Light and electron microscopy characteristics of the muscle of patients withSURF1gene mutations associated with Leigh disease

Abstract

Aims:Leigh syndrome (LS) is characterised by almost identical brain changes despite considerable causal heterogeneity. SURF1 gene mutations are among the most frequent causes of LS. Although deficiency of cytochrome c oxidase (COX) is a typical feature of the muscle in SURF1-deficient LS, other abnormalities have been rarely described. The aim of the present work is to assess the skeletal muscle morphology coexisting with SURF1 mutations from our own research and in the literature.Methods:Muscle samples from 21 patients who fulfilled the criteria of LS and SURF1 mutations (14 homozygotes and 7 heterozygotes of c.841delCT) were examined by light and electron microscopy.Results:Diffuse decreased activity or total deficit of COX was revealed histochemically in all examined muscles. No ragged red fibres (RRFs) were seen. Lipid accumulation and fibre size variability were found in 14 and 9 specimens, respectively. Ultrastructural assessment showed several mitochondrial abnormalities, lipid deposits, myofibrillar disorganisation and other minor changes. In five cases no ultrastructural changes were found. Apart from slight correlation between lipid accumulation shown by histochemical and ultrastructural techniques, no other correlations were revealed between parameters investigated, especially between severity of morphological changes and the patient’s age at the biopsy.Conclusion:Histological and histochemical features of muscle of genetically homogenous SURF1-deficient LS were reproducible in detection of COX deficit. Minor muscle changes were not commonly present. Also, ultrastructural abnormalities were not a consistent feature. It should be emphasised that SURF1-deficient muscle assessed in the light and electron microscopy panel may be interpreted as normal if COX staining is not employed.

Phenotype-genotype correlations in Leigh syndrome: new insights from a multicentre study of 96 patients

“…Specific myopathic findings are linked to specific mitochondrial myopathies and to certain mtDNA defects in particular 34. In our study, the only genetic subgroup with consistently abnormal histopathological findings on muscle biopsy was the SURF1 subgroup showing COX deficiency and mitochondrial proliferation as described in the literature 35. In the total cohort, only 32% of patients with either mtDNA or nDNA-associated Leigh syndrome had histopathological findings in muscle suggestive of mitochondrial disease.…”

SURF1 missense mutations promote a mild Leigh phenotype

“…The progression of the disease in our patients is relatively slow and their state is stable. Three children (patients 3,6,8) are still alive at respectively 22, 16 and 18 years (patient 7 died at the age of 20 years). Their mental status is undisturbed and they are in good emotional contact with their families.…”

“…Histological and histochemical examination of serial frozen sections of muscles included hematoxylin and eosin, modified Gomori trichrome, oil red O stainings, and enzymatic reactions for: myosin ATPase, succinate dehydrogenase (SDH), NADH‐dehydrogenase (NADH‐DH), COX and acid phosphatase (3).…”

A New Semantic Functional Similarity over Gene Ontology

“…Leigh syndrome is a rare neurometabolic disorder caused by mutations in mitochondrial DNA and leads to loss of head control and motor skills by affecting the central nervous system [73]. Melas syndrome is one of the families of mitochondrial cytopathies caused by defects in the mitochondrial genome which is inherited purely from the female parent and leads to vision loss, problems with movement, and a loss of intellectual function [74].…”