Elsevier

Pediatric Neurology

Volume 27, Issue 2, August 2002, Pages 141-144
Pediatric Neurology

Case report
l-2-hydroxyglutaric aciduria in two siblings

https://doi.org/10.1016/S0887-8994(02)00405-8Get rights and content

Abstract

Two Pakistani siblings with l-2-hydroxyglutaric aciduria are reported herein. A 6-year-old male and a 2-year-old female, born to consanguineous parents, had chronic slowly progressive neurodegenerative disorder with insidious onset after infancy. Mental regression and seizures were evident in both patients, whereas cerebellar dysfunction was the main motor handicap in the male and pyramidal symptoms were prominent in the female. Magnetic resonance imaging revealed bilateral symmetrical abnormal signal in the subcortical white matter, internal and external capsules, basal ganglia, and dentate nuclei. The underlying metabolic defect, which is likely inherited in an autosomal recessive mode, remains unknown in this disorder.

Introduction

Organic acidurias are a group of inherited metabolic disorders characterized by increased urinary excretion of organic acids. These disorders may present with episodes of severe metabolic decompensation or exclusively with severe neurologic disease. l-2-Hydroxyglutaric aciduria is a rare disorder belonging to the latter category.

l-2-Hydroxyglutaric aciduria was first reported in 1980 in a 5-year-old male who was investigated for global developmental delay [1]. A review of eight patients with characteristic pattern of a neurodegenerative disorder associated with the excretion of large amount of l-2-hydroxyglutaric acid was published in 1992 [2]. This study delineated the clinical, biochemical, and neuroimaging features of the disease as a clinical entity. Several other patients of various ethnic origins have been reported since 1992 [3], [4], [5], [6]. A more or less characteristic picture of the disease has emerged. Most of the patients had mental and motor retardation associated with ataxia. Pyramidal signs occurred frequently, and extrapyramidal signs appeared occasionally. Macrocephaly and seizures were often reported. All investigated patients demonstrated characteristic subcortical white matter abnormalities on magnetic resonance imaging [2], [7], [8], [9].

The diagnosis is established by detection of increased levels of l-2-hydroxyglutaric acid in urine [1], [2], [7]. Two clinical entities, l-2-hydroxyglutaric aciduria and d-2-hydroxyglutaric aciduria, are associated with increased 2-hydroxyglutaric acid excretion; therefore the absolute configuration of the metabolite should be determined [1], [10]. In this study we report on two siblings with l-2-hydroxyglutaric aciduria.

Section snippets

Patient 1

Patient 1 was a male who was born at term after an uneventful pregnancy, labor, and delivery. His birth weight was 3,000 g. He began to smile at 6 weeks, sit without support at 8 months, and walk at 20 months of age. He had a febrile seizure when he was 1 year of age. Full assessment was performed at 4.5 years of age. His weight was 16.5 kg (twenty-fifth percentile), length 101.9 cm (between the tenth and twenty-fifth percentiles), and fronto-occipital circumference 53.4 cm (between ninetieth

Discussion

The increased urinary l-2-hydroxyglutaric acid excretion confirms the diagnosis of l-2-hydroxyglutaric aciduria [2]. The clinical picture of the two patients fits a chronic, slowly progressive neurodegenerative disorder with insidious onset after infancy. No significant abnormalities were noted in the first year of life; developmental delay appeared later. Mental regression and seizures were found in both children. Clinically cerebellar dysfunction was the main motor handicap in Patient 1,

Acknowledgements

We thank Professor Peter G. Barth for his useful comments on the magnetic resonance imaging study and Ashok Prasad for taking the photographs for this report.

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1

Peter Vreken is deceased.

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