Elsevier

Brain and Development

Volume 30, Issue 4, April 2008, Pages 305-307
Brain and Development

Case report
l-2-Hydroxyglutaric aciduria presenting with severe autistic features

https://doi.org/10.1016/j.braindev.2007.09.005Get rights and content

Abstract

l-2-Hydroxyglutaric aciduria (l-2-HGA) is an autosomal recessive neurometabolic disorder characterized by psychomotor delay, ataxia, macrocephaly and typical neuroradiological findings of subcortical leucoencephalopathy. Recently, the disease causing gene has been discovered (L2HGDH) encoding l-2-hydroxyglutarate dehydrogenase. We present a 3-year-old boy with l-2-HGA, who demonstrated macrocephaly, noted already in utero with ultrasound. Cranial MRI demonstrated diffuse subcortical encephalopathy with increased signal of the subcortical white matter. Subsequent metabolic screening revealed increased levels of l-2-HGA, and genomic DNA analysis demonstrated two missense mutations in l-2-HGDG. Patient’s further motor development was mildly impaired, whilst his speech development was profoundly impaired (first words at the age of 2 years). Since the age of 2 years he started demonstrating autistic repetitive behaviors and movements, increasing aloofness to his environment and limitations in the variety of spontaneous activity (CARS score: 44/60-severe autism). Autism has not so far been described in l-2-HGA and may be considered as an additional feature of the phenotypic spectrum.

Introduction

l-2-Hydroxyglutaric aciduria (l-2-HGA) is a rare autosomal recessive metabolic disorder, affecting exclusively the central nervous system. It is characterized by a defect in the metabolism of l-2-hydroxyglutaric acid and, consequently, increased levels of the acid in urine, cerebrospinal fluid and plasma [1]. The disorder has been mapped to chromosome 14q22.1 and, more specifically, to the gene encoding l-2-hydroxyglutarate dehydogenase (L2HGDH) [2]. l-2-HGA was first described in 1980 and since then about 75 cases have been reported worldwide [1]. Nevertheless, a distinct clinical and neuroradiological picture has emerged, as the disease has a relatively consistent pattern of presentation.

Clinically, l-2-HGA is characterized by mild psychomotor delay in the first years of life, followed by progressive cerebellar ataxia, dysarthria and moderate-to-severe mental deterioration, whereas macrocephaly, pyramidal and extrapyramidal signs, seizures and dystonia are present in the majority of patients. As far as behavioral and communication issues are concerned, several patients demonstrate language deficits and hyperactivity, whereas others are described during childhood as “talkative, almost in an uninhibited manner”. Briefly, MRI findings, which seem to be consistently unique of l-2-HGA, include subcortical white matter loss, cerebellar atrophy and bilateral signal changes in dentate nuclei and putamens [1].

In this brief report, the clinical and genetic features of a 3-year-old boy with l-2-HGA and severe autism are described.

Section snippets

Case report

The patient was referred to the neurodevelopmental department at the age of 4 months, because of macrocephaly, already noted in intrauterine life. He is the second child of healthy, non-consanguineous parents of caucasian origin. An older sister is entirely normal according to the parents and public health book information. Pregnancy was uneventful; however, he was delivered by caesarean section due to cephalopelvic disproportion (head circumference at birth 38.5 cm, > +2 SD). On the second day

Discussion

l-2-HGA is a rare neurometabolic disorder with a consistent clinical and radiological presentation. Psychomotor delay, ataxia and macrocephaly, in addition to the typical neuroradiological findings of subcortical leukoencephalopathy, are highly suggestive of the diagnosis. Macrocephaly is present in almost 50% of patients with l-2-HGA and it can be the first manifestation of the disease [1], [2], sometimes noted already in intrauterine ultrasound scans, as in this boy. Therefore, the presence

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