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This 48 year old woman, who was first seen by a neurologist in March 1989, with a 7 year history of progressive unilateral ptosis, mild facial weakness and generalized fatigue.
On examination she had ptosis of the right eye and bilateral limitation of upward gaze.
Myasthenia Gravis was ruled out by a negative Tensilon test, negative anti-acetylcholine receptor antibodies, and normal single fiber electromyography of the frontalis muscle.
A trial on Mestinon 60 mg t.i.d. provided no improvement.
At age 45, progression of external ophthalmoplegia led to impaired eye movements in all directions of gaze.
At age 46, a muscle biopsy showed ragged red fibers and a mitochondrial DNA deletion.
Family History: A muscle biopsy in her mother and in her daughter were normal.
In 1991, at age 47, further progression in her weakness, external ophthalmoplegia and ptosis was noted and at this time she developed late onset diabetes and depression.
Her cardiac status remained normal, her visual acuity was 20/20 and a fundus exam showed no abnormality.
In 1992, at age 48, a brain MRI showed no abnormality.
In 1993, at age 49, she had ptosis surgery of the right eye and she was started on Co-enzyme Q10 200 mg b.i.d. increasing to t.i.d.
By 1997, at age 53, she was confined to a wheelchair because of extreme fatigue on exertion.
In 1999, at age 55, she moved into a retirement home in Maine and was lost to follow-up.
The term Mitochondrial Cytopathy has been used to emphasize multisystem involvement in progressive external ophthalmoplegia (PEO).
This patient had the constellation of:
Progressive External Ophthalmoplegia
Late Onset Diabetes
Extreme Fatigue on Exertion
This 48 year old woman, with progressive external ophthalmoplegia (PEO), due to a mitochondrial DNA deletion, is unusual in her presentation. Instead of the typical bilateral ptosis, she presented with unilateral ptosis of the right eye. The myopathic signs illustrated are:
1. Unilateral ptosis of the right eye with overaction of the right frontalis muscle.
2. Weakness of the orbicularis oculi muscle with bilateral impaired eye closure and inability to bury the eyelashes fully.
3. A partial external ophthalmoplegia affecting primarily conjugate upgaze. Horizontal and vertical downgaze eye movements are of normal velocity and are full.
4. Weakness of the lower face impairing the ability to grip the lips tightly together and
5. Impairing her ability to whistle.
6. Weakness of flexion of the head against moderate resistance.
Patient also has:
1. Profound exertional fatigue.
It was this disabling symptom that resulted in her being
confined to a wheelchair.
Neuroimaging studies were not done in this case.
MR of the Brain in Mitochondrial Myopathy published in 1995 illustrates MR images in KSS and PEO (14). The figures included:
A 61-year old woman (patient 1) with KSS, moderately severe truncal and appendicular ataxia, and a documented mtDNA deletion.
A. T1-weighted sagittal image demonstrates severe cerebellar vermian atrophy (arrow)
A 23-year old man (patient 2) with KSS, cognitive impairment, ataxia and an mtDNA deletion.
A. T2 weighted image demonstrates regions of hyperintense signal (arrows) in the subcortical white matter. The periventricular regions were spared.
B. T2-weighted image shows foci of hyperintense signal (arrows) in the dorsal midbrain.
A 37-year old woman (patient 8) with CPEO manifested by external ophthalmoplegia, ataxia, and sensorineural hearing loss.
A. Long-repetition-time/short-echo-time (proton density) axial image. In the frontal lobes, abnormal hyperintense signal predominates in the subcortical white matter (arrows), whereas in the posterior temporal and parietal lobes the abnormal signal extended from the subcortical regions to the ventricular surface (curved arrows).
B. T2-weighted axial MR image demonstrates bilateral hyperintense signal abnormalities in the globus pallidus (arrows). Hyperintense white matter abnormalities and ventricular dilatation are also present.
C. T1-weighted sagittal image demonstrates cerebral cortical and cerebellar vermian atrophy (arrow) and thinning of the corpus callosum.
Other PEO patients are reported show predominantly white matter damage that correlated with spongiform degeneration of the brain verified by autopsy examinations.
A skeletal muscle biopsy is diagnostic in mitochondrial myopathy due to a mtDNA deletion.
In mitochondrial myopathy defective oxidative phosphorylation results in mitochondrial proliferation in Type 1 and 2A muscle fibers.
Fibers with the most severe biochemical defects may degenerate and adjacent fibers with less severe or no defects may appear normal.
The combination of a patchy moth-eaten appearance in individual muscle fibers along with mitochondrial proliferation gives rise to the ragged-red fiber seen on modified Gomori trichrome staining. NADH staining shows abnormal subsarcolemmal mitochondria in the muscle fibers.
The electron microscopic sections of skeletal muscle show abnormal mitochondria.
Mutations in mtDNA are maternally inherited in a graded fashion. A single mtDNA mutation can lead to dramatically different clinical phenotypes, creating a very large spectrum of expressivity.
For example, the A3243G mutation associated with mitrochondrial encephalomyopathy, lactic academia, stroke-like episodes (MELAS) can also cause cardiomyopathy, diabetes and deafness, or external ophthalmoplegia.
Deletions of mtDNA in skeletal muscle, ranging in size from 3.8 to 9.1 kilobases, were found in an identical location on muscle biopsy in five of eleven personal cases (3 KSS, 8 PEO). The deletion encompasses structural genes for the mitochondrial respiratory chain and is associated with impaired mitochondrial function. The variable involvement of multiple organs, (e.g. heart, brain and retina in PEO and KSS) may be attributable to a mixed population of mutant and normal genomes in varying amounts in different tissues.
Both muscle and brain are also involved in patients with mitochondrial encephalomyopathy, namely, the MELAS syndrome which is characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; and MERRF, characterized by myoclonic epilepsy associated with ragged-red fibers.
In MELAS, dysfunction of the central nervous system dominates the clinical picture.
While there is considerable overlap of symptoms and signs between PEO, KSS, MELAS, and MERRF, there is general agreement that cases of mitochondrial myopathy, PEO and KSS, with or without clinical involvement of the brain, should be considered separately.
The term mitochondrial encephalomyopathy or cytopathy has been applied to the multisystem diseases involving brain, skeletal muscle, and other organs. These disorders and the clinical phenotypes of mtDNA disease span the spectrum of all known oxidative phosphorylation disorders and include PEO., deafness, cardiomyopathy, MELAS and
Co-enzyme Q (ubiquinone) deficiency is present in KSS and PEO and treatment strategies are based on supplying electron transport chain cofactors and substraits, and antioxidants in an attempt to protect against mtDNA free-radical damage.
Co-enzyme Q10 (ubiquinone) 4 mg-kg/day has the largest literature-supported efficacy in mitochondrial disease.
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