GCSH – Glycine Encephalopathy (Nonketotic Hyperglycinemia)

Nonketotic hyperglycinemia (NKH) is an autosomal recessive metabolic disorder characterized by accumulation of glycine due to defects in the glycine cleavage system. GCSH encodes the H-protein, a glycine cleavage component that also contributes to protein lipoylation, intersecting one-carbon metabolism and mitochondrial enzyme function. Pathogenic variants in GCSH result in both glycine accumulation and secondary mitochondrial dysfunction, manifesting as severe neonatal encephalopathy and lactic acidosis.

Initial evidence for GCSH involvement came from identical twins with NKH and dysplastic corpus callosum, supporting a genetic role for H-protein in brain development and glycine metabolism (PMID:1775403).

In 2021, three individuals from two unrelated Indian families with variant NKH harbored a biallelic start loss variant, c.1A>G (p.Met1Val), presenting with lactic acidosis, refractory seizures, severe hypotonia and leukoencephalopathy, confirming autosomal recessive inheritance and co-segregation in each family (PMID:33890291).

A recent cohort study described six additional patients from multiple families with biallelic GCSH variants including nonsense p.Gln76Ter, frameshift p.Tyr113fs and splicing c.293-2_293-1insT, who exhibited a spectrum from classical NKH to attenuated developmental delay, behavioral issues, limited epilepsy and variable movement disorders (PMID:36190515).

All reported families demonstrate autosomal recessive inheritance, with nine probands from three unrelated lineages and segregation in twins and siblings (affected_relatives = 3). The variant spectrum comprises start loss, nonsense, frameshift and splice‐site alleles predicted to abolish H-protein function. The prototypic variant c.1A>G (p.Met1Val) recurs in unrelated pedigrees, suggesting a possible mutational hotspot or founder effect in specific populations.

Functional assays in patient fibroblasts, COS7 knockdown models and yeast revealed that most missense and splicing variants produce a hypomorphic effect on both glycine cleavage and mitochondrial protein lipoylation. In vitro enzymatic studies confirmed markedly reduced H-protein activity, correlating with elevated glycine and secondary mitochondrial dysfunction (PMID:36190515; PMID:12663448).

Collectively, nine probands with biallelic loss-of-function GCSH variants, robust segregation data and concordant functional evidence support a Moderate ClinGen clinical validity for GCSH in nonketotic hyperglycinemia. Genetic testing of GCSH by sequencing and deletion analysis should be included in diagnostic panels for NKH. Key take-home: GCSH biallelic variants cause a combined glycine encephalopathy and mitochondrial lipoylation defect, informing precise diagnosis and potential therapeutic strategies.

References

• Pediatric pathology • 1991 • Dysplasia of the corpus callosum in identical twins with nonketotic hyperglycinemia. PMID:1775403
• Clinical genetics • 2021 • Biallelic start loss variant, c.1A>G in GCSH is associated with variant nonketotic hyperglycinemia PMID:33890291
• Human molecular genetics • 2023 • Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency PMID:36190515
• Blood • 2003 • A novel missense mutation in the gamma-glutamylcysteine synthetase catalytic subunit gene causes both decreased enzymatic activity and glutathione production PMID:12663448

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