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

https://doi.org/10.1016/j.ymgme.2003.11.013Get rights and content

Abstract

A 19-month-old boy with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency, a defect of isoleucine degradation, had cognitive and motor development delay, spastic diplegia, dysmorphism, and occipital periventricular white matter lesions on MRI scan of the brain. The urinary accumulation of the isoleucine metabolites 2-methyl-3-hydroxybutyrate and tiglylglycine was only moderate under basal conditions. These abnormalities became more pronounced after a 100 mg/kg oral isoleucine challenge. Enzyme studies showed a markedly decreased activity of MHBD in fibroblasts and lymphocytes. Sequence analysis of the involved X-chromosome gene (HADH2), revealed the presence of 364C  G mutation in the patient. His mother was heterozygous for the 364C  G mutation, whereas the mutation was not found in the other members of the family (father, brother, and sister). This report indicates that an enzyme defect in the metabolism of branched-chain fatty acid oxidation and isoleucine may present features resembling sequelae of neonatal hypoxic–ischemic brain injury. All patients with MHBD deficiency identified so far are characterized by a neurologic phenotype rather than ketoacidotic attacks, unlike patients with the related isoleucine defect β-ketothiolase deficiency.

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

References (12)

  • R. Ofman et al.

    2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene

    Am. J. Hum. Genet.

    (2003)
  • J. Brismar et al.

    CT and MRI of the brain in the diagnosis of organic acidemia. Experiences from 107 patients

    Brain Dev.

    (1994)
  • P. Strømme et al.

    Atypical methylmalonic aciduria with progressive encephalopathy, microcephaly and cataracts in two siblings—a new recessive syndrome?

    Clin. Genet.

    (1995)
  • E. Mayatepek et al.

    Atypical vitamin B12-unresponsive methylmalonic aciduria in a sibship with severe progressive encephalomyelopathy: a new genetic disease?

    Eur. J. Pediatr.

    (1996)
  • K.M. Gibson et al.

    2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of l-isoleucine metabolism

    Pediatr. Res.

    (2000)
  • J. Zschocke et al.

    Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism

    Pediatr. Res.

    (2000)
There are more references available in the full text version of this article.

Cited by (30)

  • A 5-methylcytosine hotspot responsible for the prevalent HSD17B10 mutation

    2013, Gene
    Citation Excerpt :

    Hydroxysteroid (17β) dehydrogenase X deficiency also known as 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, is a relatively rare X linked neurological syndrome resulting from a missense mutation in the HSD17B10 gene (Ofman et al., 2003; Seaver et al., 2011; Yang et al., 2009). The urine organic acid profile of affected individuals is characterized by high levels of isoleucine metabolites, namely 2-methyl-3-hydroxy butyrate and tiglylglycine, which indicate a blockade of the isoleucine and branched-chain fatty acid degradation pathway (Cazorla et al., 2007; Ensenauer et al., 2002; García-Villoria et al., 2009, 2010; He and Yang, 2006; Olpin et al., 2002; Perez-Cerda et al., 2005; Poll-The et al., 2004; Sass et al., 2004; Sutton et al., 2003; Zschocke et al., 2000). Although the accumulation of these isoleucine and branched-chain fatty acid metabolites (He and Yang, 2006) may not be completely benign (Rossa et al., 2005), it does not cause neurological symptoms in patients with a different blockade of such pathways, β-KT thiolase deficiency (Fukao et al., 2001) that also shows an accumulation of these metabolites.

  • Gene Associated with Seizures, Autism, and Hepatomegaly in an Amish Girl

    2009, Pediatric Neurology
    Citation Excerpt :

    Certainly, periventricular leukomalacia can be seen in term infants, often associated with low Apgar scores [4] and perinatal asphyxia [5], as well as in infants with no known perinatal complications [6]. Metabolic disorders, such as those of isoleucine metabolism [7], as well as various chromosomal abnormalities [8], have also been associated with periventricular leukomalacia, as have complex partial seizures, and possibly intractability of these seizures [9]. While it is certainly possible the magnetic resonance imaging findings of this patient are incidental, the strong association between periventricular leukomalacia, neurodevelopmental disabilities, and seizures implicates this feature in the CNTNAP2 phenotype.

  • Submicroscopic Duplications of the Hydroxysteroid Dehydrogenase HSD17B10 and the E3 Ubiquitin Ligase HUWE1 Are Associated with Mental Retardation

    2008, American Journal of Human Genetics
    Citation Excerpt :

    Finally, we observed changes in the expression of many cell-cycle genes with a central role for TP53 (P53), consistent with an upregulation of HUWE1 (Figure S2). Metabolic screening of the dehydrogenase activity of HSD10 in lymphocytes21 will not allow for the detection of this microduplication because we did not find altered levels of a number of acylcarnitines or amino acids associated with the isoleucine degradative pathway in a blood spot of one of the patients from family MRX17, compared to age-matched controls, by using tandem mass spectrometry (MS/MS) (data not shown). For HUWE1 activity, we analyzed the TP53 mRNA and TP53 protein abundances by RT-qPCR and western blotting, respectively, in EBV-PBLs from affected individuals from families MRX17, MRX31, A057, P083 (duplications), and A323 (missense change) but did not find reduced levels compared to control cell lines (data not shown).

View all citing articles on Scopus
View full text