The ataxin-2 (SCA2) mutation causing a CAG repeat expansion within the coding region of the cytoplasmic protein (ataxin-2) on chromosome 12q has been reported in several patients of Chinese origin who have dopa-responsive familial parkinsonism.166-168 Members of a large ethnic Chinese family with SCA2 mutation and autosomal dominant inheritances have been described as having typical dopa-responsive asymmetric Parkinson's disease, parkinsonism-ataxia, or parkinsonism resembling progressive supranuclear palsy.166 Shan et al.167 also reported expanded CAG repeats in the SCA2 gene in two patients of Chinese origin who presented with dopa-responsive familial parkinsonism at the age of 50 yr. Both of these patients presented predominantly with 4 Hz resting tremor of the legs that responded to treatment with levodopa in one patient and to alcohol, primidone, or trihexiphenidyl in the other patient. Overt signs of cere-bellar dysfunction were absent, and there was mild slowing of the ocular saccades and gait hesitation suggestive of Parkinson-plus syndrome. Gait ataxia has been reported to occur as much as 25 yr after the onset of dopa-respon-sive parkinsonism.168
Neuroimaging studies have shown features typical of idiopathic Parkinson's disease, such as reduced 18F-labeled dopa uptake in the striatum with a rostrocaudal gradient,169 bilateral asymmetric reduction of striatal dopamine transporters,168 and normal 11C-raclopride binding of the striatum.169 However, Shan et al.167 reported a severe involvement of the caudate nucleus unlike that observed in patients with sporadic Parkinson's disease.
The dopa-responsive parkinsonism phenotype of SCA2 is observed mainly in Chinese persons. Kock et al.170 did not find any expanded trinucleotide repeats in the SCA2 gene in all 270 unrelated patients of mixed ethnicity who had dopa-responsive parkinsonism (young-onset familial, young-onset sporadic, or late-onset familial), and thus far there is only one published report of an SCA2 mutation in a family of non-Chinese origin (English family in Alberta, Canada) with levodopa-responsive parkin-sonism without cerebellar abnormalities.169
Parkinsonism and ataxia have been described in patients with SCA3 or Machado-Joseph disease, both of which have identical mutation on chromosome 14q24.3-q32; currently, these two terms have become interchange-able.171-174 Levodopa-responsive parkinsonism and levodopa-responsive motor complications have been reported in patients with the SCA3 mutation.166 175 176
Familial Dystonia Parkinsonism
Rapid-Onset Dystonia Parkinsonism
This autosomal dominant movement disorder is characterized by the abrupt onset of dysarthria, dysphagia, dys-
tonic spasms, bradykinesia, or postural instability.177 The onset of symptoms usually occurs in late childhood or early adulthood and may be triggered by stressful events. Treatment with levodopa/carbidopa is usually unsatisfactory. Linkage has been established to chromosome 19q13, and the locus has been named DYT12, but the mutation is unknown.177
Lubag, reported in men from the island of Panay in the Philippines,178 is characterized by parkinsonism, action tremor, or dystonia manifesting usually in the fourth or fifth decade but also occurring as early as adoles-cence.179-182 The neuropathologic features of this form of parkinsonism, which responds poorly to levodopa, are neuronal loss restricted to the caudate and the putamen, without evidence of Lewy bodies.180 Linkage has been established to chromosome Xq13.1, and the gene has been named DYT3.183184
Familial Parkinsonism Related to Mitochondrial Dysfunction
Mitochondrial DNA (mtDNA) represents a well recognized non-Mendelian genetic system, abnormalities of which cause a multitude of human diseases.185 The mtDNA codes for constituents of the mitochondrial electron transport chain, such as the nicotinamide-adenine-dinucleotide ubiquinone reductase (complex 1). A role of decreased activity of complex 1 in the pathogenesis of Parkinson's disease comes from observations that (1) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which produces clinical and pathologic features of Parkinson's disease, is an inhibitor of complex 1,186 or that (2) complex 1 patients with Parkinson's disease exhibit decreased activity.187-191 Swerdlow et al.191 reported a large family with multiple members in three generations who were affected with levodopa-responsive Parkinson's disease (age at onset, 35 to 79 yr; mean, 42 yr) through exclusively maternal lines. This kindred had complex 1 dysfunction in mtDNA of maternal descendants with Parkinson's disease and in asymptomatic young maternal descendants. In another large family with maternally inherited, adult-onset, multisystem degeneration and prominent parkin-sonism, a G-to-A missense mutation was found at nucle-otide position 11778 of the mitochondrial ND4 gene of complex 1 that converts a highly conserved arginine to a histidine.192 This family had variable clinical features that included levodopa-responsive parkinsonism, dementia, dystonia, dysarthria, areflexia or hyperreflexia, spasticity, ptosis, and progressive external ophthalmoplegia. Neuro-pathologic findings in one patient showed a marked loss of pigmented neurons in the substantia nigra, the loss of large neurons in the caudate and the putamen, and the absence of Lewy bodies, neurofibrillary tangles, or amyloid plaques.
The identification of the G11778A mutation demonstrates that adult-onset, multisystem, neurodegenerative disease with prominent parkinsonism can be associated with an inherited mtDNA mutation.192
Familial Parkinsonism with Central
Hypoventilation (Perry Syndrome)
The clinical features of this syndrome include the onset of symptoms at 45 to 50 yr of age, autosomal dominant inheritance, parkinsonism in the form of bradykinesia and resting tremor not responding to levodopa, depression, dementia, weight loss, sleep disorders, and central hypoventilation.193 194 After its initial description, other cases were reported in Canada, the United States, the United Kingdom, France, Turkey,195 and Japan.196-200 The disease progresses relentlessly, and persons die suddenly or of respiratory failure in 4 to 8 yr.197 198 Neuropathologic studies show the presence of severe neuronal loss and gliosis mainly in the substantia nigra, with or without scarce Lewy bodies.196-200
Family A (German-Canadian)
The characteristic features of this family include autosomal dominant inheritance, symptom onset at a mean age of 51 yr, levodopa-responsive parkinsonism (resting tremor, bradykinesia, rigidity, and postural instability), amyotrophy, dementia, and dystonia.201 Affected persons have a reduction in the uptake of striatal 18F-labeled dopa (increased caudate-putamen ratio) and an increase in 11C-raclopride binding, whereas neuropathologic findings in autopsied patients have included neuronal loss and gliosis but an absence of Lewy bodies in the substantia nigra.202 The affected persons in the Canadian branch of this family have been found to have linkage to the PARK8 locus on chromosome 12p11.23-q13.11.59 Members of the Sag-amihara family, the first to be linked to the PARK8 locus,62 typically have the Parkinson's disease phenotype, which indicates the marked variability of phenotypic expression in the PARK8-linked disorders.
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