Galvin, J. E., V. M. Lee, et al. (2001). "Synucleinopathies: clinical and pathological implications." Arch Neurol 58(2): 186-90.
The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic lesion composed of aggregates of insoluble alpha-synuclein protein in selectively vulnerable populations of neurons and glia. Growing evidence links the formation of abnormal filamentous aggregates to the onset and progression of clinical symptoms and the degeneration of affected brain regions in neurodegenerative disorders. These disorders may share an enigmatic symmetry, i.e., missense mutations in the gene encoding for the disease protein (alpha-synuclein) cause familial variants of Parkinson disease as well as its hallmark brain lesions, but the same brain lesions also form from the corresponding wild-type brain protein in the more common sporadic varieties of Parkinson disease. It is likely that clarification of this enigmatic symmetry in 1 form of synucleinopathy will have a profound impact on understanding the mechanisms underlying all these disorders. Furthermore, these efforts will likely lead to novel diagnostic and therapeutic strategies in regard to the synucleinopathies.

Galvin, J. E., T. M. Schuck, et al. (2001). "Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra." Exp Neurol 168(2): 347-55.
Although the functions of alpha-, beta-, and gamma-synuclein (alphaS, betaS, gammaS, respectively) are unknown, these synaptic proteins are implicated in the pathogenesis of Parkinson's disease (PD) and related disorders. For example, alphaS forms Lewy bodies (LBs) in substantia nigra (SN) neurons of PD. However, since it is not known how these hallmark PD lesions contribute to the degeneration of SN neurons or what the normal function of alphaS is in SN neurons, we studied the developing human SN from 11 weeks gestational age (GA) to 16 years of age using immunohistochemistry and antibodies to alphaS, betaS, gammaS, other synaptic proteins, and tyrosine hydoxylase (TH). SN neurons expressed TH at 11 weeks GA and alphaS, betaS, and gammaS appeared initially at 15, 17, and 18 weeks GA, respectively. These synucleins first appeared in perikarya of SN neurons after synaptophysin, but about the same time as synaptotagmin and synaptobrevin. Redistribution of alphaS from perikarya to processes of SN neurons occurred by 18 weeks GA in parallel with synaptophysin, while betaS and synaptotagmin were redistributed similarly between 20 and 28 weeks GA and this also occurred with gammaS and synaptobrevin between 33 weeks GA and 9 months postnatal. These data suggest that alphaS, betaS, and gammaS may play a functional role in the development and maturation of SN neurons, but it remains to be determined how sequestration of alphaS as LBs in PD contributes to the degeneration of SN neurons.

Garcia de Yebenes, J. (2001). "[Genetics of Parkinson's disease]." Neurologia 16(1): 1-6.

Gasser, T. (2001). "Genetics of Parkinson's disease." J Neurol 248(10): 833-40.
Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Gasser, T. (2001). "Molecular genetics of Parkinson's disease." Adv Neurol 86: 23-32.
Over the last few years, several genes for monogenically inherited forms of Parkinson's disease have been mapped and/or cloned. In a large family with autosomal dominant inheritance and typical Lewy-body pathology, a first gene locus has been mapped to the long arm of chromosome 4, and mutations in this and a few other families linked to this locus have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy bodies may be a crucial step in the molecular pathogenesis of familial and sporadic Parkinson's disease. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6, and the causative gene has been identified and named parkin. A third locus, again in families with dominant inheritance, typical Lewy-body pathology, and late onset, has been mapped to chromosome 2p13, and two additional genes on chromosome 4p have been linked to other dominantly inherited forms of the disease. At present, there is no direct evidence that any of the genes for familial parkinsonian syndromes has a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely also to shed light on the molecular pathogenesis of the common sporadic disorder.

Gerlai, R., A. McNamara, et al. (2001). "Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation." Eur J Neurosci 14(7): 1153-63.
Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities.

Giasson, B. I. and V. M. Lee (2001). "Parkin and the molecular pathways of parkinson's disease." Neuron 31(6): 885-8.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective demise of specific neuronal populations leading to impairment of motor functions. Recent genetic studies have uncovered several genes involved in inherited forms of the disease. These gene products are implicated in the biochemical pathways underlying the etiology of sporadic PD. Mutations in the parkin gene causal of autosomal recessive juvenile parkinsonism highlight that ubiquitin-mediated proteolysis may play an important role in the pathobiology of PD.

Goedert, M. (2001). "Alpha-synuclein and neurodegenerative diseases." Nat Rev Neurosci 2(7): 492-501.

Goedert, M. (2001). "Parkinson's disease and other alpha-synucleinopathies." Clin Chem Lab Med 39(4): 308-12.
Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Recent work has shown that rare, familial forms of Parkinson's disease are caused by missense mutations in the alpha-synuclein gene and that the filamentous lesions of Parkinson's disease are made of alpha-synuclein. The same is true of the Lewy body pathology that is associated with other neurodegenerative diseases, such as dementia with Lewy bodies. The filamentous inclusions of multiple system atrophy have also been found to be made of alpha-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant alpha-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-beta diffraction pattern characteristic of amyloid. The related proteins beta-synuclein and gamma-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. The new work has established the alpha-synucleinopathies as a major class of neurodegenerative disease.

Goedert, M. (2001). "The significance of tau and alpha-synuclein inclusions in neurodegenerative diseases." Curr Opin Genet Dev 11(3): 343-51.
Intracellular filamentous inclusions made of either the microtubule-associated protein tau or the protein alpha-synuclein define the majority of cases of neurodegenerative disease. Mutations in the tau gene in familial forms of frontotemporal dementia and in the alpha-synuclein gene in familial cases of Parkinson's disease have provided causal links between the dysfunction of these proteins and neurodegeneration. Over the past year, several novel tau gene mutations have been identified and more has been learned about possible mechanisms by which tau gene mutations lead to frontotemporal dementia. Experimental animal models have provided a link between tau filament formation and nerve cell degeneration. Along similar lines, animal models have been produced that result in the formation of alpha-synuclein filaments and the degeneration of dopaminergic nerve cells. Building on previous work, synthetic alpha-synuclein filaments have been shown to exhibit the characteristics of amyloid.

Goedert, M., M. G. Spillantini, et al. (2001). "From genetics to pathology: tau and alpha-synuclein assemblies in neurodegenerative diseases." Philos Trans R Soc Lond B Biol Sci 356(1406): 213-27.
The most common degenerative diseases of the human brain are characterized by the presence of abnormal filamentous inclusions in affected nerve cells and glial cells. These diseases can be grouped into two classes, based on the identity of the major proteinaceous components of the filamentous assemblies. The filaments are made of either the microtubule-associated protein tau or the protein alpha-synuclein. Importantly, the discovery of mutations in the tau gene in familial forms of frontotemporal dementia and of mutations in the alpha-synuclein gene in familial forms of Parkinson's disease has established that dysfunction of tau protein and alpha-synuclein can cause neurodegeneration.

Goetz, C. G., P. F. Burke, et al. (2001). "Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study." Arch Neurol 58(2): 209-13.
BACKGROUND: Visual hallucinations in Parkinson disease (PD) occur in approximately one third of patients treated long-term with dopaminergic medications. In Alzheimer disease, hallucinations and psychosis have been linked to increased representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without hallucinations did not show differences in D2 and D3 polymorphisms, although careful case-control matching was not performed. Another study linked the apolipoprotein E4 (APOE4) allele to hallucinations in PD. OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease. METHODS: We conducted a case-control study of 44 patients with PD and chronic hallucinations and 44 patients with PD who had never hallucinated. Cases and controls were matched for current age and medications. DNA was isolated from blood samples and assayed for DRD1, DRD2, DRD3, DRD4, and APOE polymorphisms. Receptor polymorphisms were genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies were compared using Wilcoxon signed rank tests within pairs. RESULTS: Neither D1 receptor genotypes (P =.37) nor allele frequencies (P =.38) differed, and there was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there was a higher frequency of allele 2 (P =.047), but there was no significant difference between frequencies of homozygotes vs heterozygotes (P =.39) as reported in Alzheimer disease. D4 receptor distribution of long and short alleles did not differ between the 2 patient groups, and there were too few C alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99). CONCLUSIONS: With careful case-control matching, visual hallucinations in PD are not associated with the pattern seen for patients with Alzheimer disease and visual hallucinations. Furthermore, there was no association between hallucinations and APOE. Similar methods using larger sample sizes might be adapted to test whether specific dopaminergic receptor genetic variants are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.

Golbe, L. I., A. M. Lazzarini, et al. (2001). "The tau A0 allele in Parkinson's disease." Mov Disord 16(3): 442-7.
Parkinson's disease (PD) is primarily an alpha-synucleinopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis. Copyright 2001 Movement Disorder Society.

Gollob, M. H., M. S. Green, et al. (2001). "Identification of a gene responsible for familial Wolff-Parkinson-White syndrome." N Engl J Med 344(24): 1823-31.
BACKGROUND: The Wolff-Parkinson-White syndrome, with a prevalence in Western countries of 1.5 to 3.1 per 1000 persons, causes considerable morbidity and may cause sudden death. We identified two families in which the Wolff-Parkinson-White syndrome segregated as an autosomal dominant disorder. METHODS: We studied 70 members of the two families (57 in Family 1 and 13 in Family 2). The subjects underwent 12-lead electrocardiography and two-dimensional echocardiography. Genotyping mapped the gene responsible to 7q34-q36, a locus previously identified to be responsible for an inherited form of Wolff-Parkinson-White syndrome. Candidate genes were identified, sequenced, and analyzed in normal and affected family members to identify the disease-causing gene. RESULTS: A total of 31 members (23 from Family 1 and 8 from Family 2) had the Wolff-Parkinson-White syndrome. Affected members of both families had ventricular preexcitation with conduction abnormalities and cardiac hypertrophy. The maximal combined two-point lod score was 9.82 at a distance of 5 cM from marker D7S636, which confirmed the linkage of the gene in both families to 7q34-q36. Haplotype analysis indicated that there were no alleles in common in the two families at this locus, suggesting that the two families do not have a common founder. We identified a missense mutation in the gene that encodes the gamma2 regulatory subunit of AMP-activated protein kinase (PRKAG2). The mutation results in the substitution of glutamine for arginine at residue 302 in the protein. CONCLUSIONS: The identification of this genetic defect has important implications for elucidating the pathogenesis of ventricular preexcitation. Further understanding of how this molecular defect leads to supraventricular arrhythmias could influence the development of specific therapies for other forms of supraventricular arrhythmia.

Gollob, M. H., J. J. Seger, et al. (2001). "Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Preexcitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy." Circulation 104(25): 3030-3033.
BACKGROUND: We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results- DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. CONCLUSIONS: We identified a novel mutation (Arg531Gly) in the gamma-2 regulatory subunit (PRKAG2) of AMP-activated protein kinase (AMPK) to be responsible for a syndrome associated with ventricular preexcitation and early onset of atrial fibrillation and conduction disease. These observations confirm an important functional role of AMPK in the regulation of ion channels specific to cardiac tissue. The identification of the cardiac ion channel(s) serving as substrate for AMPK not only would provide insight into the molecular basis of atrial fibrillation and heart block but also may suggest targets for the development of more specific therapy for these common rhythm disturbances.

Gomez, C., J. Reiriz, et al. (2001). "Low concentrations of 1-methyl-4-phenylpyridinium ion induce caspase-mediated apoptosis in human SH-SY5Y neuroblastoma cells." J Neurosci Res 63(5): 421-8.
There is growing evidence that apoptotic mechanisms underlie the neurodegeneration leading to Parkinson's disease. 1-Methyl-4-phenylpyridinium ion (MPP(+)), the active metabolite of the parkinsonism-inducing drug MPTP, induced apoptosis in cultures of human SH-SY5Y neuroblastoma cells. Nuclear fragmentation, DNA laddering, and a 20% decrease in viability were seen after a 4-day incubation with 5 microM MPP(+). Cell viability decreased by 40% at 100 microM MPP(+), but the degree of apoptosis was not correlatively increased. The MPP(+)-induced apoptosis was completely prevented by the broad caspase inhibitor zVAD.fmk but not by the caspase-8 inhibitor IETD.fmk. Furthermore, MPP(+) had no effect on the levels of Fas or Fas-L, suggesting lack of activation of the Fas-L/Fas/caspase-8 pathway of apoptosis. There was no evidence of mitochondrial dysfunction at 5 microM MPP(+): No differences were seen in transmembrane potential or in cytochrome c release from controls. At 100 microM MPP(+), the mitochondrial potential decreased, and cytoplasmic cytochrome c and caspase-9 activation increased slightly. At both low and high concentrations of MPP(+), VDVADase and DEVDase activities increased. We conclude that MPP(+) can induce caspase-mediated apoptosis, which is prevented by caspase inhibition, at concentrations lower than those needed to trigger mitochondrial dysfunction and closer to those found in the brains of MPTP-treated animals. Copyright 2001 Wiley-Liss, Inc.

Grunblatt, E., S. Mandel, et al. (2001). "Gene expression analysis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mice model of Parkinson's disease using cDNA microarray: effect of R-apomorphine." J Neurochem 78(1): 1-12.
To establish the possible roles of oxidative stress, inflammatory processes and other unknown mechanisms in neurodegeneration, we investigated brain gene alterations in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of Parkinson's disease using Atlas mouse cDNA expression array membrane. The expression of 51 different genes involved in oxidative stress, inflammation, glutamate and neurotrophic factors pathways as well as in still undefined processes, such as cell cycle regulators and signal transduction molecules, was differentially affected by the treatment. The present study indicates the involvement of an additional cascade of events that might act in parallel to oxidative stress and inflammation to converge eventually into a common pathway leading to neurodegeneration. The attenuation of these gene changes by R-apomorphine, an iron chelator-radical scavenger drug, supports our previous findings in vivo where R-apomorphine was neuroprotective.

Guillin, O., J. Diaz, et al. (2001). "BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization." Nature 411(6833): 86-9.
Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

Gulcher, J. R., A. Kong, et al. (2001). "The role of linkage studies for common diseases." Curr Opin Genet Dev 11(3): 264-7.
Linkage analysis when applied to common diseases has had limited success in mapping the genes contributing to them. We present a genealogic approach applied to the relatively isolated population of Iceland. We use an affecteds-only, allele-sharing method--which does not specify any particular inheritance model--implemented in the new statistical program, Allegro, which calculates lod scores based on multipoint calculations. We describe how this approach has helped us to map a gene contributing to the common late-onset form of Parkinson's disease to statistical significance.

Guzman, M., C. Sanchez, et al. (2001). "Control of the cell survival/death decision by cannabinoids." J Mol Med 78(11): 613-25.
Cannabinoids, the active components of Cannabis sativa (marijuana), and their derivatives produce a wide spectrum of central and peripheral effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids in recent years. One of the most exciting and promising areas of current cannabinoid research is the ability of these compounds to control the cell survival/death decision. Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells, including neurons, lymphocytes, and various transformed neural and nonneural cells. The variation in drug effects may depend on experimental factors such as drug concentration, timing of drug delivery, and type of cell examined. Regarding the central nervous system, most of the experimental evidence indicates that cannabinoids may protect neurons from toxic insults such as glutamaergic overstimulation, ischemia and oxidative damage. In contrast, cannabinoids induce apoptosis of glioma cells in culture and regression of malignant gliomas in vivo. Breast and prostate cancer cells are also sensitive to cannabinoid-induced antiproliferation. Regarding the immune system, low doses of cannabinoids may enhance cell proliferation, whereas high doses of cannabinoids usually induce growth arrest or apoptosis. The neuroprotective effect of cannabinoids may have potential clinical relevance for the treatment of neurodegenerative disorders such as multiple sclerosis, Parkinson's disease, and ischemia/stroke, whereas their growth-inhibiting action on transformed cells might be useful for the management of malignant brain tumors. Ongoing investigation is in search for cannabinoid-based therapeutic strategies devoid of nondesired psychotropic effects.

Gwinn-Hardy, K., A. Singleton, et al. (2001). "Spinocerebellar ataxia type 3 phenotypically resembling parkinson disease in a black family." Arch Neurol 58(2): 296-9.
BACKGROUND: Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), can present with parkinsonism. However, classically, atypical features, including pyramidal and cerebellar signs, peripheral neuropathy, and/or anterior horn cell dysfunction, are also seen. Levodopa responsiveness is unusual in this disorder. OBJECTIVE: To determine the cause of apparent parkinsonism suggestive of Parkinson disease (PD) in a large family of African origin. METHODS: We studied a large family in which apparent autosomal dominant parkinsonism suggestive of PD occurs in order to find the causal genetic mutation. Affected and unaffected family members were screened for the presence of a pathogenic expansion at the MJD/SCA3 locus using a polymerase chain reaction polyacrylamide gel electrophoresis-based assay. RESULTS: Three of the 4 individuals who were examined have a phenotype reminiscent of PD. Specifically, they have at least 2 of the cardinal features, are levodopa responsive, and have no atypical features. All affected family members were shown to possess pathogenic expansions in the MJD/SCA3 gene. CONCLUSIONS: Parkinsonism suggestive of PD due to MJD/SCA3 has not been previously reported, to our knowledge. However, atypical, though also levodopa-responsive, parkinsonism has been previously reported to occur in African American families, suggesting that that this phenotype is associated with African ancestry. In this regard, it is perhaps significant that all the individuals with parkinsonism have relatively low numbers of repeats (normal, 16-34; pathologic, 60-84). In families in which linkage analysis is being performed to determine a locus for autosomal dominant parkinsonism suggestive of PD, evaluation for the MJD/SCA3 mutation is indicated.

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