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The GLYCTK gene encodes d-glycerate kinase, an enzyme that catalyzes the conversion of d-glycerate to 2-phosphoglycerate in serine and fructose metabolism. Recessive pathogenic variants in GLYCTK cause D-glyceric aciduria, an autosomal recessive metabolic disorder characterized by accumulation of urinary d-glycerate. D-glyceric aciduria exhibits broad phenotypic variability ranging from asymptomatic glycerateuria to severe neurological impairment. Reported clinical features include global developmental delay, progressive microcephaly, intractable seizures, and cortical blindness. Diagnosis typically involves urinary organic acid analysis followed by molecular genetic testing of GLYCTK. A clear understanding of genotype–phenotype correlations in DGA is essential for precision diagnosis and management.
Genetically, DGA follows autosomal recessive inheritance, with biallelic GLYCTK variants identified in affected individuals. Initial characterization in 2010 described three unrelated probands of Serbian, Mexican, and Turkish origin harboring homozygous exon 5 variants, including c.1478T>G (p.Phe493Cys), c.1448delT (p.Phe483SerfsTer2), and c.1558delC (p.Leu520CysfsX108), each demonstrating loss of enzyme activity in HEK293 cells (PMID:20949620). Subsequent case reports include two siblings—one with severe autism and global developmental delay and one asymptomatic carrier—both homozygous for c.767C>G (p.Pro256Arg) (PMID:28190537). A 2019 study described an additional proband with c.455T>C (p.Leu152Pro) and reviewed 15 previously reported patients, bringing the total to over 20 individuals with biallelic GLYCTK variants (PMID:30637540). The most recent report in 2024 identified a novel homozygous c.853A>T (p.Lys285Ter) allele, raising the count to more than 22 probands (PMID:39619776). Segregation analysis in one family and consistent recessive transmission across cohorts reinforce the inheritance model.
The variant spectrum spans missense, nonsense, and frameshift changes distributed throughout GLYCTK. Recurrent missense alleles such as c.1478T>G (p.Phe493Cys) have been observed across multiple ethnicities, suggesting mutational hotspots. Truncating mutations, including c.1448delT (p.Phe483SerfsTer2) and c.853A>T (p.Lys285Ter), lead to premature termination and protein instability. The missense variant c.455T>C (p.Leu152Pro) affects a conserved residue in a putative catalytic domain. No deep-intronic or regulatory variants have been reported to date. The diversity of allele types supports a loss-of-function mechanism underlying DGA.
Functional studies provide experimental support for pathogenicity. Transient overexpression of variant GLYCTK alleles in HEK293 cells demonstrated complete loss of glycerate kinase activity and reduced immunoreactivity for both truncating and missense variants (PMID:20949620). Patient-derived enzyme assays corroborate markedly reduced or absent d-glycerate kinase function. These data are consistent with haploinsufficiency as the primary mechanism of disease. No animal models have been reported, and rescue experiments remain to be performed. Overall, functional concordance strengthens the causal link.
Despite strong genetic and biochemical evidence, some individuals with biallelic GLYCTK variants remain asymptomatic. Notably, one sibling homozygous for c.767C>G (p.Pro256Arg) had normal neurodevelopment despite elevated urinary d-glycerate (PMID:28190537). This phenotypic heterogeneity suggests incomplete penetrance or genetic modifiers that influence clinical expression. The threshold of residual enzyme activity necessary for protection against neurological impairment is not yet defined. Larger longitudinal studies are required to delineate prognostic markers. At present, clinical management should account for variable expressivity.
In summary, biallelic GLYCTK variants cause D-glyceric aciduria via a loss-of-function mechanism, with over 22 probands across more than 11 unrelated families and concordant in vitro enzymatic studies. The cumulative data meet ClinGen criteria for a Strong gene–disease association. Genetic testing for GLYCTK should be integrated into metabolic screening panels to enable early diagnosis and inform genetic counseling. Functional assays can aid variant interpretation in uncertain cases. Key Take-home: Biallelic loss-of-function GLYCTK variants underlie D-glyceric aciduria, and comprehensive genetic testing is essential for accurate diagnosis and management.
Gene–Disease AssociationStrong
Genetic EvidenceStrongOver 22 individuals with autosomal recessive biallelic variants across four cohorts; multiple variant types and consistent segregation Functional EvidenceModerateIn vitro overexpression studies show complete loss of enzymatic activity and immunoreactivity for truncating and missense alleles |