An Adult Form of L-2-Hydroxyglutaric Aciduria Revealed by Tremor

L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare autosomal recessively inherited neurometabolic disorder. Since its first description in 1980, about 30 other cases have been reported. Occurring mostly in childhood, it is characterized by slow and progressive neurological dysfunction with cerebellar ataxia, pyramidal signs, intellectual decline, seizures and extrapyramidal symptoms; MRI is highly characteristic [1, 2, 3]. We report another case of L-2-HGA, unusual because it was revealed in an adult by abnormal movements.When we first saw our patient, she was 26. Her parents were healthy and nonconsanguineous; she began to walk at 16 months. She presented with a postural and intentional tremor of both hands associated with a slight head tremor and dysarthria; when walking, facial muscles adopted an inappropriate grin, and hands assumed dystonic postures. There were no pyramidal signs or axial ataxia. The patient was intellectually slow; she worked in a workcenter for the handicapped. Two years before our first examination, she had an episode of renal lithiasis. MRI revealed multiple areas of high signal intensity on T2-weighted images within the subcortical white matter, but centrally located white matter was not involved; signal abnormalities also involved globus pallidus and dentate nuclei; on T2-weighted sequences low signal was observed in the thalamus; the fourth ventricle was enlarged and the cerebellar vermis was atrophic (fig. 1). Routine blood analysis as well as serum ceruloplasmin, serum and urinary copper, enzyme activity of beta-galactosidase, galactosylceramidase, arylsulfatase and glucosaminidase were normal.Clinical status remained unchanged for about 10 years. When she was 37 years old, she began to worsen rather rapidly. Several generalized seizures occurred, mental deficiency increased; gait disturbances related to cerebellar ataxia appeared and worsened. Within 6 months she could no longer walk. Pyramidal syndrome and akinesia appeared. Urinary organic acid analysis by gas chromatography and mass spectrometry revealed a high increase of L-2-hydroxyglutaric acid (622 µmol/mol creatinine; controls <20). Separation of L and D isomers (courtesy of C. Jakobs, Amsterdam) demonstrated accumulation of L form.Abnormal movement can reveal not only Wilson’s disease, Dopa-sensitive dystonia and mitochondrial disorders but also some diseases affecting amino acid and organic acid metabolism, such as glutaric aciduria type 1 and 2 [4]. L-2-HGA must be added to this list. The clinical and MRI features of this newly defined inborn error of metabolism have been reviewed by Barth et al. [1]. The underlying metabolic defect in 2-HGA is still unknown and a deficiency of 2-hydroxyglutarate dehydrogenase has been postulated [5]. However, a recent paper demonstrated normal liver activity of this enzyme in 2 patients [6]. A specific diagnosis requires methodologies which distinguish L from D isomers since two distinct diseases with different phenotypes exist [7]. Urinary organic acid profile is generally performed in laboratories involved in diagnosis of inborn errors of metabolism in pediatric hospitals. This may explain why this disease has been mostly reported in children.In our case diagnosis was difficult: abnormal movements were the most predominant signs in this adult patient. It is likely that tremor was cerebellar in nature. Given the hand and head tremor associated with dystonic postures, we first tested for Wilson’s disease. However, when reviewing the entire dossier today, we should have evoked diagnosis of L-2-HGA, as MRI abnormalities were highly suggestive, with striking subcortical white matter, globus pallidus and dentate nucleus involvement, and atrophic cerebellar vermis: distinct features which are quite different from other leukodystrophies, and have been described by previous authors [1, 2, 3, 8]. Another original characteristic of our observation is the secondary rapid worsening of the disease, which had scarcely evolved over a 10-year period. Such rapid deterioration has already been reported in children [8]. Mechanisms responsible for brain damage are still unclear. Is the brain damage related to the action of L-2-hydroxyglutarate on other metabolic pathways [9]? Or is it related to an abnormal metabolic pathways of serine [10]?Anyway, our observation should encourage MRI as a first exam in young adults with abnormal movements and mental retardation. Because MRI follows a characteristic pattern for L-2-HGA, other exams can be avoided. Confirmation of the diganosis can be done by the urinary organic acid profile.The authors are grateful to L. Rose for her help with the English version of the paper.