L2HGDH – L-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the L2HGDH gene (HGNC:20499). Affected individuals accumulate L-2-hydroxyglutarate in urine, plasma and cerebrospinal fluid, leading to progressive neurological dysfunction including seizures, cerebellar ataxia, macrocephaly and intellectual disability. Magnetic resonance imaging consistently reveals subcortical white matter hyperintensities with characteristic centripetal spread and involvement of the basal ganglia and dentate nuclei. The disorder typically presents in early childhood but adult-onset phenotypes without classic imaging findings have been reported (PMID:19863265).

Genetic evidence for a definitive L2HGDH–L-2-HGA association includes over 100 unrelated probands from 83 families with confirmed biallelic L2HGDH variants and consistent segregation under an autosomal recessive model (PMID:20052767). Homozygosity mapping and targeted sequencing identified at least 70 unique loss-of-function and missense mutations distributed across all 10 exons of L2HGDH, with no clear genotype–phenotype correlation. Three recurrent alleles in Portuguese patients—c.529delC (p.Pro177HisfsTer6), c.208C>T (p.Arg70Ter) and c.293A>G (p.His98Arg)—accounted for 76% of mutant alleles, suggesting founder effects in isolated populations (PMID:16134148; PMID:20052767).

Segregation analysis in large consanguineous pedigrees further supports pathogenicity, with 19 additional affected relatives demonstrating co-segregation of homozygous or compound heterozygous L2HGDH variants and L-2-HGA phenotypes. Key variants include the frameshift allele c.529delC (p.Pro177HisfsTer6), which truncates the FAD-binding domain and is absent from control databases, confirming its deleterious nature.

Functional studies provide strong mechanistic evidence: L2hgdh knockout mice accumulate L-2-hydroxyglutarate in brain and testis, develop progressive leukoencephalopathy, neuroinflammation, and late-onset neurodegeneration, recapitulating human disease pathology and confirming loss-of-function as the primary mechanism (PMID:28137912).

Clinical heterogeneity is well documented, ranging from early-onset developmental delay, ataxia and epilepsy to adult presentations with isolated cognitive decline or dystonia. Urinary organic acid profiling remains a critical diagnostic tool, and high-throughput sequencing ensures definitive molecular diagnosis, enabling carrier testing and prenatal counseling.

Integration of extensive genetic, segregation, and functional data meets ClinGen criteria for a Definitive gene–disease association. Early recognition of L-2-HGA through metabolite screening and genetic testing allows timely supportive care, genetic counseling, and exploration of experimental therapies. Key take-home: L2HGDH sequencing should be performed in all patients with unexplained subcortical leukoencephalopathy and compatible biochemical findings to confirm diagnosis and guide family planning.

References

• Human mutation • 2010 • An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study PMID:20052767
• Molecular and cellular biology • 2017 • L2hgdh deficiency accumulates l-2-hydroxyglutarate with progressive leukoencephalopathy and neurodegeneration PMID:28137912

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