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We present a kindred with a previously undescribed combination of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and mild dementia. The propositus, a 72-year-old man, had pes cavus, peripheral neuropathy, ptosis, parkinsonism, hyperreflexia, orthostatic hypotension, central hypoventilation, and mild dementia. Peripheral electrophysiologic studies showed features of an axonal neuropathy. The electroencephalogram showed intermittent 2 to 4 Hz activity symmetrically in the hemispheres. Several family members in 3 generations had pes cavus, neuropathy, ptosis, parkinsonism, and dementia although not all of the features were consistently present. Survival past the 7th decade was common. Autopsy in 2 affected members revealed the neuropathy to be axonal in type and showed mild to moderate loss of anterior horn cells in the spinal cord and pigmentary loss with gliosis in the substantia nigra. This is a unique, benign, autosomal dominant syndrome which shows complete penetrance, variable expression, and both central and peripheral nervous system involvement.
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PMID:Benign autosomal dominant syndrome of neuronal Charcot-Marie-Tooth disease, ptosis, parkinsonism, and dementia. 218 81

A clinicopathological report is presented of a British male, aged 59 years, who died after an illness of 10 years, manifested by progressive respiratory failure, ptosis, and dysphagia. At no time was there evidence of ophthalmoplegia, Parkinsonism or dementia. At necropsy the main finding was of neurofibrillary tangles in the neurons of the pontine and medullary reticular formation, with particularly severe involvement of the nucleus ambiguus, dorsal motor nucleus of the vagus and nucleus tractus solitarius. Morphologically, by light and electron microscopy and immunostaining, the tangles were similar to those of other neurofibrillary degenerative diseases. Although similar in some respects to progressive supranuclear palsy and amyotrophic lateral sclerosis of the Guam type, the combination of clinical and neuropathological features suggest that this is a distinct disease entity.
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PMID:Progressive medullary failure associated with neurofibrillary degeneration. 273 35

In one of two siblings a clinical disorder was described, consisting of a slowly progressive juvenile parkinsonism with extensor plantar responses, external ophthalmoplegia with severe ptosis and a motor and sensory polyneuropathy. The younger sibling had only juvenile parkinsonism, Unilateral ptosis and a motor and sensory polyneuropathy. Their father was neurologically normal except for a unilateral ptosis. There did not seem to be consanguinity in this family.
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PMID:External ophthalmoplegia, juvenile parkinsonism and axonal polyneuropathy in two siblings. 627 73

Peroneal muscular atrophy (PMA) may be occasionally associated with other neurodegenerative features including parkinsonism. We report the association of PMA of neuronal type with parkinsonism, ptosis and congenital strabismus in a 62-year-old Sicilian woman. The complete syndrome was present only in the proband, but variously combined features were present in ten other family members over four generations, with likely autosomal dominant inheritance. Although a similar syndrome of PMA, ptosis, parkinsonism and dementia was already reported, this family showed a previously undescribed combination of features in view of the presence of congenital strabismus.
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PMID:Peroneal muscular atrophy with parkinsonism, ptosis, and congenital strabismus. 825 67

We report a 63-year-old woman who presented myotonia and parkinsonism. The patient was well until 15 years of the age when she noted that the ring finger of her left hand at times flexed when she did not intend to do so. She noted weakness in her left upper extremity at the age of 40, and difficulty in relaxing her hand grip at 45. She had an onset of tremor in her right foot at age 50, which was followed by difficulty in gait and hand writing. She was admitted to Juntendo University Urayasu Hospital when she was 63-year-old. Her mother, two sisters, and a son were affected with similar muscle weakness and myotonia. Although some of them developed stooped posture in the late stage of the disease, none of them had overt parkinsonism. General physical examination was unremarkable. Neurologic examination revealed an alert and oriented woman with some recent memory loss. She had bilateral ptosis, facial weakness, and a masked face. Myerson's sign was present. Her speech was small and monotonous. The sternocleidomastoid muscles were markedly atrophic and weak. The remaining of the cranial nerves were intact. She walked in small steps with freezing with support. She showed bradykinesia, retropulsion, and resting tremor in her right leg. Slight distal dominant weakness was noted in both upper and lower extremities more on the left. No cerebellar signs were noted. Muscle stretch reflexes were within normal limits in the upper extremities and diminished in the lower limbs. Sensation was intact. Routine laboratory findings were unremarkable. Cranial CT scan and MRI revealed slight cortical atrophy and leukoaraiosis. She responded to levodopa and she became able to walk by herself. She was transferred to another hospital one month after her admission. She had several bouts of airway obstruction with one episode of respiratory arrest. She expired six month after the transfer. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that this patient suffered from myotonic dystrophy and Parkinson's disease which set in later years. Postmortem examination on the iliopsoas muscle revealed uneven muscle fiber diameters, central nuclei, and type 1 fiber predominance; the pathologic finding was consistent with myotonic dystrophy. The substantia nigra showed marked cell loss and Lewy bodies in the remaining neurons. The finding was consistent with Parkinson's disease. In myelin stain, diffuse myelin pallor was noted in the cerebral white matter which was the pathologic substrate of leukoaraiosis in this patient. Combination of these two disorders have never been reported in the literature to our knowledge. It appears to be that the coincidence is just a by-chance phenomenon, but it seems interesting to note that accelerated aging process appears to be present in both myotonic dystrophy and Parkinson's disease.
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PMID:[A 63-year-old woman with muscle weakness, myotonia, and parkinsonism]. 886 42

We studied the clinical features and molecular genetics of a family, afflicted with a form of atypical parkinsonism, originating from the Madeira Islands of Portugal. We examined four affected individuals and reviewed clinical information on one other affected family member. Mean age at onset was 31 years. Parkinsonism (akinesia, rigidity, gait disturbance) was the most prominent feature in advanced disease. Levodopa responsiveness with peak-dose dyskinesia was present in one individual. Initial symptoms and other clinical features were variable and included other extrapyramidal signs (dystonia, action tremor of the limbs and bulbar muscles, synkinesis), ophthalmologic abnormalities (ptosis, slow saccades, progressive external ophthalmoplegia, hypometric saccades, saccadic pursuit movements), speech abnormalities (dysarthria, hypernasality), cortical impairment (dementia, frontal lobe dysfunction, palilalia, perseveration), minor cerebellar signs (dysmetria, gait ataxia), pyramidal abnormalities (spasticity, hyperreflexia), and peripheral nervous system abnormalities (propioceptive loss, areflexia, distal weakness, atrophy). The length of trinucleotide repeats in the MJD1 gene was in the normal range for all affected individuals.
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PMID:Atypical parkinsonism in a family of Portuguese ancestry: absence of CAG repeat expansion in the MJD1 gene. 915 59

In a 63-year-old, 165-cm-tall woman with a history of repeated tick bites, dilative cardiomyopathy, osteoporosis, progressive head ptosis with neck stiffness and cervical pain developed. The family history was positive for thyroid dysfunction and neuromuscular disorders. Neurological examination revealed prominent forward head drop, weak anteflexion and retroflexion, nuchal rigidity, weakness of the shoulder girdle, cogwheel rigidity, and tetraspasticity. The lactate stress test was abnormal. Electromyograms of various muscles were myogenic. Muscle biopsy showed non-specific myogenic abnormalities and generally weak staining for cytochrome oxydase. Mitochondriopathy with multi-organ involvement was suspected. The response to anti-Parkinson medication was poor. In conclusion, dropped head syndrome (DHS) may be due to multi-organ mitochondriopathy, manifesting as Parkinsonism, tetraspasticity, dilative cardiomyopathy, osteoporosis, short stature, and myopathy. Anti-Parkinson medication is of limited effect.
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PMID:Dropped head syndrome in mitochondriopathy. 1476 8

The eyelid movements are mediated mainly by the orbicularis oculi (OO) and the levator palpebrae superioris (LPS) muscles. Dissociated upper lid functions exhibit different counterbalanced action of these muscles, and in blinking they show a strictly reciprocal innervation. The disturbance of this close LPS-OO relationship likely leads to many of the central lid movement disorders. Three groups of supranuclear motor impairment of lid movements are considered: the disorders of the lid-eye movements' coordination, the disturbances of blinking and lid "postural" maintenance, and the alteration of voluntary lid movements. Nuclei of the posterior commissure control the inhibitory modulation of LPS motor-neuronal activity and they are involved in the lid-eye coordination disorders such as lid retraction, which is observed in the Parinaud's syndrome and also in parkinsonism and progressive supranuclear palsy. Spontaneous (SB) and reflex blinking consist of two components: the inhibition of the basal tonic LPS activity, which keeps the eyes open, and the concurrent activation of the OO muscles. LPS inhibition precedes and outlasts the OO activation. This normal configuration is impaired in parkinsonism and blepharospasm (BSP). SB shows a highly interindividual rate variation (among 10-20 per minute in adults) and abnormal blink rates occur in neurological diseases related to dopaminergic transmission impairments. Lid postural abnormalities include involuntary eyelid closure, which is usually associated with inability to open the eyes. Two major disorders share these two aspects: BSP and blepharocolysis (BCO). BSP consists of an involuntary overactivity of the OO, with LPS co-contraction activity, and is expressed as frequent and prolonged blinks, clonic bursts, prolonged tonic contraction or a blend of all of them. BCO (commonly named "so-called lid opening apraxia") is an overinhibition of the LPS with no evidence of ongoing OO activity. BSP and BCO occur in many instances of idiopathic dystonias and basal ganglia diseases and, less frequently, in rostral brainstem lesions. Both may coincide in the same patient. Voluntary lid movement disorders comprise the impairment of Bell's phenomenon, the voluntary eyelid closure palsy and the so-called cerebral ptosis, all related to lesions of frontal cortical areas and/or the corticospinal system.
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PMID:Eyelid movements in health and disease. The supranuclear impairment of the palpebral motility. 1503 Jul 96

Defects of mitochondrial polymerase gamma (POLG) underlie neurological diseases ranging from myopathies to parkinsonism and infantile Alpers syndrome. The most severe manifestations have been associated with mutations of the 'spacer' region of POLG, the function of which has remained unstudied in humans. We identified a family, segregating three POLG amino acid variants, A467T, R627Q and Q1236H. The first two affect the spacer region and the third is a polymorphism, allelic with R627Q. Three grades of disease severity appeared to correlate with the genotypes. The patient with the most severe outcome, cerebellar ataxia syndrome, had all three variants, those with R627Q and Q1236H had juvenile-onset ptosis and gait disturbance and those with a single A467T allele had late-onset ptosis. To evaluate the molecular pathogenesis of these spacer defects, we expressed and purified the mutant proteins and studied their catalytic properties in vitro. The A467T substitution resulted in clearly decreased activity, DNA binding and processivity of the polymerase. Our biochemical data, the dominant manifestation of A467T and its previously reported high frequency in the Belgian population (0.6%), emphasize the role of this mutation as a common cause of neurological disease. Further, biochemical evidence that a polymorphic variant may modify the function of a mutant POLG, if occurring in the same polypeptide, is shown here. Finally, and surprisingly, other pathogenic spacer mutants showed DNA-binding affinities and processivities similar to or higher than the controls, suggesting that the disease-causing mechanisms of spacer mutations extend beyond the basic catalytic functions of POLG.
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PMID:Functional defects due to spacer-region mutations of human mitochondrial DNA polymerase in a family with an ataxia-myopathy syndrome. 1591 73

Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease. In some cases, mitochondrial DNA primary genetic abnormalities, or more commonly, secondary rearrangements due to polymerase gamma (POLG1) gene mutation, can directly cause parkinsonism. The case of a Parkinson disease patient with some signs or symptoms suggestive of mitochondrial disease (i.e., ptosis, myopathy, neuropathy) is a relatively common event in the neurological practice. Mitochondrial parkinsonisms do not have distinctive features allowing an immediate diagnosis, and a negative family history does not rule out a possible diagnosis of mitochondrial disorder. In this article, we do not revise the mitochondrial hypothesis of sporadic, idiopathic Parkinson disease, extensively discussed elsewhere, but we review POLG1-related parkinsonism and other well-defined forms of "mitochondrial parkinsonisms", with mtDNA mutations or rearrangements. Lastly, we try to introduce a possible diagnostic approach for patients with parkinsonism and suspected mitochondrial disorder.
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PMID:POLG1-related and other "mitochondrial Parkinsonisms": an overview. 2122 44


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