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The accumulation of multiple mitochondrial DNA (mtDNA) deletions in stable tissues is a distinctive feature of several autosomal disorders, characterized by Progressive External Ophthalmoplegia (PEO), ptosis, and proximal myopathy. At least three nuclear genes are responsible for these disorders: ANT1 and C10orf2 cause autosomal dominant PEO, while mutations of DNA polymerase gammaA (POLG1 or POLG) gene on chromosome 15q25 causes both autosomal dominant and recessive forms of PEO. To investigate the contribution of these genes to the sporadic cases of PEO with multiple mtDNA deletions, we studied 31 mitochondrial myopathy patients without any family history for the disorder: 23 had PEO with myopathy, with or without the additional features of pigmentary retinopathy, ataxia, neurosensorial hypoacusia and diabetes mellitus, 7 presented isolated myopathy and one a peripheral neuropathy with ptosis. In all patients Southern blot of muscle DNA showed multiple mtDNA deletions; screening for ANT1 and C10ORF2 genes was negative. POLG analysis revealed mutations in eight patients; in six of them the mutations were allelic, while two patients were heterozygous. Five mutations were new, namely one stop codon (c.2407C>T/p.R709X) and four missense mutations (c.1085G>C/p.G268A; c.1967G>A/p.R562Q; c.2702G>C/p.R807P; c.3076C>T/p.H932W). A high degree of conservation was observed for all the new missense mutations. Only patients presenting PEO as part of their clinical phenotype had POLG mutations, in seven of them together with myopathic signs and in one with a sensori-motor peripheral neuropathy.
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PMID:POLG mutations in sporadic mitochondrial disorders with multiple mtDNA deletions. 1463 18

A case of pulmonary thromboembolism with transient pulmonary hypertension of a rare cause is presented. In 24-year-old woman myasthenia was recognised on the ground of ptosis and fixation of eyes muscles from the 14th year of age. The treatment with mestinon was ineffective. Before planned thymectomy serious disturbances of heart rhythm and conduction were confirmed. Stimulator was implanted and thymectomy was done. No improvement of neurological state was observed despite the treatment with mestinone and prednisone. When she was 30 years old disease of lung appeared with fever, cough and parenchymal and pleural lesions of right lung. Antibiotic therapy was ineffective. CT scan and US examination revealed large thrombus inside the right auricle connected with stimulator electrodes. Embolisation of right pulmonary arteria was confirmed also. Treatment with heparin was ineffective and thrombectomy was performed. Exact neurological examination stated that the patient had no typical symptoms of myasthenia and that symptoms related with eyes and heart could be result of mitochondrial myopathy. Diagnosis was confirmed by EMG examination and muscle biopsy.
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PMID:[Pulmonary thromboembolism as a late complication of mitochondrial myopathy (Kearns-Sayer syndrome ]. 1505 81

Mitochondrial myopathy, associated with muscle weakness and progressive external ophthalmoplegia, is caused by mutations in mitochondria oxidative phosphorylation genes including the heart-muscle isoform of the mitochondrial adenine nucleotide translocator (ANT1). To develop therapies for mitochondrial disease, we have prepared a recombinant adeno-associated viral vector (rAAV) carrying the mouse Ant1 cDNA. This vector has been used to transduce muscle cells and muscle from Ant1 mutant mice, which manifest mitochondrial myopathy. AAV-ANT1 transduction resulted in long-term, stable expression of the Ant1 transgene in muscle precursor cells as well as differentiated muscle fibers. The transgene ANT1 protein was targeted to the mitochondrion, was inserted into the mitochondrial inner membrane, formed a functional ADP/ATP carrier, increased the mitochondrial export of ATP and reversed the histopathological changes associated with the mitochondrial myopathy. Thus, AAV transduction has the potential of providing symptomatic relief for the ophthalmoplegia and ptosis resulting from paralysis of the extraocular eye muscles cause by mutations in the Ant1 gene.
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PMID:Adeno-associated virus-mediated gene transfer of the heart/muscle adenine nucleotide translocator (ANT) in mouse. 1564 64

Mitochondrial myopathy is a genetic disorder characterized by chronic progressive external ophthalmoplegia and upper eyelid, ptosis which occurs before 30 to 40 years of life. The authors reviewed the literature and reported two cases of reading diplopia in female patients.
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PMID:[Mitochondrial myopathy: two case reports]. 1632 68

The diagnosis of mitochondrial myopathy depends upon a constellation of findings, family history, type of muscle involvement, specific laboratory abnormalities, and the results of histological, pathobiochemical and genetic analysis. In the present paper, the authors describe the diagnostic approach to mitochondrial myopathies manifesting as extraocular muscle disease. The most common ocular manifestation of mitochondrial myopathy is progressive external ophthalmoplegia (PEO). To exclude myasthenia gravis, ocular myositis, thyroid associated orbitopathy, oculopharyngeal muscular dystrophy, and congenital fibrosis of the extraocular muscles in patients with an early onset or long-lasting very slowly progressive ptosis and external ophthalmoplegia, almost without any diplopia, and normal to mildly elevated serum creatine kinase and lactate, electromyography, nerve conduction studies and MRI of the orbits should be performed. A PEO phenotype forces one to look comprehensively for other multisystemic mitochondrial features (e.g., exercise induced weakness, encephalopathy, polyneuropathy, diabetes, heart disease). Thereafter, and presently even in familiar PEO, a diagnostic muscle biopsy should be taken. Histological and ultrastructural hallmarks are mitochondrial proliferations and structural abnormalities, lipid storage, ragged-red fibers, or cytochrome-C negative myofibers. In addition, Southern blotting may reveal the common deletion, or molecular analysis may verify specific mutations of distinct mitochondrial or nuclear genes.
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PMID:Extraocular mitochondrial myopathies and their differential diagnoses. 1676 Jan 17

An 18-year-old man presented with progressive weakness of proximal muscles with prominent diurnal variation for 3 months. He had bilateral ptosis since his childhood without diurnal variation or double vision. Neurological examination showed involvement of levator palpebrae superioris and lateral rectus muscles bilaterally. The plasma glucose after 75 gm glucose load was 302 mg/dL. The electrophysiological study revealed myopathic pattern and a decremental response in repetitive nerve stimulation. The plasma lactate was elevated and the muscle biopsy showed numerous ragged-red fibers. Serum acetylcholine receptor antibody assay was positive. We diagnosed myasthenia gravis with mitochondrial myopathy.
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PMID:Mitochondrial myopathy associated with myasthenia gravis in a young man. 1746 3

Ptosis has long been recognized as a presenting sign of myasthenia gravis, and the appearance of ptosis or increasing ptosis with passive lid elevation of opposite eye is a useful bedside diagnostic test for this disease. We describe a patient whose ptosis worsened in either eye when the examiner passively held the opposite eyelid. She was initially thought to have myasthenia gravis, but ultimately it was discovered her ocular findings were caused by a mitochondrial myopathy.
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PMID:Enhancement of contralateral ptosis on passively holding an eyelid in mitochondrial myopathy resembling myasthenia gravis. 1907 72

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder caused by mutations in nuclear genes. Here we report the clinical and genetic features of adPEO in a Chinese family. All patients had gradual onset of ptosis, with or without ophthalmoplegia, around age 30. Thirteen patients had limb weakness around age 40. Eight patients developed dysphagia around age 50. Four patients died of cardiac abnormalities around age 60. Muscle biopsy of the proband indicated mitochondrial myopathy characterized by ragged-red fibers, cytochrome c oxidase-negative fibers, and multiple deletions of mitochondrial DNA. A heterozygous missense mutation of c.1342A>G in the C10orf2 gene resulting in the p.448N>D mutation in the protein was found in the proband and four other affected family members. In summary, we identified an adPEO family with a novel C10orf2 gene mutation that manifested an age-dependent phenotype. It suggests that greater attention must be paid to cardiac abnormalities in the late stages of this disease.
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PMID:Clinical phenotype of autosomal dominant progressive external ophthalmoplegia in a family with a novel mutation in the C10orf2 gene. 1970 78

The organ most frequently affected in mitochondrial disorders is the skeletal muscle (mitochondrial myopathy). Mitochondrial myopathies may be part of syndromic as well as non-syndromic mitochondrial disorders. Involvement of the skeletal muscle may remain subclinical, may manifest as isolated elevation of the creatine-kinase, or as weakness and wasting of one or several muscle groups. The course of mitochondrial myopathies is usually slowly progressive and only rarely rapidly progressive leading to restriction of mobility and requirement of a wheel chair or even muscular respiratory insufficiency. Frequently reported symptoms of mitochondrial myopathies are permanent tiredness, easy fatigability, muscle aching at rest or already after moderate exercise, muscle cramps, muscle stiffness, fasciculations and muscle weakness. The diagnosis is based on the history, clinical neurologic examination, blood chemical investigations, lactate stress test, electromyography, magnetic resonance imaging, magnetic resonance spectroscopy, muscle biopsy, biochemical investigations of the skeletal muscles, and genetic investigations. Only symptomatic therapy is available and includes physiotherapy and orthopedic supportive devices, diet, symptomatic drug therapy (analgetics, cramp-releasing drugs, antioxidants, lactate-lowering drugs, alternative energy sources, co-factors), avoidance of mitochondrion-toxic drugs, surgery (correction of ptosis or orthopedic problems), and invasive or non-invasive mechanical ventilation. General anesthesia needs to be performed in the same way as in patients with susceptibility for malignant hyperthermia.
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PMID:[Mitochondrial myopathies]. 1989 Jul 72

The classic ocular motor presentation of mitochondrial disorders is chronic, symmetric, and diffuse weakness. We describe a man with 25 years of asymmetric ptosis, ophthalmoparesis, and facial weakness that partially responded to steroid therapy. Serologic and electrophysiological investigations for myasthenia gravis were negative, but muscle biopsy confirmed a mitochondrial myopathy. This case illustrates the potential of mitochondrial ophthalmoparesis to mimic the features of ocular myasthenia.
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PMID:Mitochondrial pseudomyasthenia. 2054 42


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