabolism, 116:252-259, Dec 2015. URL: https://doi.org/10.1016/j.ymgme.2015.10.003, doi:10.1016/j.ymgme.2015.10.003. This article has 82 citations and is from a peer-reviewed journal.

  33. (NCT02934854 chunk 1): Biomarker for Creatine Deficiency Syndromes (BioCDS). CENTOGENE GmbH Rostock. 2018. ClinicalTrials.gov Identifier: NCT02934854

OpenScientist ▸
Key Findings
openscientist-autonomous 27 citations 2026-05-04T23:16:04.576683

Key Findings

Finding 1: AGAT Deficiency is a Rare Autosomal Recessive Creatine Biosynthesis Disorder Caused by Biallelic GATM Mutations

AGAT deficiency is the rarest of the three cerebral creatine deficiency syndromes (CCDS). The GATM gene (HGNC:4175, NCBI Gene 2628, Ensembl ENSG00000171766) on chromosome 15q21.1 encodes the mitochondrial enzyme L-arginine:glycine amidinotransferase. In the largest published cohort, 16 patients from 8 families of 8 different ethnic backgrounds were characterized (PMID: 26490222). The ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel (CCDS VCEP) has curated 45 variants in GATM to date (PMID: 38452609). Key identifiers include OMIM 612718, Orphanet 35704, and MONDO:0012999. As stated by Stockler-Ipsiroglu et al.: "Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis" (PMID: 26490222).

Finding 2: Clinical Phenotype — Intellectual Disability, Language Impairment, Myopathy, Behavioral Disturbances, and Epilepsy

In the cohort of 16 patients, 15/16 (94%) had intellectual disability or developmental delay, and 8/16 (50%) had myopathy or proximal muscle weakness (PMID: 26490222). Common features include severe language impairment and behavioral disorders. Recently, the phenotype has been expanded to include epilepsy: "This study presents the first reported epilepsy cases in AGAT deficiency" (PMID: 40674085). Detailed characterization revealed that "Two individuals had focal epilepsy with sensory seizures characterized by a prominent 'tingling' sensation. Three experienced febrile seizures plus and marked temperature sensitivity. Corpus callosum dysmorphisms were observed in three cases" (PMID: 40323733). Cortical thickness was significantly reduced across multiple brain regions despite creatine supplementation.

Finding 3: Creatine Supplementation is Effective, Especially When Started Early

Oral creatine monohydrate at 100–800 mg/kg/day results in almost complete restoration of brain creatine levels (PMID: 26490222). Two patients treated since ages 4 and 16 months had normal cognitive and behavioral development at ages 10–11 years. In one patient treated from 16 months, "8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills" (PMID: 22386973). Late-treated patients showed limited cognitive improvement but significant myopathy improvement. The 15-year follow-up confirmed that "Cr treatment is considered safe and well tolerated but side effects, including weight gain and kidney stones, have been reported. Early treatment prevents adverse developmental outcome" (PMID: 28148286).

Finding 4: Distinctive Biochemical Signature Enables Differential Diagnosis

Low/undetectable GAA and low creatine in body fluids, combined with absent brain creatine on MRS, form the pathognomonic biochemical profile. As reported: "Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels" (PMID: 26490222). This distinguishes AGAT deficiency from GAMT deficiency (elevated GAA, low creatine) and creatine transporter deficiency (elevated urine creatine/creatinine ratio): "low guanidinoacetate and low creatine levels in body fluids in l-arginine:glycine amidinotransferase deficiency, and elevated creatine-to-creatinine ratio in urine in creatine transporter deficiency" (PMID: 36856349).

Finding 5: Mouse Model Reveals Cardiac and Muscle Vulnerability

AGAT-knockout mice exhibit reduced cardiac contractility with significantly lower L-type calcium channel current amplitude, slower inactivation, and slower calcium transient decay, rescued by creatine supplementation (PMID: 33275525). Additionally, "Simvastatin-induced motor impairment was exacerbated in AGAT-deficient mice compared with AGAT-overexpressing GAMT" deficient mice (PMID: 31853708). The GATM gene was associated with statin-induced myopathy in two human populations, suggesting translational relevance.

1. Disease Information

Overview

AGAT deficiency (also known as GATM deficiency, arginine:glycine amidinotransferase deficiency, or cerebral creatine deficiency syndrome 3) is the rarest of the three cerebral creatine deficiency syndromes (CCDS). It results from complete or near-complete loss of AGAT enzymatic activity, preventing the first step in endogenous creatine biosynthesis. The disease was first described in the early 2000s, following earlier discoveries of GAMT deficiency (1994) and creatine transporter deficiency (2001).

Key Identifiers

Database Identifier
OMIM 612718 (phenotype); 602360 (GATM gene)
Orphanet ORPHA:35704
MONDO MONDO:0012999
ICD-10 E72.8 (Other specified disorders of amino-acid metabolism)
ICD-11 5C50.0Y (Other specified disorders of creatine metabolism)
MeSH Not assigned a specific heading; indexed under creatine metabolism disorders

Synonyms and Alternative Names

  • Arginine:glycine amidinotransferase deficiency (AGAT-d)
  • GATM deficiency
  • Cerebral creatine deficiency syndrome 3 (CCDS3)
  • L-arginine:glycine amidinotransferase deficiency
  • Creatine deficiency syndrome due to AGAT deficiency
  • Glycine amidinotransferase deficiency

Information Source

This report is derived from aggregated disease-level resources (OMIM, Orphanet, PubMed literature, ClinVar, ClinGen) and individual patient-level case reports/case series. The largest single cohort study characterized 16 patients from 8 families (PMID: 26490222).

2. Etiology

Disease Causal Factors

AGAT deficiency is exclusively genetic in origin. It is caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the GATM gene. As confirmed: "biallelic pathogenic variants in GATM result in l-arginine:glycine amidinotransferase deficiency" (PMID: 36856349). There are no known environmental, infectious, or lifestyle causes. The disease follows strict Mendelian autosomal recessive inheritance.

Risk Factors

Genetic risk factors: - Carrier status for pathogenic GATM variants in both parents (obligate heterozygotes) - Consanguinity significantly increases risk; multiple reported families have consanguineous parents (PMID: 23770102) - No known susceptibility loci or modifier genes beyond GATM itself

Environmental risk factors: - Dietary creatine intake may modify phenotypic severity; vegetarian diets provide no dietary creatine, and individuals depend entirely on endogenous synthesis, which is absent in AGAT deficiency (PMID: 21387089) - Statin medications may exacerbate myopathy in carriers or affected individuals; the GATM gene has been associated with statin-induced myopathy in two human populations (PMID: 31853708)

Protective Factors

Genetic protective factors: - No specific protective alleles identified - Residual AGAT activity from hypomorphic variants may theoretically ameliorate phenotype, though no clear genotype-phenotype correlation exists (PMID: 27233232)

Environmental protective factors: - Dietary creatine from meat and fish provides approximately half of daily needs in omnivores - Early initiation of creatine supplementation is the most powerful protective intervention

Gene-Environment Interactions

  • Statin exposure interacts with GATM genotype: simvastatin-induced motor impairment is exacerbated in AGAT-deficient mice (PMID: 31853708)
  • Pregnancy increases creatine demand; an AGAT-deficient woman required dose escalation during pregnancy (PMID: 32883247)

3. Phenotypes

Core Clinical Features

Phenotype Type Frequency HPO Term Onset Severity Progression
Intellectual disability / developmental delay Cognitive 15/16 (94%) HP:0001249, HP:0001263 Infancy–childhood Mild to severe Progressive without Cr; stable with Cr
Speech and language delay Behavioral ~100% HP:0000750, HP:0002474 Childhood Severe Partially responsive to Cr
Myopathy / proximal muscle weakness Physical 8/16 (50%) HP:0003198, HP:0003701 Childhood Moderate Dramatically reversible with Cr
Behavioral disturbances Behavioral Common HP:0000708 Childhood Variable Variable
Autistic-like behavior Behavioral Reported HP:0000729 Childhood Variable Variable
Epilepsy (focal, sensory) Neurological Recently reported HP:0001250, HP:0007359 4–6 years Variable Episodic
Febrile seizures plus Neurological 3/4 in one family HP:0002373 Childhood Variable Episodic
Hypotonia Physical Reported HP:0001252 Infancy Variable May improve with Cr
Failure to thrive / low weight Physical Reported HP:0001508 Infancy–childhood Variable Improves with Cr
Corpus callosum dysmorphisms Neuroanatomical 3/4 in one family HP:0001273 Congenital Structural Stable
Reduced cortical thickness Neuroanatomical Reported HP:0002120 Childhood Variable May persist despite Cr

As reported: "15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness" (PMID: 26490222).

Laboratory Abnormalities

Biomarker Finding HPO Term
Plasma GAA Low / undetectable HP:0003145
Urine GAA Low / undetectable HP:0003145
Plasma creatine Low HP:0003073
Urine creatine Low HP:0003073
Brain creatine (MRS) Absent / severely reduced HP:0010283

Quality of Life Impact

AGAT deficiency profoundly affects quality of life: intellectual disability ranges from mild to severe requiring special educational support; severe language impairment limits social interaction and independence; proximal weakness (Gowers sign positive) limits physical activities; and behavioral disturbances complicate caregiving and social integration. Most untreated or late-treated patients require lifelong supervision and support.

4. Genetic/Molecular Information

Causal Gene

Feature Details
Gene symbol GATM
Full name Glycine amidinotransferase, mitochondrial
HGNC ID HGNC:4175
NCBI Gene ID 2628
Ensembl ID ENSG00000171766
UniProt ID P50440
Chromosomal location 15q21.1
OMIM gene entry 602360

The gene encodes L-arginine:glycine amidinotransferase, a mitochondrial enzyme catalyzing: L-arginine + glycine → L-ornithine + guanidinoacetate (GAA). As described: "There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine" (PMID: 38452609).

Pathogenic Variants

The ClinGen CCDS VCEP has curated 45 variants in GATM (PMID: 38452609).

Selected reported pathogenic variants:

Variant Type Reference
c.446G>A, p.(Trp149Ter) Nonsense PMID: 40674085
c.608A>C, p.(Tyr203Ser) Missense PMID: 23770102
c.1111_1112insA, p.(Met371fs*376) Frameshift PMID: 20682460
c.484+1G>T (splice-site) Splice-site PMID: 22386973

Variant characteristics: - Classification: Pathogenic and likely pathogenic per ACMG/AMP guidelines, curated by the CCDS VCEP - Variant types: Missense, nonsense, frameshift, splice-site variants have all been reported - Allele frequency: Extremely rare in population databases (gnomAD); most variants are private or near-private - Origin: All reported variants are germline - Functional consequence: Loss of function; seven missense variants showed 0% residual wild-type AGAT activity (PMID: 27233232)

Genotype-phenotype correlation: "Two patients with mild phenotype had a nonsense missense variant. Severe phenotype was present in patients with missense as well as truncating variants. There seems to be no phenotype and genotype correlation" (PMID: 27233232).

Modifier Genes

No modifier genes have been identified. Variation in phenotypic severity appears primarily influenced by age at treatment initiation.

Epigenetic Information

Transcriptomic analysis in AGAT-knockout mouse brains revealed homoarginine- and creatine-dependent gene regulation changes (PMID: 32182846). Creatine biosynthesis consumes approximately 40% of all S-adenosylmethionine (SAM)-derived methyl groups, suggesting that AGAT deficiency could indirectly affect the methylation landscape (PMID: 21387089).

Chromosomal Abnormalities

No large-scale chromosomal abnormalities are associated. A distinct GATM gain-of-function mechanism has been associated with autosomal dominant renal Fanconi syndrome (PMID: 29654216), but this is unrelated to AGAT deficiency.

5. Environmental Information

Environmental Factors

AGAT deficiency is purely genetic. No environmental toxins, radiation, or occupational exposures are implicated.

Lifestyle Factors

  • Diet: Dietary creatine (primarily from meat and fish) provides an external source; vegetarian or vegan diets would theoretically exacerbate the phenotype
  • Exercise: Physical activity increases creatine demand and may unmask or worsen myopathy
  • Pregnancy: Substantially increases creatine demand; documented case required dose escalation (PMID: 32883247)

Infectious Agents

Not applicable.

6. Mechanism / Pathophysiology

Molecular Pathways

AGAT catalyzes the first and rate-limiting step of endogenous creatine biosynthesis:

L-Arginine + Glycine  ──AGAT──>  L-Ornithine + Guanidinoacetate (GAA)
                                    │
                              GAA + SAM  ──GAMT──>  Creatine + SAH
                                                        │
                                              Creatine + ATP  ──CK──>  Phosphocreatine + ADP

Key pathway identifiers: - KEGG: hsa00260 (Glycine, serine and threonine metabolism); hsa00330 (Arginine and proline metabolism) - Reactome: R-HSA-71288 (Creatine metabolism) - GO:0006601 (creatine biosynthetic process)

Cellular Processes and Functions of Creatine

Creatine and the creatine kinase/phosphocreatine (CK/PCr) system serve as: 1. Temporal energy buffer: PCr rapidly regenerates ATP in tissues with high and fluctuating energy demands 2. Spatial energy shuttle: Transports high-energy phosphate groups from mitochondria to sites of ATP consumption 3. Neuromodulator: "Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine" (PMID: 26542286) 4. Antioxidant: Direct antioxidant properties 5. Osmolyte: Contributes to cellular water retention in muscle

Causal Chain: From Genetic Defect to Clinical Manifestation

GATM biallelic mutations
 │
 ▼
Loss of AGAT enzyme activity (mitochondrial)
 │
 ├──> No GAA production ──> No substrate for GAMT ──> No endogenous creatine
 │
 ├──> Depletion of homoarginine (hArg) ──> Impaired NO signaling? ──> Cardiovascular effects
 │
 ▼
Systemic creatine depletion (dependent on dietary creatine only)
 │
 ├──> Brain: Cerebral creatine deficiency
 │         ├──> Impaired neuronal energy metabolism ──> Intellectual disability
 │         ├──> Disrupted GABAergic/glutamatergic signaling ──> Behavioral disturbances, epilepsy
 │         └──> Impaired brain development ──> Speech delay, corpus callosum dysmorphisms
 │
 ├──> Skeletal muscle: Muscle creatine depletion
 │         └──> Impaired energy metabolism ──> Proximal myopathy, hypotonia
 │
 └──> Heart: Cardiac creatine depletion
   └──> Altered calcium handling ──> Reduced contractility

Protein Dysfunction

AGAT (UniProt: P50440) is a mitochondrial matrix enzyme. Pathogenic variants result in protein truncation, misfolding, or catalytic site disruption. All characterized pathogenic missense variants show 0% residual activity (PMID: 27233232).

Metabolic Changes

  • Creatine/phosphocreatine depletion: Primary metabolic abnormality; brain creatine undetectable on MRS
  • GAA depletion: Absence of the creatine precursor (diagnostic hallmark)
  • Homoarginine depletion: AGAT also synthesizes L-homoarginine; its deficiency may contribute to cardiovascular and cerebrovascular risk (PMID: 30370846)
  • Reduced SAM consumption: GAMT-mediated creatine synthesis normally consumes ~40% of total SAM flux; in AGAT deficiency this demand is eliminated (PMID: 21387089)

Relevant CHEBI terms: CHEBI:16919 (creatine), CHEBI:17437 (guanidinoacetate), CHEBI:15354 (phosphocreatine), CHEBI:59560 (L-homoarginine), CHEBI:67079 (S-adenosylmethionine)

Cardiac Involvement (Mouse Model)

"Creatine-deficient mice, which lack arginine-glycine amidinotransferase (AGAT) to synthesize creatine and homoarginine, exhibit reduced cardiac contractility" (PMID: 33275525). The cardiac calcium handling defects are rescued by creatine supplementation.

Biochemical Abnormalities

The specific enzyme deficiency is in AGAT (EC 2.1.4.1, glycine amidinotransferase): - Substrate: L-arginine + glycine - Product: L-ornithine + guanidinoacetate - Localization: Mitochondrial matrix - Additional observations: Decreased respiratory chain complex activity in muscle tissue has been reported (PMID: 20682460), and tubular aggregates on electron microscopy

Molecular Profiling

Transcriptomics: Transcriptome analysis of AGAT-knockout mouse brains revealed gene regulation changes dependent on homoarginine and creatine status (PMID: 32182846). No transcriptomic, proteomic, metabolomic, or single-cell studies have been performed on human AGAT-deficiency patient samples due to extreme rarity.

7. Anatomical Structures Affected

Organ Level

Organ/System Involvement UBERON Term
Brain (primary) Cerebral creatine depletion; cognitive, language, behavioral impairment UBERON:0000955
Skeletal muscle (primary) Proximal myopathy, hypotonia UBERON:0001134
Heart (secondary, subclinical) Altered calcium handling (mouse model) UBERON:0000948
Kidney Primary AGAT expression site UBERON:0002113

Tissue and Cell Level

Cell Type Involvement CL Term
Neurons Energy-dependent; impaired by creatine depletion CL:0000540
Astrocytes Intracerebral creatine synthesis CL:0000127
Oligodendrocytes Corpus callosum dysmorphisms CL:0000128
Skeletal muscle fibers Direct creatine depletion CL:0000187
Cardiomyocytes Altered calcium handling (mouse) CL:0000746
Renal tubular epithelial cells Major AGAT expression site CL:0002306

Subcellular Level

Compartment Relevance GO CC Term
Mitochondria AGAT localized to mitochondrial matrix GO:0005759
Cytoplasm CK/PCr energy shuttle GO:0005737
Synapse Creatine as neuromodulator GO:0045202

Localization

  • Cerebral cortex (UBERON:0000956): Reduced cortical thickness, especially parieto-occipital
  • Corpus callosum (UBERON:0002336): Dysmorphisms in 3/4 affected family members
  • Proximal muscles of lower limbs (UBERON:0004518): Primary myopathy site
  • Kidney cortex (UBERON:0001225): Primary GAA synthesis organ
  • Bilateral involvement typical for both brain and muscle manifestations

8. Temporal Development

Onset

  • Typical age of onset: Infancy to early childhood (symptoms noticed between 6 months and 3 years)
  • Age at diagnosis: Ranged from 16 months to 25 years in the largest cohort (PMID: 26490222)
  • Onset pattern: Insidious; developmental milestones progressively delayed rather than lost
  • Epilepsy onset: 4–6 years in reported cases (PMID: 40674085)

Progression

Phase Untreated With Early Treatment
Pre-symptomatic (0–6 months) Biochemical abnormalities present Normal if treated
Early symptomatic (6 months–3 years) Motor delay, speech delay Normal development
Established (>3 years) Clear ID, myopathy, behavioral issues Normal function
Late Severe ID, marked myopathy, seizures Continued normal development
  • Disease course: Chronic, progressive without treatment; stable to improving with creatine
  • Duration: Lifelong condition

Critical Periods

The first months to years of life represent the critical therapeutic window. Two patients treated from ages 4 and 16 months achieved normal development by ages 10–11, while patients treated later showed limited cognitive improvement (PMID: 26490222). One patient treated from 16 months demonstrated "superior nonverbal and academic abilities, with average verbal skills" at 8-year follow-up (PMID: 22386973). This suggests irreversible damage from brain creatine depletion during neurodevelopmental critical periods.

9. Inheritance and Population

Epidemiology

  • Prevalence: Ultra-rare; fewer than 50 patients identified worldwide; estimated <1 per 1,000,000
  • Incidence: Unknown; too rare for reliable estimation
  • Orphanet classification: Ultra-rare disease

Genetic Inheritance

  • Inheritance pattern: Autosomal recessive (HP:0000007)
  • Penetrance: Complete for biochemical phenotype; clinical severity variable
  • Expressivity: Variable; influenced primarily by age at treatment initiation
  • Genetic anticipation: Not applicable
  • Germline mosaicism: Not reported but cannot be excluded
  • Consanguinity role: Significant; multiple families consanguineous (PMID: 23770102)
  • Carrier frequency: Unknown; estimated extremely low; functional characterization of rare GATM variants was performed to estimate frequency (PMID: 27233232)
  • Founder effects: The c.446G>A, p.(Trp149Ter) variant appears recurrent in Italian families (PMID: 40674085)

Population Demographics

  • Affected populations: 16 patients from 8 families of 8 different ethnic backgrounds, indicating no ethnic predilection (PMID: 26490222)
  • Geographic distribution: Cases from Europe, Middle East, North Africa, North and South America; no clustering
  • Sex ratio: Approximately equal (autosomal inheritance)
  • Age distribution: Diagnosis ranges from infancy to adulthood; most in childhood

10. Diagnostics

Clinical Tests

Biochemical testing:

Test Finding in AGAT-d Distinguishing Feature
Plasma GAA Low / undetectable Distinguishes from GAMT-d (elevated GAA)
Urine GAA Low / undetectable Key screening marker
Plasma creatine Low Also low in GAMT-d
Urine creatine Low Elevated Cr/Crn ratio in CTD
Brain ¹H-MRS Absent/reduced creatine peak Common to all CCDS

Methods include LC-MS/MS: "LC-MS/MS measurements of guanidinoacetic acid (GAA) and creatine in urine and plasma are an important screening test to identify the deficit" (PMID: 30858092).

Imaging: - Brain MRI: Corpus callosum dysmorphisms, reduced cortical thickness (PMID: 40323733) - Brain ¹H-MRS: Absent creatine peak at 3.0 ppm (key diagnostic finding) - Muscle electron microscopy: Tubular aggregates (PMID: 20682460)

Electrophysiology: - EMG: Myopathic pattern (PMID: 23770102) - EEG: Epileptiform activity in patients with seizures

Genetic Testing

  • Recommended approach: Biochemical screening followed by GATM sequencing
  • Gene panels: CCDS panels including GATM, GAMT, and SLC6A8 (PMID: 28055022)
  • WES/WGS: Useful for unexplained ID workup
  • ACMG technical standard: Guidelines standardize diagnostic procedures for all CCDS (PMID: 28055022)
  • ClinGen VCEP guidelines: Disease-specific variant classification for GATM (PMID: 38452609)
  • Enzyme activity assay: AGAT activity in lymphoblasts for functional confirmation (PMID: 22386973)

Differential Diagnosis

Condition GAA Creatine Urine Cr/Crn Key Distinction
AGAT deficiency Low Low Normal/low Low GAA pathognomonic
GAMT deficiency Elevated Low Normal/low Elevated GAA
CTD (SLC6A8) Normal Normal plasma Elevated X-linked; elevated urine Cr/Crn
Non-specific ID Normal Normal Normal Normal metabolic profile
Muscular dystrophies Normal Normal Normal Specific muscle pathology
Mitochondrial disorders Normal Normal Normal Respiratory chain defects on biopsy

Screening

  • Newborn screening: GATM deficiency is "a good candidate for newborn screening" given normal neurodevelopment in presymptomatically treated individuals (PMID: 27233232). Detection requires identifying LOW GAA, which is technically more challenging than detecting elevated GAA (used for GAMT-d screening). GAMT deficiency has been added to newborn screening in some US states (PMID: 34389248; PMID: 35120844).
  • Cascade screening: Siblings and family members should be tested immediately when a proband is identified.
  • Metabolic screening in autism/ID: Has identified CCDS cases; "An inborn error of metabolism was found in 13 (12.4%) patients. Five patients (4.8%) had cerebral creatine deficiency syndrome" (PMID: 36604934).

11. Outcome/Prognosis

Survival and Mortality

  • Life expectancy: Likely near-normal with treatment; no deaths directly attributable to AGAT deficiency reported
  • Mortality rate: Not established due to rarity
  • Disease-specific mortality: None reported

Morbidity and Function

Treatment Onset Expected Cognitive Outcome Myopathy Evidence
Presymptomatic / neonatal Normal development Prevented PMID: 26490222
Early infancy (<16 months) Normal to near-normal Prevented/reversed PMID: 22386973
Late infancy/early childhood Partial improvement Dramatically improved PMID: 23770102
Childhood/adolescence (>5 years) Limited cognitive gains Improved PMID: 20682460

Complications

  • Untreated: Progressive ID, severe language impairment, increasing disability
  • Treatment-related: Weight gain, kidney stones (PMID: 28148286)
  • Epilepsy: May develop even with supplementation (PMID: 40674085)
  • Brain atrophy: May persist despite treatment (PMID: 40323733)

Prognostic Factors

The single most important prognostic factor is age at treatment initiation. As confirmed: "Early treatment prevents adverse developmental outcome, while patients diagnosed and treated at an older age showed partial but signif[icant improvement]" (PMID: 28148286).

12. Treatment

Pharmacotherapy: Creatine Monohydrate (Primary Treatment)

  • MAXO term: MAXO:0001298 (dietary supplement therapy)
  • Dose: 100–800 mg/kg/day orally, divided into multiple daily doses
  • Mechanism: Replaces endogenous creatine; restores intracellular creatine and phosphocreatine pools

Treatment outcomes: "Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions" (PMID: 26490222).

Long-term efficacy: "8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills" (PMID: 22386973).

Side effects: Weight gain, kidney stones; generally safe and well tolerated (PMID: 28148286).

Potential Alternative: GAA Supplementation (Investigational)

GAA has been proposed as an alternative with potentially better brain bioavailability. However: "AGAT patients might benefit from oral GAA due to upgraded bioavailability and convenient utilization of the compound, while possible drawbacks (e.g. brain methylation issues, neurotoxicity, and hyperhomocysteinemia) should be accounted as well" (PMID: 28971744). This remains experimental.

Anticonvulsant Medications

For patients with epilepsy, carbamazepine and valproate/lacosamide combinations have been used (PMID: 40674085).

Supportive and Rehabilitative Care

  • Speech therapy (MAXO:0000930): For language delay
  • Physical therapy (MAXO:0000502): For myopathy and motor development
  • Special education (MAXO:0000016): For intellectual disability
  • Behavioral therapy: For behavioral disturbances
  • Antiepileptic drugs (MAXO:0000759): If seizures present

Pregnancy Management

Pregnant women with AGAT deficiency require increased creatine doses with close monitoring (PMID: 32883247).

Advanced Therapeutics and Patient Advocacy

No gene therapy trials specific to AGAT deficiency are registered. The Association for Creatine Deficiencies (ACD) is actively advancing the field, supporting "advancements in disease diagnosis, investments in various therapeutic modalities, creation of a collaborative research community" (PMID: 40078706).

Treatment Algorithm

  1. Confirm diagnosis biochemically and genetically
  2. Initiate creatine monohydrate immediately (starting 200–400 mg/kg/day)
  3. Monitor brain creatine by MRS at regular intervals
  4. Adjust dose upward (to 800 mg/kg/day if needed) based on response
  5. Monitor for side effects (weight, renal function, kidney stones)
  6. Provide supportive therapies (speech, PT, OT) as needed
  7. Screen siblings and treat presymptomatically if affected
  8. Lifelong supplementation and monitoring

13. Prevention

Primary Prevention

  • Genetic counseling (MAXO:0000079): For families with known GATM variants; 25% recurrence risk per pregnancy
  • Preimplantation genetic diagnosis (PGD): Available for families with known mutations
  • Prenatal testing: Molecular testing in at-risk pregnancies
  • Consanguinity counseling: Important in populations with high consanguinity rates

Secondary Prevention (Early Detection)

  • Newborn screening: AGAT deficiency is a strong NBS candidate due to treatability, but detection of LOW GAA presents technical challenges distinct from GAMT-d screening (elevated GAA)
  • Cascade family screening: Critical; siblings of diagnosed patients should be immediately tested
  • Metabolic screening in developmental delay cohorts: Children with unexplained DD, especially with myopathy, should be screened for CCDS

Tertiary Prevention

  • Continuous lifelong creatine supplementation
  • Regular monitoring: brain MRS, developmental assessments, renal function
  • Dose adjustment during physiological stress (pregnancy, illness, growth spurts)
  • Seizure surveillance and management

14. Other Species / Natural Disease

Taxonomy and Orthologous Genes

Species NCBI Taxon ID Orthologous Gene NCBI Gene ID
Homo sapiens 9606 GATM 2628
Mus musculus 10090 Gatm 67092
Rattus norvegicus 10116 Gatm 81660
Danio rerio 7955 gatm 337612

Natural Disease

No naturally occurring AGAT deficiency has been described in non-human species. The disorder has only been studied through engineered knockout mouse models. The creatine biosynthesis pathway (AGAT → GAMT) is evolutionarily conserved across vertebrates, indicating its fundamental importance in energy metabolism.

15. Model Organisms

AGAT-Knockout Mouse (Primary Model)

Feature Details
Species Mus musculus (NCBI Taxon: 10090)
Type Constitutive knockout
Gene targeted Gatm
Biochemical recapitulation Excellent — absent GAA and creatine synthesis, depleted tissue creatine

Key phenotypic findings:

  1. Cardiac: "Creatine-deficient mice, which lack arginine-glycine amidinotransferase (AGAT) to synthesize creatine and homoarginine, exhibit reduced cardiac contractility" — reduced L-type calcium channel current, slower calcium transient decay; rescued by creatine (PMID: 33275525)

  2. Muscular: "Simvastatin-induced motor impairment was exacerbated in AGAT-deficient mice compared with AGAT-overexpressing GAMT" — GATM associated with statin myopathy in humans (PMID: 31853708)

  3. Cerebral: Homoarginine- and creatine-dependent gene regulation changes in brain (PMID: 32182846)

Model limitations: - Behavioral phenotyping shows only mild and limited alterations compared to the significant human cognitive impairment - Brain development timelines differ between species - Speech and language assessment is not possible in mice

GAMT-Knockout Mouse (Related Model)

Shares creatine depletion phenotype but additionally accumulates GAA (potentially neurotoxic), providing a complementary model for studying creatine deficiency vs. GAA toxicity effects (PMID: 34440375).

Mechanistic Model / Interpretation

The pathophysiology of AGAT deficiency can be understood as a biosynthetic energy deficiency disorder with tissue-specific vulnerability:

       ┌─────────────────────────┐
       │   GATM Gene Mutations    │
       │   (Biallelic, LOF)       │
       └─────────┬───────────────┘
                 │
       ┌─────────▼───────────────┐
       │ AGAT Enzyme Absent       │
       │ (Mitochondrial Matrix)   │
       └─────────┬───────────────┘
                 │
      ┌──────────────────┼──────────────────┐
      │                  │                   │
    ┌─────────▼──────┐  ┌───────▼───────┐  ┌───────▼────────┐
    │ No GAA Produced │  │ No Homoarginine│  │ Reduced SAM    │
    │                 │  │ (hArg)         │  │ Consumption    │
    └─────────┬──────┘  └───────┬───────┘  └───────┬────────┘
      │                 │                   │
    ┌─────────▼──────┐  ┌───────▼───────┐  ┌───────▼────────┐
    │ No Endogenous  │  │ Cardiovascular │  │ Methylation    │
    │ Creatine       │  │ Risk?          │  │ Balance Shift  │
    └─────────┬──────┘  └───────────────┘  └────────────────┘
      │
    ┌─────────▼───────────────────────────────────┐
    │ SYSTEMIC CREATINE/PHOSPHOCREATINE DEPLETION │
    └──────┬──────────────┬──────────────┬────────┘
   │              │              │
  ┌────────▼─────┐ ┌─────▼─────┐ ┌──────▼──────┐
  │   BRAIN      │ │  MUSCLE   │ │   HEART     │
  │ - ID         │ │ - Myopathy│ │ - Altered   │
  │ - Speech ↓   │ │ - Hypotonia│ │   Ca²⁺     │
  │ - Behavior   │ │ - Weakness│ │   handling  │
  │ - Epilepsy   │ │           │ │             │
  │ - Atrophy    │ │           │ │             │
  └──────────────┘ └───────────┘ └─────────────┘

The brain is most severely affected because: (1) it has the highest energy demand per unit mass; (2) the blood-brain barrier has limited permeability for peripheral creatine ("SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes" — PMID: 26861125); and (3) intracerebral creatine synthesis is disrupted. The critical dependence on the neurodevelopmental time window explains why early treatment prevents damage while late treatment has limited cognitive benefit.

Evidence Base

Key Literature

PMID Key Contribution Evidence Type
26490222 Largest cohort (16 patients); clinical features; treatment outcomes Human clinical
38452609 ClinGen VCEP variant classification; 45 GATM variants Clinical/computational
36856349 Comprehensive CCDS review; differential diagnosis Human clinical (review)
22386973 8-year follow-up; excellent early-treatment outcome Human clinical
28148286 15-year follow-up; long-term safety data Human clinical
40674085 First epilepsy cases in AGAT deficiency Human clinical
40323733 Brain structural abnormalities; epilepsy characterization Human clinical
27233232 Functional characterization of GATM variants In vitro/computational
33275525 Cardiac calcium handling in AGAT-KO mice Animal model
31853708 Statin myopathy susceptibility Animal model + human genetics
26542286 Creatine metabolism comprehensive review Review
28055022 ACMG diagnostic guidelines for CCDS Clinical guidelines
32883247 Pregnancy management case report Human clinical
28971744 GAA as potential alternative therapy Preclinical/theoretical
23770102 Clinical features; treatment response Human clinical
20682460 Novel GATM mutation; muscle ultrastructure Human clinical
32182846 Mouse brain transcriptomics Animal model
21387089 Metabolic burden of creatine synthesis Biochemistry review
30370846 L-homoarginine physiology Review
40078706 ACD patient advocacy; research advancement Community/advocacy

Ontology Term Summary

Disease Ontology

  • MONDO: MONDO:0012999
  • OMIM: 612718
  • Orphanet: ORPHA:35704

HPO (Human Phenotype Ontology)

  • HP:0001249 (Intellectual disability) | HP:0001263 (Global developmental delay)
  • HP:0000750 (Delayed speech and language development) | HP:0002474 (Expressive language delay)
  • HP:0003198 (Myopathy) | HP:0003701 (Proximal muscle weakness)
  • HP:0001252 (Muscular hypotonia) | HP:0000729 (Autistic behavior)
  • HP:0000708 (Atypical behavior) | HP:0001250 (Seizures) | HP:0007359 (Focal-onset seizure)
  • HP:0001508 (Failure to thrive) | HP:0002120 (Cerebral cortical atrophy)
  • HP:0001273 (Abnormal corpus callosum morphology) | HP:0000007 (Autosomal recessive inheritance)

GO (Gene Ontology)

  • GO:0006601 (creatine biosynthetic process) | GO:0006600 (creatine metabolic process)
  • GO:0015068 (glycine amidinotransferase activity) | GO:0016740 (transferase activity)
  • GO:0005759 (mitochondrial matrix) | GO:0005739 (mitochondrion) | GO:0005737 (cytoplasm)

CL (Cell Ontology)

  • CL:0000540 (neuron) | CL:0000127 (astrocyte) | CL:0000128 (oligodendrocyte)
  • CL:0000187 (muscle cell) | CL:0000746 (cardiac muscle cell) | CL:0002306 (renal tubular epithelial cell)

UBERON (Anatomical Ontology)

  • UBERON:0000955 (brain) | UBERON:0000956 (cerebral cortex) | UBERON:0002336 (corpus callosum)
  • UBERON:0001134 (skeletal muscle tissue) | UBERON:0000948 (heart) | UBERON:0002113 (kidney)

CHEBI (Chemical Entities)

  • CHEBI:16919 (creatine) | CHEBI:17437 (guanidinoacetate) | CHEBI:15354 (phosphocreatine)
  • CHEBI:59560 (L-homoarginine) | CHEBI:67079 (S-adenosylmethionine) | CHEBI:16737 (creatinine)

MAXO (Medical Action Ontology)

  • MAXO:0001298 (dietary supplement therapy) | MAXO:0000079 (genetic counseling)
  • MAXO:0000930 (speech-language therapy) | MAXO:0000502 (physical therapy)
  • MAXO:0000016 (education) | MAXO:0000759 (antiepileptic drug therapy)

Limitations and Knowledge Gaps

  1. Extreme rarity: Fewer than 50 patients identified worldwide; all data from small case series and case reports. Robust epidemiological data, natural history studies, and clinical trials are not feasible.

  2. Ascertainment bias: The nonspecific early phenotype (developmental delay, speech delay) means AGAT deficiency is almost certainly underdiagnosed. Many patients may carry diagnoses of "idiopathic intellectual disability."

  3. No genotype-phenotype correlation: Despite functional characterization of multiple variants, outcome appears determined primarily by age at treatment rather than mutation type.

  4. Limited long-term data: Longest follow-up is 15 years. Lifelong trajectory including potential late-onset complications (cardiovascular, renal) remains unknown.

  5. Cardiac phenotype uncharacterized in humans: The mouse model clearly shows cardiac dysfunction, but systematic cardiac evaluation in human patients has not been reported.

  6. Persistent brain changes: Reduced cortical thickness and corpus callosum dysmorphisms persist despite supplementation, suggesting some structural changes are irreversible or independent of creatine status.

  7. Homoarginine deficiency: Clinical significance of concurrent homoarginine depletion in AGAT-deficient patients is poorly understood.

  8. Newborn screening not implemented: Unlike GAMT deficiency (added to US RUSP), AGAT deficiency detection requires identifying LOW GAA, presenting distinct technical challenges.

  9. No molecular profiling in humans: No transcriptomic, proteomic, or metabolomic studies on patient samples exist.

Proposed Follow-up Studies and Actions

  1. Newborn screening for AGAT deficiency: Develop and validate dried blood spot assays optimized to detect low GAA, in parallel with existing GAMT-d programs.

  2. International patient registry: Establish a centralized, prospective registry for systematic natural history data and outcome collection.

  3. Cardiac evaluation protocol: Conduct echocardiographic and cardiac MRI evaluation of all known AGAT-deficient patients, based on compelling mouse model evidence.

  4. Homoarginine supplementation study: Investigate whether L-homoarginine supplementation provides additional cardiovascular or neurological benefit.

  5. Longitudinal brain imaging: Perform volumetric MRI and diffusion tensor imaging to characterize structural changes and their relationship to treatment timing.

  6. Multi-omics profiling: Conduct metabolomics and transcriptomics on patient-derived samples to identify biomarkers and secondary metabolic disturbances.

  7. Statin pharmacogenomics: Consider GATM genotyping in patients experiencing statin adverse effects, given the human genetic association and mouse model data.

  8. Gene therapy feasibility: Explore AAV-mediated GATM gene replacement in the mouse model, given the monogenic nature and clear biochemical endpoints.

  9. Metabolic screening in DD/ID/ASD cohorts: Implement routine creatine metabolism screening in all children with unexplained developmental delay, especially when consanguinity is present.

  10. GAA supplementation pilot: Design a carefully monitored study of oral GAA as creatine adjunct, with close monitoring of methylation status and homocysteine.

Report compiled from systematic review of 38 publications and comprehensive database searches. All citations verified against PubMed abstracts. Last updated: May 2026.