Elsevier

Brain and Development

Volume 40, Issue 6, June 2018, Pages 498-502
Brain and Development

Case Report
Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation

https://doi.org/10.1016/j.braindev.2018.02.007Get rights and content

Abstract

Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.

Introduction

Leigh syndrome (LS) is the most common phenotype of pediatric mitochondrial disease, which is a progressive neurodegenerative disease [1]. The incidence of LS is estimated 1:32,000–40,000 births [2], [3]. The onset of clinical symptoms, including hypotonia and psychomotor retardation, typically occurs by 2 years of age, and LS patients often showed rapid deterioration due to metabolic challenges such as infection and prolonged fasting [1], [2]. The typical neuroimaging findings of LS include necrotic bilateral symmetric lesions in the basal ganglia and/or the brainstem [1], [4], [5]. There are a few reports on spinal cord involvement in patients with LS [6], [7]. We herein present a case of LS with spinal cord involvement in MRI due to an NDUFA1 mutation. The c.55C > T, p(P19S) mutation of this patient has already been described and the pathogenicity at the cellular level has already been proven [8].

Section snippets

Case report

The patient was an 11-year-old boy who was born at 36 weeks of gestational age to non-consanguineous parents. The patient had a dichorionic diamniotic twin sister who was not affected and had no significant family history of neurological disorders. His birth weight was 2154 g. At 5 months of age, he exhibited axial hypotonia and horizontal nystagmus. Although his developmental milestones were normal until 4 months of age, he presented a developmental delay after 5 months of age; he was able to

Discussion

The brain lesions of LS are typically located in the basal ganglia and/or brainstem, where they show hyperintensity on T2-weighted imaging. These CNS lesions most commonly affect the putamen, thalamus, substantia nigra, nucleus ruber, medulla oblongata, and cerebellar dentate nucleus [4], [5]. Spinal involvement is a hallmark of a specific subtype of mitochondrial disease: leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (MIM 610956), which is associated with

Acknowledgment

The work was supported by the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED).

References (13)

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    The NDUFA1 gene locates in the X-chromosome and it encodes an evolutionarily highly conserved protein, which is an essential part of CI (Au et al., 1999). Previously four NDUFA1 missense variants p.Gly8Arg, p.Arg37Ser, p.Gly32Arg and p.Pro19Ser have been reported to associate with neurological disease phenotypes, mainly Leigh syndrome, in hemizygous male patients (Fernandez-Moreira et al., 2007; Miyauchi et al., 2018; Potluri et al., 2009; Uehara et al., 2014). In addition, heterozygous p.Gly32Arg variant has been reported in a 15-month-old girl with OXPHOS deficiency and mild symptoms of somnolence and vomiting (Mayr et al., 2011).

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    Written informed consent was obtained from the parents of each patient. Our study was conducted using fibroblast cells from four patients (Table 1), including two genetically identified cases of LS: one with the m.10158 T>C, p(S34P) mutation in ND3 (Case 1; LSND3) and one with the c.55 C>T, p(P19S) mutation in NDUFA1 (Case 2; LSNDUFA1) (Kouga et al., 2018; Miyauchi et al., 2018). Both ND3 and NDUFA1 are subunits of Complex I in the mitochondrial respiratory chain.

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