SLC6A9 – Atypical Glycine Encephalopathy

Atypical glycine encephalopathy (MONDO_0015010) is a rare autosomal recessive disorder characterized by arthrogryposis, hypertrichosis, seizures, and early lethality. Causative biallelic variants in the glycine transporter gene SLC6A9 have been implicated in affected fetuses and neonates.

To date, ten patients from five unrelated families have been reported (PMID:36195292), including a consanguineous Turkish pedigree with three fetuses homozygous for c.250G>A (p.Glu84Lys) exhibiting short neck, thoracic kyphosis, hypertrichosis, joint contractures, hypertonia, knee hyperextension, and seizures with neonatal exitus (PMID:36195292).

Earlier, a homozygous c.1000A>G (p.Ser334Gly) variant segregated with a non-ketotic hyperglycinemia-like phenotype in one kindred, extending the glycine transporter deficiency spectrum (PMID:27481395). The variant spectrum now includes missense, nonsense, and frameshift alleles predicted to abolish transporter function.

Segregation analysis confirms autosomal recessive inheritance with homozygous or compound heterozygous pathogenic alleles in affected individuals and absence of biallelic variants in unaffected relatives.

Functional studies demonstrate that murine Slc6a9 knockout recapitulates respiratory distress and hypotonia seen in patients (PMID:27481395), while in vitro assays of truncating and missense mutations—including p.Val45Met—show intracellular retention or severely diminished glycine uptake, consistent with a loss-of-function mechanism (PMID:32712301).

The convergence of robust genetic segregation and concordant functional data supports a strong gene–disease relationship for SLC6A9 in atypical glycine encephalopathy. Key Take-home: Autosomal recessive SLC6A9 testing guides definitive diagnosis and genetic counseling in neonates with arthrogryposis, hypertrichosis, and seizures.

References

• European Journal of Medical Genetics • 2022 • A lethal and rare cause of arthrogryposis: Glyt1 encephalopathy. PMID:36195292
• Human Genetics • 2016 • Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. PMID:27481395
• Neurochemistry International • 2020 • GlyT1 encephalopathy: Characterization of presumably disease causing GlyT1 mutations. PMID:32712301

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