GLDC – Glycine Encephalopathy (Nonketotic Hyperglycinemia)

Glycine decarboxylase (GLDC) encodes the P‐protein of the mitochondrial glycine cleavage system, and biallelic pathogenic variants lead to nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy. NKH is characterized by elevated glycine in plasma and cerebrospinal fluid, with clinical features including hypotonia, lethargy, apnea, and intractable seizures in the neonatal period. The condition follows an autosomal recessive inheritance pattern and exhibits severe neurologic impairment with high mortality without early intervention.

Multiple case series and population studies have demonstrated a definitive gene–disease relationship. In Finnish NKH patients, a founder c.1691G>T (p.Ser564Ile) variant accounts for 70% of GLDC alleles, abolishing P‐protein activity in COS‐7 cells and segregating in homozygosity in affected siblings ([PMID:1634607]). Comprehensive mutation screening across 69 NKH families identified GLDC or AMT variants in 75–83% of neonatal and infantile cases, including 36 families with biallelic GLDC mutations and evidence of segregation in consanguineous pedigrees ([PMID:16450403]). Additional cohorts reveal over 100 unique GLDC variants in unrelated probands worldwide, confirming broad allelic heterogeneity.

The variant spectrum in GLDC encompasses missense, nonsense, splice, frameshift, and large‐deletion alleles. Over 50 missense changes (e.g., p.Pro329Thr, p.Gly762Arg), multiple LoF alleles (e.g., c.1054del leading to p.Thr352GlnfsTer?), and recurrent founder variants have been reported in diverse populations ([PMID:12126939]). The Finnish p.Ser564Ile founder allele (c.1691G>T) serves as a molecular diagnostic marker in high‐incidence regions, with carrier frequency estimates supporting targeted screening in northern Finland.

Functional studies corroborate pathogenicity through enzymatic and expression analyses. In vitro assays of P‐protein variants in COS‐7 cells reveal absent or markedly reduced activity for missense and frameshift mutants. RNA blotting and semiquantitative PCR demonstrate large homozygous GLDC deletions in patient lymphoblasts, confirming loss of transcript and enzyme function ([PMID:10798358]). Residual activity assays in neonatal‐onset NKH patients identify hypomorphic alleles associated with attenuated phenotypes, guiding prognosis and therapeutic consideration ([PMID:15192636]).

No conflicting evidence has been reported that refutes the GLDC–NKH association. Phenotypic variability relates primarily to residual enzyme activity rather than alternative genetic etiologies. Late‐onset and mild forms correspond to specific hypomorphic missense alleles, reinforcing the genotype–phenotype correlation.

Integration of genetic and functional data establishes GLDC as a definitive NKH gene. Diagnostic testing should include full gene sequencing and deletion analysis, with particular attention to c.1691G>T in Finland. Early molecular diagnosis enables carrier screening, prenatal testing, and tailored management strategies, including sodium benzoate and NMDA receptor antagonists. Key take‐home: GLDC mutation analysis is essential for accurate NKH diagnosis, prognostication, and genetic counseling.

References

• The Journal of Clinical Investigation • 1992 • Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia. PMID:1634607
• Human Genetics • 2000 • Human glycine decarboxylase gene (GLDC) and its highly conserved processed pseudogene (psiGLDC): their structure and expression, and the identification of a large deletion in a family with nonketotic hyperglycinemia. PMID:10798358
• Molecular Genetics and Metabolism • 2002 • Novel mutations in the P‐protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non‐ketotic hyperglycinemia). PMID:12126939
• The Journal of Pediatrics • 2004 • Mild variant of nonketotic hyperglycinemia with typical neonatal presentations: mutational and in vitro expression analyses in two patients. PMID:15192636
• Human Mutation • 2006 • Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. PMID:16450403

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