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L-2-hydroxyglutaric aciduria: clinical heterogeneity versus biochemical homogeneity in a sibship
J B de Klerk1, J G Huijmans, H Stroink
1Department of Pediatrics, Sophia Children's Hospital, Erasmus University Rotterdam, The Netherlands.
Insights
L-2-hydroxyglutaric aciduria, a rare metabolic disorder, frequently causes neurological disease in affected siblings. Symptom severity can vary within families, independent of biochemical abnormality levels.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- L-2-hydroxyglutaric aciduria is an inherited metabolic disorder.
- This study investigates a North-African family with multiple affected siblings.
Observation:
- Three out of four siblings presented with L-2-hydroxyglutaric aciduria and varying degrees of psychomotor retardation.
- All affected individuals exhibited increased head circumference.
- Brain MRI revealed white matter abnormalities consistent with demyelination or spongiosis.
Findings:
- Biochemical analysis showed similar L-2-hydroxyglutaric acid levels across affected siblings.
- Cerebrospinal fluid analysis indicated elevated lysine and decreased glutamine in the most severely affected child.
- Neurological symptoms did not strictly correlate with the extent of biochemical abnormalities.
Implications:
- L-2-hydroxyglutaric aciduria is strongly associated with neurological impairment.
- Disease manifestation can be variable within families, suggesting other genetic or environmental factors may influence severity.
- Further research is needed to understand the full spectrum and pathogenic mechanisms of this disorder.
Abstract:
Three out of four sibs in a North-African family were affected with L-2-hydroxyglutaric aciduria. The youngest sib was most severely handicapped: she was diagnosed at 2.5 years of age, whereas the then 7- and 10-year-old siblings had a less pronounced psychomotor retardation. All patients had an increased head circumference in contrast to the healthy, non-affected sibling. Urine and plasma levels of L-2-hydroxyglutaric acid in the three sibs were similar and showed only a small variation. Magnetic resonance imaging (MRI) of the brain in the eldest sib showed hyperintense signal on T2-weighted images of the basal ganglia, dentate nucleus and subcortical white matter. The youngest sib showed identical white matter abnormalities of the corpus medullare cerebelli. These abnormalities were consistent with demyelination and/or spongiosis. On two occasions cerebrospinal fluid amino acid chromatography in the youngest sib showed an increased concentration of lysine and a decreased level of glutamine. Plasma lysine was normal. It is concluded that L-2-hydroxyglutaric aciduria is almost invariably associated with neurological disease; the severity of the symptoms does not seem to be completely dependent on the extent of the biochemical abnormalities and may even be variable within a family.