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D-2-Hydroxyglutaric aciduria: biochemical marker or clinical disease entity?
M S van der Knaap1, C Jakobs, G F Hoffmann
1Department of Child Neurology, Free University Hospital, Amsterdam, The Netherlands.
Annals of Neurology
|January 23, 1999
Summary
D-2-Hydroxyglutaric aciduria is a distinct neurometabolic disorder. This study identified two phenotypes: a severe infantile encephalopathy and a milder form, confirming its disease entity.
Area of Science:
- Neurology
- Metabolic Disorders
- Genetics
Background:
- D-2-Hydroxyglutaric aciduria presents with highly variable clinical symptoms, questioning its status as a distinct disease.
- Previous observations lacked sufficient data to establish a clear disease entity.
Purpose of the Study:
- To investigate the clinical spectrum and confirm D-2-Hydroxyglutaric aciduria as a distinct neurometabolic disorder.
- To delineate the phenotypes associated with D-2-Hydroxyglutaric aciduria.
Main Methods:
- International survey and retrospective analysis of 17 patients with D-2-Hydroxyglutaric aciduria.
- Review of clinical history, neuroimaging, and biochemical data.
Main Results:
- Two distinct phenotypes were identified: a severe early-infantile encephalopathy (10 patients) with epilepsy, hypotonia, visual failure, developmental delay, and sometimes cardiomyopathy; and a milder, variable phenotype (7 patients) with intellectual disability, hypotonia, and macrocephaly.
- Neuroimaging consistently showed delayed cerebral maturation, with specific findings like ventriculomegaly and subependymal cysts in younger patients.
- Elevated D-2-hydroxyglutaric acid in bodily fluids confirmed the biochemical marker across both phenotypes. Elevated gamma-aminobutyric acid in cerebrospinal fluid was also noted.
Conclusions:
- D-2-Hydroxyglutaric aciduria represents a distinct neurometabolic disorder.
- The disorder manifests with at least two clinically and neuroimaging-defined phenotypes.