Mitochondrial myopathy associated with a novel mutation in mtDNA

doi:10.1016/j.nmd.2007.04.005

Neuromuscular Disorders

Volume 17, Issue 8, August 2007, Pages 651-654

https://doi.org/10.1016/j.nmd.2007.04.005 Get rights and content

Abstract

A 6-year-old boy had progressive muscle weakness since age 4 and emotional problems diagnosed as Asperger syndrome. His mother and two older siblings are in good health and there is no family history of neuromuscular disorders. Muscle biopsy showed ragged-red and cytochrome coxidase (COX)-negative fibers. Respiratory chain activities were reduced for all enzymes containing mtDNA-encoded subunits, especially COX. Sequence analysis of the 22 tRNA genes revealed a novel G10406A base substitution, which was heteroplasmic in multiple tissues of the patient by RFLP analysis (muscle, 96%; urinary sediment, 94%; cheek mucosa, 36%; blood, 29%). The mutation was not detected in any accessible tissues from his mother or siblings. It appears that this mutation arose de novo in the proband, probably early in embryogenesis.

Introduction

The mitochondrial encephalomyopathies are a diverse group of disorders often caused by defects in mitochondrial DNA (mtDNA). Hundreds of large-scale mtDNA rearrangements and over 150 mtDNA point mutations have been associated with disease [1]. Patients harboring these mutations usually have multisystem disorders, but phenotypic expression can vary in different families and even in different members of the same family. This complex genotype-phenotype correlation is due to many factors, including the abundance of mutant mDNA and its tissue distribution. Most pathogenic point mutations occur in tRNA genes, are heteroplasmic, and are maternally inherited.

Here, we report a patient with weakness and hypotonia, who harbors a previously undescribed and apparently de novo G-to-A mutation at nucleotide position 10406 in the tRNA arginine (tRNA^Arg) gene.

Section snippets

Case Report

A 6-year-old boy was the third child of non-consanguineous parents. He had normal birth and early development, but showed emotional problems and, at age 4, was given the diagnosis of Asperger syndrome. At the same age, the mother also noted motor problems: the child could not walk long distances, required a walker or a wheelchair for family outings, and needed a handrail to push himself up stairs. The condition did not seem to progress significantly. At age 7, he has occasional dysphagia for

Histochemistry and biochemistry

Histochemical study of muscle using 8-um-thick frozen sections was carried out as described [2]. Biochemical analysis was performed in 10% muscle homogenates as previously described [3].

Molecular analysis

Total DNA was extracted by standard protocol (PUREGENE, Gentra System, Inc, Minneapolis, Minn) following the manufacturer’s instructions. Protocols used for blood, urine, hair roots, and cheek mucosa were as described [4].

Direct sequencing of the 22 tRNA genes of mtDNA was performed in an ABI Prism 310 Genetic

Results

Histochemical analysis of the muscle biopsy showed frequent ragged-red fibers (RRF) and cytochrome c oxidase (COX)-deficient fibers. In keeping with the mitochondrial proliferation shown by histochemistry, biochemical analysis revealed markedly increased citrate synthase and succinate dehydrogenase (SDH) activities. In contrast, activities of respiratory chain complexes I+III, II+III, and especially IV (COX) were decreased (Table 1). When normalized to either citrate synthase or SDH, the

Discussion

We describe a novel mutation, a G10406A in the tRNA^Arg gene, which appears to have arisen de novo in the proband, a 6-year-old boy with proximal myopathy and Asperger syndrome. We believe that this mutation is pathogenic for several reasons. First, it is heteroplasmic, and heteroplasmy is a common feature of pathogenic mtDNA mutations. Second, it has not been previously reported and was not detected by us in a group of 100 controls. Third, the point mutation that we encountered in a tRNA gene

Acknowledgement

This work has been supported by NIH grant HD32062, a grant from the Muscular Dystrophy Association, and the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF).

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Citation Excerpt :
Some patients have been also described with mtDNA deletions and depletion (Filiano et al., 2002; Pons et al., 2004; Shoffner et al., 2010; Varga et al., 2018). In most cases these were putative mutations with unclear functional meaning (Pancrudo et al., 2007; Weissman et al., 2008; Avdjieva-Tzavella et al., 2012; Patowary et al., 2017; Valiente-Pallejà et al., 2018). Instead, in our study, we have found an already known pathogenic mutation (m.4320C>T), a mutation (m.8836A>G) already described in association with ASD, a novel heteroplasmic mutation (m.12235T>A) satisfying accepted criteria for pathogenicity, a novel homoplasimc mutation (m.1683C>T) in the 16S mitochondrial ribosomal RNA involved in mtDNA-encoded protein synthesis, and multiple mtDNA deletions recognized to lead to significant pathology.
Autism spectrum disorders (ASD) are neurodevelopmental disorders, with heterogeneous etiology, characterized by deficiencies in social interaction, communication, and by repetitive and stereotyped behaviors.
Mitochondrial encephalomyopathies are inherited disorders of oxidative metabolism, with a wide clinical, biochemical and genetic heterogeneity, requiring a complex diagnostic flow-chart. Infantile forms often occur with defects in development, intellectual disabilities and dysmorphisms.
ASD has been associated with mitochondrial respiratory chain deficiency and/or mitochondrial DNA (mtDNA) mutations. However, few studies carried out detailed clinical, instrumental, morphological, biochemical investigations, and mtDNA sequencing in ASD patients.
The purpose of this study was the identification of mitochondrial dysfunction due to mtDNA variants in 19 selected subjects presenting ASD and clinical features of mitochondrial disease. For these patients we adopted a multidisciplinary approach combining clinical and laboratory investigations on muscle biopsy, with biochemical, histological and genetic techniques.
The histological examination showed myogenic or neurogenic changes in 79 % of patients; furthermore, 58 % of the patients had lipid accumulation, mitochondrial proliferation and COX deficient fibers. The biochemical investigations reported in three patients impairments involving one or more of the respiratory chain complexes. In addition, genetic studies revealed in one patient with normal histology and biochemistry multiple mtDNA deletions, and in four patients different mtDNA point mutations.
The present study confirms the hypothesis of an association between ASD and mitochondrial dysfunction. However, further studies in a larger group of subjects are needed.
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Case reportMitochondrial myopathy associated with a novel mutation in mtDNA

Abstract

Introduction

Section snippets

Case Report

Histochemistry and biochemistry

Molecular analysis

Results

Discussion

Acknowledgement

Meth Cell Biol

J Biol Chem

J Pediatr

Case report
Mitochondrial myopathy associated with a novel mutation in mtDNA