Phenotypic variability of mitochondrial disease caused by a nuclear mutation in complex II
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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Cited by (43)
Leigh syndrome
2023, Handbook of Clinical NeurologyThe genetic basis of isolated mitochondrial complex II deficiency
2020, Molecular Genetics and MetabolismCitation Excerpt :Moreover, the p.(Arg554Trp) and p.(Gly555Glu) substitutions result in a more negative charge in the external loop of the flavoprotein, suggesting a shared pathomechanism, where modifications to either residue are capable of jeopardising the SDHA-SDHB interaction to the detriment of mitochondrial complex II assembly [29]. Defective complex II assembly was in fact confirmed in Cases 28 and 29, who presented with either Leigh syndrome or in acute metabolic crisis, respectively [28,29], where immunoblotting against the SDHA and SDHB subunits following Blue-Native PAGE revealed a marked decrease in the amount of fully-assembled complex II [28,29]. There is an enigmatic element relating to the pathogenicity of the c.1664G>A p.(Gly555Glu) SDHA variant in that a homozygous c.1664G>A p.(Gly555Glu) SDHA variant has also been detected in a healthy adult within the extended consanguineous Bedouin pedigree [27].
Rapamycin as a potential treatment for succinate dehydrogenase deficiency
2019, HeliyonCitation Excerpt :SDH performs this dual role located in the inner mitochondrial membrane where it oxidizes succinate into fumarate in the citric acid cycle and it reduces ubiquinone in the process of oxidative phosphorylation as complex II of the electron transport chain [1, 4, 11, 13]. Therefore, defects in its operation will affect the homeostatic nature of metabolic networks and a complex organelle-systemic response [14]. Overall, therapies for mitochondrial disorders are normally based on vitamin supplements, modifications to diet and exercise [15, 16, 17].
Nuclear Genetic Causes of Leigh and Leigh-Like Syndrome
2016, Mitochondrial Case Studies: Underlying Mechanisms and DiagnosisPhysiological consequences of complex II inhibition for aging, disease, and the mK<inf>ATP</inf> channel
2013, Biochimica et Biophysica Acta - BioenergeticsThe role of complex II in disease
2013, Biochimica et Biophysica Acta - BioenergeticsCitation Excerpt :Although the patient was too young to allow assessment of LS symptoms, genetic analysis identified a homozygous missense mutation of SDHA [73]. The same homozygous missense mutation was reported in a patient with a relatively mild LS and complex II deficiency phenotype [74]. This patient, also born to first cousin parents, initially showed normal developmental but by 22 months, myopathy, poor walking and frequent falls were apparent.