D2HGDH – D-2-hydroxyglutaric Aciduria

D-2-hydroxyglutaric aciduria is a rare autosomal recessive neurometabolic disorder characterized by accumulation of D-2-hydroxyglutarate and a wide clinical spectrum ranging from severe encephalopathy to asymptomatic cases. Causative biallelic loss-of-function variants in D2HGDH result in enzyme deficiency and metabolite accumulation.

Inheritance is autosomal recessive, with compound heterozygous and homozygous variants described across unrelated families. A multi-patient cohort identified pathogenic variants in 24 of 50 patients (PMID:20020533) and additional probands have been reported in single-patient series and case reports.

The variant spectrum includes missense, frameshift, and splice-site alleles. For example, the missense variant c.1331T>C (p.Val444Ala) abolishes enzyme activity in overexpression assays (PMID:15609246). Other loss-of-function alleles such as c.325_326dup (p.Glu110fs) and splice-site mutations (e.g., c.853+2T>C) further confirm deleterious impact.

Segregation analysis in monozygotic twins compound heterozygous for c.325_326dup (p.Glu110fs) and c.1123G>T (p.Asp375Tyr) demonstrated phenotypic discordance likely driven by postzygotic or environmental modifiers, affirming variant pathogenicity (PMID:16081310).

Functional evidence includes significantly reduced D-2-HGDH activity in patient-derived cell homogenates measured by LC-MS/MS and almost complete loss of catalytic function in HEK293 overexpression models (PMID:19283509; PMID:30908763). This supports loss-of-function as the disease mechanism.

Although a subset of idiopathic D-2-HGA patients without D2HGDH variants exhibit normal enzyme activity and higher metabolite levels (PMID:20020533), this underscores genetic heterogeneity without refuting the role of D2HGDH in Type I disease.

Collectively, multiple unrelated probands, segregation studies, and concordant functional assays definitively establish that biallelic D2HGDH variants cause D-2-hydroxyglutaric aciduria. Key take-home: D2HGDH genetic testing enables definitive diagnosis, informs recurrence risk, and guides targeted metabolic surveillance.

References

• American journal of human genetics • 2005 • Mutations in the D-2-hydroxyglutarate dehydrogenase gene cause D-2-hydroxyglutaric aciduria. PMID:15609246
• Human mutation • 2010 • Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria. PMID:20020533
• Molecular genetics and metabolism • 2005 • Phenotypic heterogeneity in the presentation of D-2-hydroxyglutaric aciduria in monozygotic twins. PMID:16081310
• Journal of inherited metabolic disease • 2009 • Measurement of D: -2-hydroxyglutarate dehydrogenase activity in cell homogenates derived from D: -2-hydroxyglutaric aciduria patients. PMID:19283509
• Human mutation • 2019 • D-2-hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants. PMID:30908763

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