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Because of genetic heteroplasmy, the clinical manifestations of mitochondropathies are quite varied. We report an unusual presentation in a patient with asymmetric ophthalmoplegia and unilateral myopathic facial weakness caused by a deletion in mitochondrial DNA.
The patient, a 42 year old white women, was evaluated in our neurology clinic for double vision and right sided facial weakness in early 2000. She first noticed these symptoms in 1994. At that time, she had isolated weakness of adduction of the right eye and she was felt to have a right internuclear ophthalmoplegia. A demyelinating process was considered initially, but magnetic resonance imaging of the brain on four subsequent occasions (annual scans) did not show any structural lesions to support such a diagnosis. The diplopia remained unchanged and an insidious facial weakness developed.
During the course of her illness she had extensive investigations, including normal cerebrospinal fluid, antinuclear antibodies, erythrocyte sedimentation rate, serum protein electrophoresis, and thyroid profile. Rapid plasma reagin and Lyme's titre were negative. She received several courses of high dose steroids without any improvement.
There had been no substantial change in her general physical condition since 1994. Her past medical history was otherwise unremarkable. She is a computer operator and is quite active in sports. She has smoked moderately for 30 years. She has no family history of any neurological disorders. There was no diurnal variation of her symptoms and no complaint of dysphagia, dysarthria, or limb weakness.
Neurological examination revealed a pupillary sparing ophthalmoplegia without ptosis. Specifically she had bilateral exotropia on primary gaze, with total paralysis of adduction of the right eye and mild weakness of abduction of the left eye. She also had mild paresis of infraduction of the right eye. Nystagmus was absent in both horizontal and vertical gaze. She had an infranuclear right facial weakness involving both the orbicularis oculi and the orbicularis oris, without lid synkinesis. The strength in the left facial muscles was normal. Ophthalmoscopic examination was normal. The remainder of her neurological examination was unremarkable. In summary, this patient had a chronic asymmetrical pupil and lid sparing ophthalmoplegia with binocular diplopia and right facial weakness (fig 1).
The patient had several normal MRI scans. Previous attempts at treatment with high dose steroids were unsuccessful and the diagnosis was uncertain. With no structural lesion to explain her clinical condition, we suspected muscular or neuromuscular pathology. An unusual presentation of oculopharyngeal dystrophy, ocular myopathies, myasthenia gravis, and mitochondrial myopathies were in the differential diagnoses for this progressive ophthalmoplegia. However, we did not have an explanation for her right facial weakness, which we suspected represented a neuropathic process. Further investigations showed normal serum lactic acid and thyroid profile. The blink reflex was normal, excluding the possibility of a cranial neuropathy. Electromyography of the right orbicularis oculi and orbicularis oris showed myopathic features; on the left side it was normal. This suggested an asymmetric facial myopathy. There was no decremental response of the compound muscle action potential, excluding a possible neuromuscular transmission defect. Muscle biopsy from the right quadriceps muscle showed ragged red fibres. Cytochrome C oxidase stains revealed an absence of staining in many fibres, which showed hyperreactivity on succinic dehydrogenase staining. Electronmicroscopic examination of muscle tissue showed an increase in the number and size of the mitochondria, especially in subsarcolemmal locations—many showing abnormal crista structure and paracrystalline inclusions. These findings were diagnostic of mitochondrial myopathy. Genetic testing of muscle tissue was positive for a deletion in mitochondrial DNA of about 3.5 kilobases, spanning the ATPase 6 gene to the ND5 gene.
Our patient represents a variant of sporadic progressive external ophthalmoplegia with the m-DNA mutation typical of Kearns–Sayre–Daroff syndrome.1 We were able to find one previous report of this syndrome with a similar clinical presentation.2 It was a unique problem because of its atypical clinical features, which presented a challenging diagnosis. This case shows the heterogeneity of the clinical manifestations, course, and tissue involvement in mitochondrial disorders.3 The blink reflex was normal and symmetrical, thus suggesting a non-neuropathic facial weakness, which was confirmed by electromyography. The presentation of this disorder in our patient shows how supranuclear, brain stem, neuropathic, or myopathic abnormalities may be encountered in patients with mitochondrial disorders, either in isolation or in combination. Mitochondriopathies should be included in the differential diagnosis of progressive asymmetric facial palsies, while asymmetrical myopathic facial weakness should be included in the differential diagnosis of infranuclear facial palsies. Our patient's genetic study identified a deletion of mitochondrial DNA in a region that encodes different subunits of the respiratory chain complex. Given the clinical manifestations observed, it is clear that the patient has a significant degree of tissue heteroplasmy.4,5
We would like to emphasise the diagnostic value of the muscle biopsy in cases with atypical clinical presentation and normal serum lactate levels. Genetic testing in blood may become the initial test of choice, with muscle biopsy as an alternative diagnostic aid.
Mitochondrial DNA testing was performed at the Emory Molecular Laboratory.
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