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There is evidence that α-synuclein gene ( SNCA ) point mutations and gene multiplications play a pivotal role in the development of Lewy bodies (LBs) and Lewy neuritic (LN) pathology. Dysregulation of the production/degradation of the α-synuclein protein, a major component of LBs and LNs, is speculated to result in its accumulation and produce the neuropathological features of SNCA -related neurodegeneration.1 The identification of SNCA multiplications in families with parkinsonism suggests that SNCA gene dosage may play a role in the onset of Parkinson disease (PD).2 Most patients with SNCA triplication develop cognitive and autonomic dysfunction in early stage of the disease.3,4 However, three families with SNCA duplication have been reported with symptoms more reminiscent of typical PD.5,6 Interestingly, a recent study reported that one triplication (a Swedish-American pedigree) and one duplication pedigree have a common ancestor.7 As a common mechanism of multiplications, the area including the SNCA-MMRN1 locus could play a role in multiple copy numbers. Another multiplication family has been reported also to have the rearrangement change in the same region indicating the SNCA-MMRN1 locus may be fragile.2,5–7 With regard to clinical aspects, patients with SNCA duplication tend to have milder symptoms compared to those with triplication.5–7 The onset of disease in SNCA duplication patients occurs approximately 15 years later (50 years of age) than that of SNCA triplication families (35 years of age). These features suggest that differences in genetic copy numbers could influence the clinical features of PD. Recently, we identified two families of Japanese origin with SNCA duplications.8 One patient from Family B (named as B-1) developed severe parkinsonism and dementia. These findings indicate that SNCA duplication also causes PD with dementia (PDD). Three copies of the locus SNCA-MMRN1 were identified in the two duplication families. The length of …

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

PARK9, a form of autosomal recessive parkinsonism, or Kufor-Rakeb syndrome (KRS), is characterized by subacute or slowly progressive, juvenile-onset, levodopa-responsive parkinsonism, pyramidal signs, dementia, and supranuclear gaze palsy.1–5 Recently, ATP13A2 was identified as the causative gene for PARK9 in Chilean and Jordanian families.4 This gene contains 29 exons encoding a lysosomal type 5 P-type ATPase. Six mutations have been reported in only five probands so far.4,5 Here, we describe a Japanese patient with KRS with a novel mutation who developed early onset parkinsonism, dementia, and other features. We also describe PET findings of PARK9 -linked parkinsonism. ### Methods. Haplotype analysis was conducted in 117 (mainly Japanese) patients with early onset (≤50, 26.8 ± 11.7 years, mean ± SD) parkinsonism. Among them, 14 patients had dementia. Patients who exhibited homozygosity on PARK9 locus by haplotype analysis underwent direct sequencing for all 29 exons (e-Methods on the Neurology ® Web site at www.neurology.org); the remaining patients underwent direct sequencing for exons 13, 16, and 26, in which mutations …

Early onset parkinsonism with diurnal fluctuation (EPDF) is a dopa-responsive parkinsonism characterized by early onset and improvement of parkinsonian symptoms after sleep. A pathologic study of one case of EPDF showed selective neuronal degeneration in the zona compacta of the substantia nigra without Lewy body formation. To determine the disease locus for EPDF, the authors examined 53 members of 17 EPDF families and analyzed 151 meioses. Multipoint linkage analysis gave a peak lod score of 14.2 at 1.0 cM telomeric to D6S305 and placed the disease locus in the 17-cM interval between D6S437 and D6S253, which is exactly the same position mapped for autosomal recessive juvenile parkinsonism (ARJP; Mendelian inheritance in man 600116). The highest two-point lod score was obtained at D6S305 (10.13 at theta = 0). Haplotype analysis agreed with the result of multipoint analysis. A high proportion of nonconsanguinity (8/17 families), the absence of commonly shared haplotypes, and the widespread geographic distribution of the families' origins suggest that EPDF has multiple founder mutations. The authors concluded that EPDF and ARJP are allelic disorders and should be included in the spectrum of a single-clinicogenetic entity of chromosome 6q-linked parkinsonism. This disease could be characterized by a benign clinical course and relatively selective degeneration of nigral dopaminergic neurons with no Lewy body formation. To determine whether ARJP/EPDF constitutes a significant proportion of familial or sporadic forms of benign early onset parkinsonism will require further study.

Article abstract-We report two patients with unilateral resting and postural tremor of the upper limb as a delayed manifestation of thalamic stroke. Neuroradiologic examination showed a lesion in the posterolateral thalamic region in both patients, but with no obvious involvement of the brainstem, the cerebellum, or the cerebellar outflow tract to the thalamic ventrolateral nucleus.NEUROLOGY 1996;46: 75-79

Three trials evaluated the efficacy and safety of pergolide. Eighty-six de novo patients and 314 patients already receiving levodopa were enrolled in an open-label study. Of the de novo patients, 47.5% showed a marked or moderate improvement and 32% showed a mild improvement. In the levodopa add-on group, 53.8% showed marked or moderate improvement and 36.3% showed mild improvement. In a short-term, double-blind study, the efficacy of pergolide was compared with that of bromocriptine. One hundred seventy-two patients were randomized to receive pergolide, and 173 were randomized to receive bromocriptine. In de novo patients, bromocriptine (n = 49) and pergolide (n = 49) demonstrated similar efficacy. However, significantly more levodopa-treated patients in the pergolide group, compared with the bromocriptine group, demonstrated marked or moderate improvements in several items of the rating scale score. In a long-term study, 151 of 314 patients receiving pergolide in combination with levodopa remained in the study for 3 years, and 127 for 4 years, and in these patients the initial improvement was maintained. In 18 of 62 de novo patients, the initial improvement was maintained for up to 3 years. These trials indicate that pergolide has efficacy in patients with Parkinson's disease, either as monotherapy or in combination with levodopa.

Article abstract-The 50-kd dystrophin-associated glycoprotein (50DAG or adhalin) in the skeletal muscle has been shown to be deficient in patients with severe childhood autosomal recessive muscular dystrophy prevalent in North Africa. To elucidate the frequency of patients having the 50DAG deficiency in a muscular dystrophy population in Japan, we immunocytochemically examined 50DAG, 43DAG, dystrophin, and utrophin. A total of 243 patients with muscular dystrophy, among 1,035 diagnostic muscle biopsies during the past 2.5 years, were analyzed. We identified five unrelated patients (three females and two males who have no family history) with 50DAG deficiency in the sarcolemma. Thus, 2.1% (5/243) of our muscular dystrophy patient population had 50DAG deficiency.NEUROLOGY 1995;45: 551-554

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course.

We report the results of pathologic and biochemical studies in a patient with 6q-linked autosomal recessive juvenile parkinsonism (AR-JP). Neuronal loss and gliosis were restricted to the substantia nigra and the locus ceruleus. No Lewy bodies were found, but neurofibrillary tangles and argyrophilic astrocytes were seen in the cerebral cortex and brainstem nuclei. The later findings, which have not been reported previously in AR-JP, suggest the pathologic heterogeneity of 6q-linked AR-JP.

8-Hydroxydeoxyguanosine (8-OHdG) has been used to evaluate oxidative stress. The authors investigated urinary 8-OHdG levels in 72 patients with Parkinson disease (PD) and in normal and disease control groups. The mean urinary 8-OHdG increased with the stage of PD and was not influenced by the current dose of DOPA. Our results suggest that urinary 8-OHdG is a potentially useful biomarker for evaluating the progression of PD.

We report thiolmethyltransferase (TMT) activity in RBC membrane preparations from patients with Parkinson's disease (PD), normal controls, and patients with symptomatic parkinsonism.Unlike previous reports, our report found no significant decrease in TMT activity in PD patients compared with normal controls. Low S-methylation capacity does not appear to be a risk factor for PD in Japanese patients.NEUROLOGY 1995;45: 2279-2281

Autosomal recessive juvenile parkinsonism (AR-JP) is a young-onset parkinsonism caused by mutations in the parkin gene.1 Exonic deletions or multiplications and truncating and missense mutations have been described.2,3⇓ The phenotype encompasses juvenile-, early-, and late-onset patients.2 We describe a large kindred with different phenotypic expressions of a mutation in the parkin gene. The patients belonged to two branches of an Arabic Israeli family (figure). Patients in Branch A have been previously described.4 The consanguinity of the branches was established to the seventh ancestral generation. Figure. The pedigree. Square symbols = men, circles = women, diagonal lines = deceased persons, ✓ = genotyped. The consanguinity of the branches of the family was established to the seventh ancestral generation. Four brothers (black squares) in Branch A (right) and two first-degree cousins (black square and circle) in Branch B (middle) are affected. All patients showed homozygous one adenine deletion at nucleotide position 202. The horizontal shaded symbols represent patients with tremor only who were clinically examined. The patient with an asterisk was genotyped …

The tau N279K mutation was identified in four separately ascertained families in the United States, Japan, and France and in another recently discovered affected individual in Japan. The authors analyzed genealogical and clinical records and DNA samples. Average age at onset was 43 years; survival time was 7 years. All families exhibited similar clinical features, with parkinsonism, dementia, and supranuclear palsy uniformly seen. A founder effect indicated by a shared disease haplotype was seen only in two Japanese families. The N279K mutation can develop independently in different parts of the world.

Recent studies using functional imaging have demonstrated that the anatomic location of the primary motor hand area is topographically localized in a specific segment of the precentral gyrus. MRI reveals that such cortical area protrudes posterolaterally from the precentral gyrus to the central sulcus, thus forming a characteristic knoblike shape similar to that of an inverted omega or epsilon in the axial plane.1 Lesions in the precentral knob cause isolated motor weakness or clumsiness of the corresponding hand.2 Recently, we encountered two patients who presented with ataxia after a cerebral infarction that selectively involved the motor cortex located at the medial part of the precentral knob. ### Patient 1. A 69-year-old right-handed-man with a history of hypertension and diabetes mellitus was admitted because of sudden difficulties in voluntary movement in his upper left limb. On neurologic examination, he was alert and oriented and there was no sensory extinction. Cranial nerves were all intact. There was no weakness in …

We read with interest the article by Khan et al.1 The authors studied asymptomatic parkin heterozygotes by 18F-dopa PET and found a significant reduction of uptake in putamen, caudate, dorsal and ventral midbrain. An interesting observation relates to the subtle extrapyramidal symptoms in four of these “asymptomatic” carriers. The authors recommended follow-up to verify whether they develop parkin disease. One of our patients with a single parkin mutation developed parkin disease 23 years after the manifestation of tremor …

Article abstract We report a Jewish family of Yemenite origin in which three brothers born from a consanguineous marriage had juvenile parkinsonism. The DNA samples from three affected brothers and one healthy brother were analyzed for the linkage to markers covering the autosomal-recessive juvenile parkinsonism (AR-JP) locus. A perfect homozygous cosegregation to the markers was found, giving a maximal lod score of 3.11 at D6S1579, D6S305, and D6S411, all of which are 0 cm apart from each other (nonparametric linkage score, 8.041; p = 0.000977). Exon 3 of the Parkin gene was homozygously deleted in all patients. The AR-JP gene also exists in the Jewish population.

Parkinson's disease is the second most common neurodegenerative disorder, next to Alzheimer's disease. Since the discovery of loss of dopamine in the nigrostriatal system in 1960 by Ehringer and Hornykiewicz,1 great progress has been made in understanding the neurochemistry, neurophysiology, etiology, pathogenesis, genetics, imaging, and treatment of Parkinson's disease. The success of levodopa treatment was achieved by the discovery of striatal loss of dopamine in this disease. Now the life expectancy of patients with Parkinson's disease is close to that of the general population. Although the primary cause of Parkinson's disease is still unknown, there has been considerable progress in …

The gene locus for Machado-Joseph disease (MJD) has been mapped to chromosome 14q by linkage analysis, mainly using a single large Japanese family. We studied the clinical and neuropathologic findings of this family with MJD, comparing them with those of spinocerebellar ataxia 1 (SCA1) and spinocerebellar ataxia 2 (SCA2) families. The pedigree included 30 affected persons in 125 members of five generations. Neurologic examination of 21 patients revealed that dystonia, difficulty in eyelid opening, slowness of movements, bulging eyes, and facial-lingual fasciculation-like movements or myokymia are characteristic of this MJD family, although these three autosomal dominant spinocerebellar degenerations have several neurologic signs and symptoms in common. In contrast with SCA1 and SCA2, degeneration of the subthalamopallidal system and relative sparing of the olivocerebellar system were the main neuropathologic features of MJD.

GM1 gangliosidosis is usually a pediatric disease caused by hereditary acid beta-galactosidase deficiency. There have been a few cases in adults. We saw a 51-year-old Japanese man with type 3 GM1 gangliosidosis who was manifesting dementia, dysarthria, gait disturbance, and limb rigidity. Radiologic studies showed platyspondylia, acetabular hypoplasia, and flattened femoral heads. Biochemical analysis revealed generalized acid beta-galactosidase deficiency.