D-2-Hydroxyglutaric Aciduria and Glutaric Aciduria Type 1 in Siblings: Coincidence, or Linked Disorders?

Abstract

Glutaric aciduria type 1 (GA1) and D-2-hydroxyglutaric aciduria (D-2-HGA) are cerebral organic acidurias characterized by the excretion of 3-hydroxyglutaric and D-2-hydroxyglutaric acids, respectively. GA1 is caused by a deficiency of glutaryl-CoA dehydrogenase encoded by the GCDH gene; the biochemical and genetic basis of D-2-HGA is unknown. We diagnosed GA1 in the son of consanguineous Palestinian parents, and D-2-HGA in his sister and brother. All three siblings were neurologically and developmentally normal. A small but abnormal increase in excretion of D-2-hydroxyglutaric acid was also found in the sibling with GA1. These observations suggested a possible pathophysiological link between these two disorders. The sibling with GA1 was homozygous whilst his siblings with D-2-HGA were heterozygous for a 1283 C>T missense mutation (T416I) in exon 11 of the GCDH gene. However, sequence analysis of the GCDH gene in 8 additional unrelated patients with D-2-HGA and 3 with combined D/L-2-HGA did not reveal any pathogenic mutations. The biochemical and genetic basis of D-2-HGA remains to be determined.

Key words

Organic acid disorders - GCDH mutation - D-2-hydroxyglutaric acid - 3-hydroxyglutaric acid

References

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