Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II

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Abstract

We report a patient with relatively mild Leigh syndrome and mitochondrial respiratory chain complex II deficiency caused by a homozygous G555E mutation in the nuclear encoded flavoprotein subunit of succinate dehydrogenase. This mutation has previously been reported in a lethal-infantile presentation of complex II deficiency. Such marked phenotypic heterogeneity, although typical of heteroplasmic mutations in the mitochondrial genome, is unusual for nuclear mutations. Comparable activities and stability of mitochondrial respiratory chain enzymes were demonstrated in both patients, so other reasons for the phenotypic variability are considered.

Introduction

Complex II (succinate-ubiquinone reductase, EC 1.3.5.1) of the mitochondrial respiratory chain (RC) has four subunits and catalyses the reduction of ubiquinone (CoQ10) by succinate. It is unique amongst the enzyme complexes of the RC as all subunits are encoded by nuclear DNA. Mutations in the SDHA gene encoding the flavoprotein subunit (SDHA) of complex II have previously been reported in patients with Leigh syndrome (Table 1) [1], [2], [3], [4], [5], [6], [7], whilst mutations in the iron-sulfur subunit (SDHB) and membrane-spanning subunits (SDHC and SDHD) are associated with hereditary phaeochromocytoma and paragangliomas [8], [9], [10], [11]. We describe a 10-year-old boy with relatively mild Leigh syndrome caused by a homozygous mutation in the SDHA gene. This mutation has previously been reported to cause a lethal-infantile presentation [6], and we performed biochemical studies of cultured fibroblasts from both patients, to try to explain the phenotypic difference.

Section snippets

Patient details

The patient (P1), born to healthy first cousin Palestinian parents, had normal early developmental milestones. He walked at 16 months but at 22 months his walking deteriorated and he had frequent falls. Examination revealed myopathic facies with mild ptosis, mild hypotonia and generalised weakness. He deteriorated rapidly over the next month and could no longer walk or sit. Repeat examination at 23 months demonstrated increased weakness, particularly affecting proximal muscles. By 25 months he

Methods

RC enzyme activities were determined in muscle biopsy homogenate and fibroblasts using standard procedures [12], [13], [14], [15]. Muscle CoQ10 was measured using HPLC [16]. Temperature sensitivity of complex II was assessed by repeating the assay at 26 and 41 °C (in addition to the standard 30 °C).

Messenger RNA was extracted from fresh blood of P1 using the PAXgene Blood RNA kit (Qiagen) and from fibroblasts from P2 (a gift from R.Van Coster) using phenol and chloroform according to standard

Results

Spectrophotometric assay of RC enzymes indicated a combined defect of complexes II+III (succinate-cytochrome c reductase) in P1’s first muscle biopsy, but the small biopsy size precluded further investigations. This combined defect of complexes II+III was confirmed in the second muscle biopsy. Further investigation demonstrated normal muscle CoQ10 concentration and complex III (ubiquinol-cytochrome c reductase, EC 1.10.2.2) activity, but reduced complex II activity (Table 2). The

Discussion

We report a patient with Leigh syndrome and isolated deficiency of complex II (Table 2). Complex II defects are rare and this is the first case identified at this centre out of more than 1000 biopsies assayed (of which the majority were paediatric). The only other report of the G555E mutation is in a patient with a lethal-infantile presentation [6]. This patient was also of Middle Eastern origin (personal communication, R. Van Coster), suggesting the possibility of an ancestral mutation, and

Acknowledgments

We are grateful to Rudy Van Coster and Joel Smet for providing cultured fibroblasts from their affected patient (P2), to Derek Burke for help with tissue culture, to Gabriel Chow in Nottingham for early clinical details and to Dawn Saunders for radiological advice. This work was supported by Children Living with Inherited Metabolic Diseases (www.climb.org.uk), the Child Health Research Appeal Trust and the Medical Research Council. Research at the Institute of Child Health and Great Ormond

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