Spastic diplegia and periventricular white matter abnormalities in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, a defect of isoleucine metabolism: differential diagnosis with hypoxic–ischemic brain diseases
Introduction
The majority of the organic acidurias caused by a disturbed catabolism of the branched-chain amino acids leucine, isoleucine, and valine are characterized by episodes of poor feeding, irritability, and lethargy, which can proceed to coma, often associated with increased protein consumption or intercurrent illness. In such cases, metabolic acidosis, with or without ketosis and hypoglycemia, may be suggestive of an organic aciduria which can be detected by urinary organic acid analysis. Apart from these episodes patients usually develop normally without neurologic features, and typically respond well to a protein-restricted diet.
There are only a few defects in these pathways which are exclusively associated with non-episodic neurologic deficits. These are the so-called cerebral methylmalonic aciduria [1], [2] and the recently discovered defects of 2-methylbutyryl-CoA dehydrogenase [3] and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD)1 [4]. MHBD deficiency has been described in literature, unanimously presenting a wide neurologic spectrum in males [4], [5], [6], [7], [8]. The molecular basis of 2-methyl-3-hydroxybutyric aciduria has been recently resolved through the identification of mutations in the HADH2 gene coding for MHBD [9]. The disorder is inherited as an X-chromosomal recessive trait.
In this paper, we report the identification of a patient with a deficiency of MHBD, a defect in the degradation of short-branched-chain fatty acids and isoleucine, who presented with mild dysmorphic features, spastic diplegia, and occipital periventricular white matter lesions, resembling the clinical phenotype of that observed in patients with sequelae of perinatal hypoxic–ischemic brain damage.
Section snippets
Case report
The boy is the third child of non-consanguineous Dutch parents. He has two normal siblings. Pregnancy, delivery, and neonatal period were unremarkable although there was meconium-stained amniotic fluid. At age 13 months he was able to sit unsupported and at 15 months he needed glasses because of astigmatism. His general condition was good and his growth was normal for age. The boy was referred to the pediatric neurology department at the age of 19 months for assessment of developmental delay.
Biochemical studies
Urine organic acid analysis by gas chromatography/mass spectrometry of the methoxim/trimethylsilyl derivates revealed consistent, moderate elevations of 2-methyl-3-hydroxybutyrate (67–99 mmol/mol creatinine; controls 11–27 [6]) and tiglylglycine (19–27 mmol/mol creatinine; controls < 3.8 [7]) without elevation of 2-methylacetoacetate. Normal results were obtained for plasma and CSF amino acids as well as neurotransmitters in CSF. Tandem mass spectroscopy analysis of plasma acylcarnitines showed a
Discussion
MHBD deficiency is a novel defect in the oxidation of 2-methyl branched-chain fatty acids and isoleucine (Fig. 3). The first patient described presented with mild developmental delay during the first year of life followed by progressive neurologic regression with seizures, blindness, and choreoathetoid movements at 2 years of age [4]. Brain MRI abnormalities in this patient were restricted to mild frontotemporal atrophy. More recently, five other patients have been described with MHBD
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