A novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy caused by cytochrome c oxidase deficiency

doi:10.1016/S0960-8966(99)00122-4

Neuromuscular Disorders

Volume 10, Issue 6, 1 August 2000, Pages 450-453

https://doi.org/10.1016/S0960-8966(99)00122-4 Get rights and content

Abstract

We report on a 5-year-old boy with clinical and neuroradiological evidence of Leigh syndrome and peripheral neuropathy. Skeletal muscle biopsy showed decreased cytochrome c oxidase stain. Ultrastructurally, the nerve biopsy showed a defect of myelination. Biochemical analyses of muscle homogenate showed cytochrome c oxidase deficiency (15% residual activity). SURF1 gene analysis identified a novel homozygous nonsense mutation which predicts a truncated surf1 protein.

Introduction

Leigh syndrome (LS) is a genetically-determined neurodegenerative disorder of infancy or childhood dominated by developmental delay or psychomotor regression, signs of brainstem dysfunction, and lactic acidosis [1]. The pathologic hallmarks of LS are bilateral, symmetric necrotizing lesions in the basal ganglia, thalamus, brainstem, and spinal cord. The visualization of symmetric basal ganglia lucencies by MRI helps confirm the clinical diagnosis.

The pathophysiology of LS is related to altered mitochondrial metabolism and alterations in the mitochondrial respiratory chain complex I, pyruvate dehydrogenase complex (PDHC)-E1α subunit, or in the mitochondrial DNA (mtDNA) have been associated with autosomal recessive, X-linked, or maternally-inherited LS, respectively [2]. Defects in cytochrome c oxidase (COX), the fourth multisubunit enzyme complex of the respiratory chain, play an important pathogenic role in LS but the underlying molecular defects are not completely clarified. Recently, two independent groups reported that this condition is associated with SURF1 gene mutations [3], [4]. The function of SURF1 is yet to be determined but a yeast homologue of SURF1 (SHY1) rescues a yeast nuclear pet mutant with a partial decrease in COX activity [5].

We identified a novel SURF1 mutation in a LS patient with COX deficiency (LS/COX−). Neurophysiological and ultrastructural studies in peripheral nerve biopsy unveiled the nature of this child's peripheral neuropathy.

Section snippets

Case report

This boy was born by C-section to healthy, unrelated parents. Shortly after birth, he developed mild respiratory distress, with metabolic acidosis. His development was delayed: he smiled at 3 months, rolled over at 6 months, sat up at 7 months, pulled to stand at 8 months, walked at 26 months. At 3 years of age, he was not able to speak full sentences. Physical examination also showed hirsutism and facial dysmorphism. On neurological examination, we observed short stature, mental retardation,

Results and discussion

Clinical and neuroradiological findings in our patient suggested the diagnosis of LS. Peripheral neuropathy was an important feature. Sural nerve biopsy showed reduced myelinated fibers (12342 fibers/mm²; normal: 22500±5091 for age 2–10 years) and the complete absence of those of large diameter. Myelin sheath was thin in relation to diameter in almost all the examined fibers, leading to an increased G-ratio (0.86; normal <0.70). We did not observe Wallerian degeneration, myelinophagic cells,

Acknowledgements

This work was supported by grants from the Italian Ministry of Health (Ricerca Corrente and Ricerche Finalizzate, 1998). We thank the technical assistance of Margherita Verardo and M. Rosaria Neglia.

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SURF1 knockout cloned pigs: Early onset of a severe lethal phenotype
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Citation Excerpt :
The typical course of LS includes neurodevelopmental regression, brain stem and basal ganglia signs (ataxia, dystonia, chorea, optic atrophy, ophthalmoparesis, swallowing and/or feeding difficulties, tongue fasciculations, and apnoeic episodes) and characteristic magnetic resonance imaging (MRI) findings, including symmetrical lesions in the basal ganglia, thalamus, cerebellum, and brain stem. Other manifestations may include failure to thrive, microcephaly, hypertrichosis, and myopathy [1,3,4]. Lactic acid levels in the blood and cerebrospinal fluid of the patients are often elevated, and COX activity is <20% compared to normal fibroblasts, lymphocytes, or muscle biopsies.
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an early onset, fatal mitochondrial encephalopathy, leading to multiple neurological failure and eventually death, usually in the first decade of life. Mutations in SURF1, a nuclear gene encoding a mitochondrial protein involved in COX assembly, are among the most common causes of LS. LS^SURF1 patients display severe, isolated COX deficiency in all tissues, including cultured fibroblasts and skeletal muscle. Recombinant, constitutive SURF1^−/− mice show diffuse COX deficiency, but fail to recapitulate the severity of the human clinical phenotype. Pigs are an attractive alternative model for human diseases, because of their size, as well as metabolic, physiological and genetic similarity to humans. Here, we determined the complete sequence of the swine SURF1 gene, disrupted it in pig primary fibroblast cell lines using both TALENs and CRISPR/Cas9 genome editing systems, before finally generating SURF1^−/− and SURF1^−/+ pigs by Somatic Cell Nuclear Transfer (SCNT). SURF1^−/− pigs were characterized by failure to thrive, muscle weakness and highly reduced life span with elevated perinatal mortality, compared to heterozygous SURF1^−/+ and wild type littermates. Surprisingly, no obvious COX deficiency was detected in SURF1^−/− tissues, although histochemical analysis revealed the presence of COX deficiency in jejunum villi and total mRNA sequencing (RNAseq) showed that several COX subunit-encoding genes were significantly down-regulated in SURF1^−/− skeletal muscles. In addition, neuropathological findings, indicated a delay in central nervous system development of newborn SURF1^−/− piglets. Our results suggest a broader role of sSURF1 in mitochondrial bioenergetics.
Leigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options
2016, Molecular Genetics and Metabolism
Leigh syndrome is a progressive neurodegenerative disorder, affecting 1 in 40,000 live births. Most patients present with symptoms between the ages of three and twelve months, but adult onset Leigh syndrome has also been described. The disease course is characterized by a rapid deterioration of cognitive and motor functions, in most cases resulting in death due to respiratory failure. Despite the high genetic heterogeneity of Leigh syndrome, patients present with identical, symmetrical lesions in the basal ganglia or brainstem on MRI, while additional clinical manifestations and age of onset varies from case to case. To date, mutations in over 60 genes, both nuclear and mitochondrial DNA encoded, have been shown to cause Leigh syndrome, still explaining only half of all cases. In most patients, these mutations directly or indirectly affect the activity of the mitochondrial respiratory chain or pyruvate dehydrogenase complex. Exome sequencing has accelerated the discovery of new genes and pathways involved in Leigh syndrome, providing novel insights into the pathophysiological mechanisms. This is particularly important as no general curative treatment is available for this devastating disorder, although several recent studies imply that early treatment might be beneficial for some patients depending on the gene or process affected. Timely, gene-based personalized treatment may become an important strategy in rare, genetically heterogeneous disorders like Leigh syndrome, stressing the importance of early genetic diagnosis and identification of new genes/pathways. In this review, we provide a comprehensive overview of the most important clinical manifestations and genes/pathways involved in Leigh syndrome, and discuss the current state of therapeutic interventions in patients.
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It has also been noted that the prevalence of peripheral neuropathy is more in COX deficient Leigh syndrome patients compared to children with Leighs syndrome with pyruvate dehydrogenase (PDH) deficiency or m.8993T > G mutations (Santorelli et al., 1993). Peripheral neuropathy has been reported in Leigh syndrome patients with COX deficiency and SURF1 mutation (Bruno et al., 2002; Santoro et al., 2000). In the report by Santoro et al., ultrastructural examination revealed large number of mitochondria with enlarged and rounded cristae in Schwann cells (Santoro et al., 2000).
There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders.
The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006–2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively.
The study cohort included 18 patients (age range: 18 months–50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n = 11), SURF1 mutations (n = 4) and POLG1(n = 3). Axonal neuropathy was noted in 12 patients (sensori-motor:n = 4; sensory:n = 4; motor:n = 4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy.
A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder.
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2014, Revue Neurologique
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Peripheral neuropathy in mitochondrial disorders
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Citation Excerpt :
Although common, neuropathy is rarely relevant in MERRF syndrome, particularly in patients with multiple lipomas, and is usually demyelinating and sensorimotor.16 Occasionally prominent neuropathy has been reported in Leber hereditary optic neuropathy,18 Kearns-Sayre syndrome,10 and Leigh syndrome,19 and in primary coenzyme Q10 deficiency due to ADCK3 mutations, which is usually characterised by cerebellar ataxia sometimes associated with mental retardation, seizures, and peripheral neuropathy.93 Moderate-to-severe progressive motor or sensorimotor axonal neuropathy with foot deformities was reported in four siblings affected by bilateral striatal necrosis with recurrent episodes of flaccid paralysis and encephalopathy.
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Short case reportA novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy caused by cytochrome c oxidase deficiency

Abstract

Introduction

Section snippets

Case report

Results and discussion

Acknowledgements

Am J Hum Genet

J Biol Chem

Subacute necrotizing encephalomyelopathy in an infant

J Neurol Neurosurg Psychiatry

Genetic heterogeneity in Leigh syndrome

Ann Neurol

SURF1, encoding a factor involved in the biogenesis of cytochrome c oxidase, is mutated in Leigh syndrome

Nat Genet

Cytochrome c oxidase deficiency in Leigh syndrome

Ann Neurol

Short case report
A novel SURF1 mutation results in Leigh syndrome with peripheral neuropathy caused by cytochrome c oxidase deficiency