Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• D-2-hydroxyglutaric aciduria (D-2-HGA) is a metabolic disorder characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) in physiological fluids.
• The genetic basis and classification of D-2-HGA are not fully understood, particularly for cases without identified mutations.

Purpose of the Study:

• To investigate the genetic and enzymatic basis of D-2-HGA in a cohort of 50 patients.
• To establish a clearer classification for D-2-HGA based on D2HGDH gene mutations and enzyme activity.

Main Methods:

• Molecular studies (mutation analysis of the D2HGDH gene).
• Enzyme assays to measure D-2-hydroxyglutarate dehydrogenase (D-2-HGDH) activity.
• Metabolic studies to quantify D-2-HG levels in patient body fluids.

Main Results:

• Pathogenic mutations in the D2HGDH gene were identified in 24 out of 50 patients.
• Patients with D2HGDH mutations exhibited impaired enzyme activity and lower D-2-HG concentrations compared to mutation-negative patients.
• Idiopathic D-2-HGA cases showed normal D-2-HGDH activity and higher D-2-HG levels than D2HGDH-deficient patients.

Conclusions:

• D-2-HGA Type I is associated with D-2-HGDH deficiency due to mutations in the D2HGDH gene.
• Idiopathic D-2-HGA is characterized by normal D-2-HGDH activity and distinct metabolic profiles.
• Multiple genetic loci may contribute to D-2-HG hyperexcretion, suggesting further heterogeneity in D-2-HGA.