AMT – Glycine Encephalopathy

Glycine encephalopathy (nonketotic hyperglycinemia) is an autosomal recessive neurometabolic disorder characterized by accumulation of glycine in body fluids leading to early-onset encephalopathy, intractable seizures, hypotonia, apnea and severe developmental impairment (PMID:11592811). Biallelic pathogenic variants in the AMT gene, encoding the T-protein of the glycine cleavage system, account for approximately 20–30% of classic neonatal cases, with similar clinical severity to GLDC-associated forms.

Genetic evidence for AMT involvement includes over 50 probands from at least 20 unrelated families harboring biallelic loss-of-function or deleterious missense variants (e.g., c.350C>T (p.Ser117Leu)) confirmed by direct sequencing and segregation analysis in three families (PMID:11139253; PMID:25231368). Compound heterozygous frameshift variants (c.977del (p.Glu326GlyfsTer12) and c.982_983insG (p.Ala328GlyfsTer22)) and consensus splice-site mutations (c.878-1G>A) have been repeatedly observed in multiple cohorts (PMID:35646099; PMID:16450403).

The variant spectrum in AMT includes missense (e.g., p.Arg265Cys), nonsense, splice-site, frameshift and small indel alleles. Founder or recurrent splice variants such as c.259-2A>C have been described in diverse populations, while private frameshift alleles further expand the mutational landscape.

Segregation evidence is robust: three unrelated pedigrees demonstrate co-segregation of AMT variants with disease, and multi-generation carrier testing supports autosomal recessive transmission (PMID:11139253). No reports of heterozygous carriers manifesting milder phenotypes have been documented, consistent with a loss-of-function mechanism.

Functional studies corroborate pathogenicity: in vitro enzymatic assays of c.350C>T (p.Ser117Leu) show markedly reduced T-protein activity, and modeling of splice variants predicts disrupted exon recognition. A therapeutic trial of L-arginine reduced glycine and ammonia levels, with clinical seizure improvement (PMID:30350008).

No credible conflicting evidence has been reported. Given early onset, consistent genotype–phenotype correlation and functional concordance, the AMT–glycine encephalopathy association meets criteria for a Definitive gene–disease relationship. Key Take-home: Biallelic AMT variants cause a severe, recessive glycine encephalopathy with clear diagnostic, prognostic and genetic counseling utility.

References

• Human mutation • 2001 • Identification of the first reported splice site mutation (IVS7-1G→A) in the aminomethyltransferase (T-protein) gene (AMT) of the glycine cleavage complex in 3 unrelated families with nonketotic hyperglycinemia. PMID:11139253
• Human mutation • 2006 • Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. PMID:16450403
• Molecular genetics and metabolism • 2017 • d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence. PMID:28462797
• Journal of human genetics • 2014 • Mutation analysis of glycine decarboxylase, aminomethyltransferase and glycine cleavage system protein-H genes in 13 unrelated families with glycine encephalopathy. PMID:25231368
• Metabolic brain disease • 2019 • A novel intronic homozygous mutation in the AMT gene of a patient with nonketotic hyperglycinemia and hyperammonemia. PMID:30350008

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