A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNATrp gene
Introduction
Mitochondrial diseases due to mitochondrial tRNA gene mutations are usually multisystem disorders with infantile or juvenile onset of symptoms. Late onset rarely exceeds middle-age and is seldom reported in full-syndrome patients. It can, however, be more commonly observed in oligosymptomatic relatives.
The biochemical phenotype expressed by a tRNA mutation is usually characterized by a partial generalized decrease of all respiratory chain enzymes containing mtDNA-encoded subunits, which reflects the generalized impairment of mtDNA translation caused by tRNA malfunction.
We now report a novel mtDNA point mutation located in the tRNATrp gene associated with a familial mitochondrial myopathy characterized by peculiar clinical and biochemical features. All affected members had a late onset of symptoms; biochemical studies on the proband's muscle showed a selective decrease of cytochrome c oxidase (COX) activity, while other respiratory chain activities were in the normal range.
Section snippets
Materials and methods
Histochemistry and biochemistry on muscle, DNA extraction, Southern blot and analysis for MELAS 3243/3271, MERRF 8344/8356 and PEO 4285/5703/5692 mutations and the sequence of tRNA genes were done as described [1]. Single-fiber PCR was performed according to Moraes and Schon [2].
Screening for the G→A at nt. 5521 of mtDNA was done by RFLP analysis of a 91 bp PCR fragment amplified by modified primers. We used a reverse oligonucleotide (nt. 5550–5580 according to Anderson's sequence [3])
Case report and results
A 68-year-old male noticed progressive bilateral ptosis and fatigue since the age of 50. His mother, deceased at age 90, and one of his brothers were reported to be similarly affected (the pedigree is represented in Fig. 3). Clinical examination documented bilateral ptosis without ophthalmoplegia, dysphonia and mild proximal muscle wasting and weakness (F=4, MRC scale).
CK and LDH were normal. EMG was myopathic. Muscle biopsy showed a mitochondrial myopathy with many COX-negative ragged red
Discussion
The G→A transition at nt. 5521 of mitochondrial tRNATrp gene fulfills all diagnostic criteria for pathogenic mutations, i.e. (i) it is located in a conserved region of the gene, (ii) it has never been reported as neutral polymorphism, nor found in 110 controls and (iii) RFLP analysis demonstrated a condition of heteroplasmy and single-fiber PCR documented higher amounts of mutated mtDNAs in COX− RRFs compared with normal fibers.
There was a good correlation between clinical phenotype,
Acknowledgements
We thank Enrico Paris and Manuela Papacci for their precious technical assistance. This work was supported by UILDM sez. Laziale, Rome and by Telethon Italy (grant n.52).
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Cytochrome c oxidase deficiency
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