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AGAT Deficiency

MONDO:0012996 Curated 2026-07-04T00:00:00Z 9 harmonized findings
falcon · 52 citations openscientist · 27 citations
Concordant asserts the finding Partial supports a weaker/qualified form Contradictory conflicts with it Silent does not address it

Harmonized findings

AGAT (GATM) deficiency is an autosomal recessive inborn error of creatine biosynthesis caused by biallelic loss-of-function variants in GATM, which encodes the enzyme L-arginine:glycine amidinotransferase (AGAT).

UNANIMOUS INTEGRATED
pathophysiologygenetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 95% biallelic loss-of-function variants in GATM → reduced/absent AGAT enzyme function
Falcon states the upstream causal trigger as biallelic loss-of-function GATM variants abolishing AGAT enzyme function, and elsewhere frames the disease as an autosomal recessive creatine biosynthesis disorder.
DOI:10.1016/j.ymgme.2024.108362
openscientist CONCORDANT 95% biallelic pathogenic variants in GATM result in l-arginine:glycine amidinotransferase deficiency
OpenScientist gives the same biallelic-GATM autosomal recessive mechanism, adding gene locus (15q21.1) and identifiers.
PMID:36856349

AGAT catalyzes the first, rate-limiting step of creatine biosynthesis, transferring an amidino group from arginine to glycine to form guanidinoacetate (GAA) and ornithine; loss of this activity abolishes endogenous creatine synthesis.

UNANIMOUS INTEGRATED
pathophysiologygene_function
ProviderStanceScoreEvidence
falcon CONCORDANT 95% AGAT catalyzes the first and rate-limiting step of creatine biosynthesis
Falcon states the rate-limiting first-step role and gives the reaction (arginine + glycine → guanidinoacetate + ornithine).
DOI:10.1016/j.ymgme.2010.06.021
openscientist CONCORDANT 95% catalyzes the first step of creatine synthesis — the transfer of an amidino group from arginine to glycine to form guanidinoacetate (GAA)
OpenScientist describes the identical enzymatic step with the amidino-group transfer and downstream GAMT/creatine-kinase pathway.
PMID:38452609

The core clinical phenotype is neurodevelopmental — intellectual disability/developmental delay (about 15/16 in the largest cohort) with severe speech and language impairment — accompanied by myopathy/proximal muscle weakness in roughly half of patients (8/16) and behavioral disturbances.

UNANIMOUS INTEGRATED
phenotype
ProviderStanceScoreEvidence
falcon CONCORDANT 90% 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
Falcon reports the same dominant neurodevelopmental presentation, the speech/language and behavioral features, and myopathy in ~half of patients.
DOI:10.1016/j.ymgme.2015.10.003
openscientist CONCORDANT 92% 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
OpenScientist cites the same cohort counts (15/16 IDD, 8/16 myopathy) from the Stockler-Ipsiroglu series.
PMID:26490222

The pathognomonic biochemical signature is low/undetectable guanidinoacetate plus low creatine in body fluids with an absent/markedly reduced brain creatine peak on 1H-MRS, distinguishing AGAT deficiency from GAMT deficiency (elevated GAA) and creatine transporter deficiency (elevated urine creatine/creatinine).

UNANIMOUS INTEGRATED
diagnosis
ProviderStanceScoreEvidence
falcon CONCORDANT 95% Low/undetectable GAA in plasma/urine and low creatine; absent or markedly decreased brain creatine peak on 1H-MRS
Falcon gives the identical biomarker triad and explicitly contrasts it with GAMT deficiency (elevated GAA) and SLC6A8 creatine transporter deficiency.
DOI:10.5152/turkarchpediatr.2023.23022
openscientist CONCORDANT 93% Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels
OpenScientist reports the same low-GAA/low-creatine/absent-brain-creatine profile and tabulates the differential against GAMT-d and CTD.
PMID:26490222

Oral creatine monohydrate (100–800 mg/kg/day) is the disease-specific therapy; restoration of neurodevelopmental outcome is strongly time-dependent, with presymptomatic/early-infancy treatment preventing adverse cognitive outcome and later-started treatment yielding only limited cognitive recovery.

UNANIMOUS INTEGRATED
treatmentprognosis
ProviderStanceScoreEvidence
falcon CONCORDANT 92% 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.
Falcon reports the 100–800 mg/kg/day dosing range and the time-dependent cognitive benefit (prevention when early, limited recovery when late).
DOI:10.1016/j.ymgme.2015.10.003
openscientist CONCORDANT 95% 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
OpenScientist gives the same dose range and the early-vs-late outcome contrast from the Stockler-Ipsiroglu cohort.
PMID:26490222

The AGAT-knockout mouse recapitulates cardiac and muscle vulnerability — reduced cardiac contractility with altered L-type calcium-channel/calcium handling, rescued by creatine supplementation.

SINGLE LEAD
pathophysiology
ProviderStanceScoreEvidence
openscientist CONCORDANT 90% Creatine-deficient mice, which lack arginine-glycine amidinotransferase (AGAT) to synthesize creatine and homoarginine, exhibit reduced cardiac contractility
OpenScientist details the AGAT-KO cardiac phenotype (reduced contractility, L-type calcium current, calcium-transient decay) rescued by creatine.
PMID:33275525
falcon SILENT —
Falcon's only mouse-model content reports that AGAT deficiency protects from metabolic syndrome; it does not address the cardiac contractility/calcium handling phenotype.

Epilepsy is a recently recognized expansion of the AGAT-deficiency phenotype (including focal sensory seizures and febrile seizures plus), alongside brain structural abnormalities such as corpus callosum dysmorphism and reduced cortical thickness that can persist despite creatine supplementation.

MAJORITY LEAD
phenotype
ProviderStanceScoreEvidence
openscientist CONCORDANT 85% This study presents the first reported epilepsy cases in AGAT deficiency
OpenScientist documents the newly reported epilepsy cases and the accompanying corpus callosum dysmorphisms and reduced cortical thickness.
PMID:40674085, PMID:40323733
falcon PARTIAL 30% rare/variable; present in some reports
Falcon lists seizures only as a rare/variable feature and does not report the expanded epilepsy phenotype or the corpus callosum/cortical structural findings — coverage divergence, not a contradiction.

AGAT deficiency is an ultra-rare, fully penetrant autosomal recessive disorder, with only a small number of patients reported worldwide (about 16 in the largest cohort).

UNANIMOUS INTEGRATED
epidemiologygenetic_factor
ProviderStanceScoreEvidence
falcon CONCORDANT 85% with <20–25 individuals reported in the literature in recent summaries
Falcon describes the disorder as ultrarare (<20–25 reported) and notes the ClinGen VCEP treated GATM biallelic variants as fully penetrant, citing an estimated prevalence of 1 in 3,450,000.
DOI:10.1016/j.ymgme.2024.108362
openscientist CONCORDANT 80% Ultra-rare; fewer than 50 patients identified worldwide; estimated <1 per 1,000,000
OpenScientist gives a slightly higher literature-case ceiling (<50, <1 per 1,000,000) and complete penetrance for the biochemical phenotype — a minor quantitative divergence, not a conflict.
PMID:26490222

AGAT deficiency is an attractive newborn-screening candidate because early treatment can prevent disease, but detecting the LOW guanidinoacetate signal is technically harder than detecting the elevated GAA used to screen for GAMT deficiency.

UNANIMOUS LEAD
diagnosisprognosis
ProviderStanceScoreEvidence
falcon CONCORDANT 85% difficult to devise a sensitive screening algorithm based on GAA quantitation alone
Falcon frames AGAT deficiency as an ideal newborn-screening candidate yet flags the difficulty of a GAA-quantitation-only algorithm, proposing multianalyte DBS or enzyme-assay approaches.
DOI:10.1016/j.ymgme.2015.10.003
openscientist CONCORDANT 85% Detection requires identifying LOW GAA, which is technically more challenging than detecting elevated GAA (used for GAMT-d screening)
OpenScientist calls AGAT deficiency a good NBS candidate but makes the same point that low-GAA detection is harder than the elevated-GAA GAMT-d assay.
PMID:27233232

Narrative

Overview

Both providers converge on AGAT (GATM) deficiency as an ultra-rare, autosomal recessive, treatable inborn error of creatine biosynthesis: loss of the first, rate-limiting creatine-synthesis enzyme (AGAT) depletes guanidinoacetate and creatine, with the brain — the highest-energy-demand tissue — most severely affected, producing intellectual disability, severe speech/language impairment, myopathy, and behavioral disturbance. Falcon is tightly focused on the genetics/biochemistry, diagnostics, dosing, and ClinGen variant-interpretation framework; OpenScientist is broader and more recent, adding organ-level mechanism, the mouse-model cardiac phenotype, and the newly reported epilepsy/structural-brain expansion of the phenotype.

Agreement

The reports agree on the core driver biology (biallelic GATM loss-of-function abolishing AGAT), the enzymatic step (arginine + glycine → guanidinoacetate + ornithine), the neurodevelopmental-plus-myopathy clinical picture with the 15/16 and 8/16 cohort fractions, the pathognomonic low-GAA/low-creatine/absent-brain-creatine biochemical signature and its differential against GAMT-d and CTD, oral creatine monohydrate (100–800 mg/kg/day) as the therapy with strongly time-dependent neurodevelopmental benefit, ultra-rarity with full penetrance, and the newborn-screening candidacy tempered by the difficulty of detecting a low GAA signal.

Divergence

Divergence is coverage and recency rather than conflict. OpenScientist uniquely develops the AGAT-knockout mouse cardiac/calcium-handling phenotype and the recently reported epilepsy cases with corpus callosum dysmorphism and reduced cortical thickness; Falcon is silent on the cardiac phenotype and treats seizures only as a rare/variable feature. Falcon uniquely emphasizes the ClinGen CCDS VCEP variant-interpretation specifications (PVS1, biomarker-based PP4, prevalence 1 in 3,450,000, carrier frequency 0.077%) and real-world diagnostic-delay statistics. The only quantitative discrepancies are minor (fewer than ~20–25 vs fewer than 50 patients reported; 1 in 3,450,000 vs <1 per 1,000,000).

Integration

Promoted to the disorder entry: the AR/biallelic-GATM etiology and AGAT enzymatic step; the neurodevelopmental/myopathy/speech phenotype with cohort fractions; the low-GAA/low-creatine/absent-brain-creatine diagnostic signature with the GAMT-d/CTD differential; oral creatine monohydrate dosing with the early-treatment prognostic window; and the ultra-rare, fully penetrant epidemiology.

Not integrated (leads)

Retained as research leads rather than curated disease mechanisms: the mouse-model cardiac/calcium-handling vulnerability (uncharacterized in humans), the recently reported epilepsy and persistent structural-brain changes, and the newborn-screening feasibility discussion, pending further human evidence and standard reference verification.

Cross-provider synthesis comparing two independent AGAT Deficiency reports: falcon (genetics/biochemistry/diagnostics-focused) and openscientist (comprehensive, 15-domain). No direct contradictions were found; divergence is coverage/recency (openscientist adds the mouse cardiac phenotype and the epilepsy/structural-brain expansion) plus minor quantitative differences in patient counts and prevalence. best_matching_text values are verbatim excerpts from the cited report files; literature evidence snippets were intentionally left unpopulated pending fetch-reference verification of the underlying PMIDs/DOIs.