Comprehensive screening of a North American Parkinson's disease cohort for LRRK2 mutation.

BACKGROUND: Recently, mutations in LRRK2 encoding the protein dardarin have been linked to an autosomal dominant form of parkinsonism. OBJECTIVE: To identify mutations causing Parkinson's disease (PD) in a cohort of North Americans with familial PD. METHODS: We sequenced exons 1-51 of LRRK2 in 79 unrelated North American PD patients reporting a family history of the disease. RESULTS: One patient had a missense mutation (Thr2356Ile) while two others had the common Gly2019Ser mutation. In addition, 1 patient had a 4-bp deletion in close proximity to the exon 19 splice donor (IVS20+4delGTAA) that in vitro abrogates normal splicing. CONCLUSIONS: Our observations in the 79 North American patients indicate that mutations in LRRK2 are associated with approximately 5% of PD cases with a positive family history. The results also show that G2019S represents approximately half of the LRRK2 mutations in United States PD cases with a family history of the disease. We have identified two novel mutations in LRRK2.

Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.

We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5' part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans.

Diagnostic criteria for psychosis in Parkinson's disease: report of an NINDS, NIMH work group.

There are no standardized diagnostic criteria for psychosis associated with Parkinson's disease (PDPsy). As part of an NIH sponsored workshop, we reviewed the existing literature on PDPsy to provide criteria that distinguish PDPsy from other causes of psychosis. Based on these data, we propose provisional criteria for PDPsy in the style of the Diagnostic and Statistical Manual of Mental Disorders IV-TR. PDPsy has a well-characterized temporal and clinical profile of hallucinations and delusions, which is different than the pattern seen in other psychotic disorders such as substance induced psychosis or schizophrenia. PDPsy is associated with a poor prognosis of chronic psychosis, nursing home placement, and death. Medications used to treat Parkinson's disease (PD) contribute to PDPsy but may not be sufficient or necessary contributors to PDPsy. PDPsy is associated with Lewy bodies pathology, imbalances of monoaminergic neurotransmitters, and visuospatial processing deficits. These findings suggest that PDPsy may result from progression of the disease process underlying PD, rather than a comorbid psychiatric disorder or drug intoxication. PDPsy is not adequately described by existing criteria for psychotic disorders. We established provisional diagnostic criteria that define a constellation of clinical features not shared by other psychotic syndromes. The criteria are inclusive and contain descriptions of the full range of characteristic symptoms, chronology of onset, duration of symptoms, exclusionary diagnoses, and associated features such as dementia. These criteria require validation and may be refined, but form a starting point for studies of the epidemiology and pathophysiology of PDPsy, and are a potential indication for therapy development.

Pathogenicity of the Lrrk2 R1514Q substitution in Parkinson's disease.

An increasing number of nonsynonymous LRRK2 variants are being reported as putative pathogenic mutations. We identified one large kindred harboring the Lrrk2 R1514Q substitution; however, the variant did not segregate fully with disease. Combined analyses of three case-control series demonstrate that the R1514Q substitution is not associated with increased risk of disease (OR: 1.3; 95% CI: 0.6-2.8; P = 0.45). These findings highlight the importance of using family-based studies and multiple population screenings when examining the association of these polymorphic LRRK2 gene variants with Parkinson's disease.

The SCA17 phenotype can include features of MSA-C, PSP and cognitive impairment.

Spinocerebellar ataxia (SCA) 17 is a dominant neurodegenerative disorder characterized by ataxia, cognitive decline, dystonia, and parkinsonism. The disease is caused by unstable cytosine-adenine-guanine (CAG) trinucleotide expansion mutation coding for polyglutamine tracts in the TATA box-binding protein (TBP), a general transcription initiation factor. Herein, we report a SCA17 case with a phenotype not previously reported, which consisted of progressive ataxia, autonomic dysfunction, parkinsonism, supranuclear palsy and cognitive impairment. Cerebrospinal fluid study and 18F-dopa PET scanning demonstrated dopamine deficiency and nigrostrital degeneration. This case expands the current phenotype associated with SCA17. SCA17 should be considered in the differential diagnosis of cases resembling multiple system atrophy, especially those with atypical features.

Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals.

The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here, we describe the utility of genome-wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408 804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts >5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.

Genetics of Parkinson's disease and parkinsonism.

Until 10 years ago, conventional wisdom held that Parkinson's disease was not a genetic disorder. Since that time, there have been a plethora of genetic findings, culminating in the cloning of several genes that derive from the loci given the nomenclature PARK1-PARK12 (OMIM 168600). Recently, these research findings have begun to impact clinical practice, and this impact is likely to increase. The primary purpose of this article is to outline these genetic advances, discuss their importance for current practice in clinical and related settings, and outline briefly how they are influencing research into the causes of and possible future treatments for this prevalent disorder.

Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data.

BACKGROUND: Several genes underlying rare monogenic forms of Parkinson's disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinson's disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinson's disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS: We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinson's disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS: We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION: We generated publicly available genotype data for Parkinson's disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.

A MAPT mutation in a regulatory element upstream of exon 10 causes frontotemporal dementia.

We report here the genetic analysis of a newly ascertained kindred in which frontotemporal dementia occurs in an apparent autosomal dominant fashion, and in which a novel MAPT gene mutation co-segregates with disease. Sequencing the MAPT gene in affected individuals revealed a change in intron 9. This finding supports earlier studies on the effect of a splice-accepting element in inclusion of exon 10 in the MAPT transcript. This mutation sheds light on a novel mechanism by which over-expression of 4-repeat tau leads to disease. Based on our current findings, we propose a novel mechanism by which intronic mutations can lead to frontotemporal dementia.

The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases.

Mutations in the leucine-rich kinase 2 gene (LRRK 2) encoding dardarin, on chromosome 12, are a common cause of familial and sporadic Parkinson's disease. The most common mutation, a heterozygous 6055 G>A transition (G 2019 S) accounts for approximately 3--10% of familial Parkinson's disease and 1--8% sporadic Parkinson's disease in several European-derived populations. Some families with disease caused by LRRK 2 mutations have been reported to include patients with highly variable clinical and pathological features. We screened for the most common LRRK 2 mutation in a series of patients with Parkinson's Disease, Alzheimer's disease, Progressive Supranuclear Palsy, Multiple System Atrophy and frontotemporal dementia, as well as in neurologically normal controls. The mutation was found only in Parkinson's disease patients or their relatives and not in those with other neurodegenerative disease.

Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease.

The spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders linked to more than 20 genetic loci. Most often, these diseases are caused by expansion of triplet repeats encoding polyglutamine (polyQ) tracts. The phenotype is variable and can cause a disease that overlaps clinically with Parkinson's disease (PD). l-Dopa-responsive parkinsonism with minimal cerebellar deficits has been described in SCA2 and SCA3. In order to define if mutation at these loci is a common cause of clinically defined parkinsonism we typed the SCA-2 and SCA-3 repeats for expansion in a series of 280 patients diagnosed with PD or parkinsonism. We identified one pathogenic expansion in SCA-2 in a North American family with autosomal dominant parkinsonism.

Unaltered alpha-synuclein blood levels in juvenile Parkinsonism with a parkin exon 4 deletion.

We recently reported here that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood from cases with hereditary Lewy body disease. This observation shows that alpha-synuclein levels in blood accurately reflect gene dosage, which we assume drives pathogenesis in these individuals. A previous report has suggested that parkin can affect alpha-synuclein metabolism in human brain. Here we have tested whether there is also an increase of alpha-synuclein in autosomal recessive juvenile Parkinsonism (ARJP). We find there is not and discuss this result in terms of the putative relationships between alpha-synuclein and parkin.

Parkin mutations and early-onset parkinsonism in a Taiwanese cohort.

BACKGROUND: Loss of function of the parkin gene (PRKN) is the predominant genetic cause of juvenile and early-onset parkinsonism in Japan, Europe, and the United States. OBJECTIVES: To evaluate the frequency of PRKN mutations in Taiwanese (ethnic Chinese) patients with early-onset parkinsonism and to explore genotype-phenotype correlations. DESIGN: Clinical assessment included medical, neurologic, and psychiatric evaluation. Genomic DNA sequencing and quantitative polymerase chain reaction were performed to identify PRKN mutations. Gene expression was examined in patient lymphoblastoid cell lines, in which PRKN mutations were identified. PATIENTS: Forty-one Taiwanese patients with early-onset parkinsonism (aged <50 years at onset). RESULTS: Four of 41 probands had PRKN mutations. One proband had compound heterozygous mutations, with a PRKN exon 2 deletion and an exon 7 G284R substitution. The phenotype resembled typical Parkinson disease. Three patients were mutation carriers. One proband had PRKN exon 2 and exon 3 deletions in the same allele. However, this patient's phenotype was that of classic "parkin-proven" autosomal recessive juvenile parkinsonism, characterized by symmetrical foot dystonia at onset, gait disturbance, diurnal change, and very slow progression. The 2 remaining carriers had novel heterozygous exon 11 R396G substitutions. Patients with PRKN mutations were younger at onset than those without mutations, and they required a lower dose of levodopa despite longer disease duration. CONCLUSIONS: Mutations in PRKN are a rare cause of early-onset parkinsonism in Taiwanese individuals. The overall mutation frequency, adjusted for age at onset, was comparable with that reported for white cohorts; however, the point mutations identified seem to be population specific.

Genetic testing in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder of adulthood characterized clinically by rigidity, bradykinesia, resting tremor, and postural instability. The annual incidence of PD ranges between 16 and 19 individuals per 100,000 (Twelves et al., Mov Disord 2003;18:19-31). Historically, PD has been commonly viewed as an idiopathic or environmentally triggered condition. However, as is true with most common conditions, there have been several families reported with PD who demonstrate a classic Mendelian pattern of inheritance. To date, nine genetic loci have been reported and four pathogenic genes have been identified: alpha-synuclein, parkin, DJ1, and PINK1. Families with alterations in these genes or linked sites demonstrate either recessive or dominant inheritance patterns and may have typical and/or atypical symptoms, with an age of onset extending from the second to the sixth decade. Commercial tests for parkin and alpha-synuclein mutations are now available. We predict that physicians, particularly neurologists, increasingly will be approached for information and referrals regarding genetic testing. To assist patients and their families, physicians will not only need to know when such testing is likely to yield a meaningful result but also be aware of the possible social and emotional consequences of testing. The following is a review of what is currently known about the genetics of PD within this context. We discuss what is known about genetic testing for Huntington's disease, a well-described model for genetic testing in a neurodegenerative disorder. We explore the utility, appropriateness, and possible implications of genetic testing for diagnostic and presymptomatic purposes.

Genome-wide analysis of the parkinsonism-dementia complex of Guam.

BACKGROUND: Parkinsonism-dementia complex (PDC) is a neurofibrillary tangle degeneration involving the deposition of Alzheimer-type tau, predominantly in the mesial temporal cortex, brainstem, and basal ganglia. It occurs in focal geographic isolates, including Guam and the Kii peninsula of Japan. The familial clustering of the disease has suggested that a genetic factor could be important in its etiology. OBJECTIVE: To determine whether a genetic locus could be identified, linked, or associated with PDC. DESIGN AND PATIENTS: We performed a genome-wide association study of 22 Guamanian PDC and 19 control subjects using 834 microsatellite markers with an approximate genome-wide marker density of 4.4 centimorgans. RESULTS: Two-point association analysis identified 17 markers (P<.015). Each of these markers then underwent conventional linkage analysis in 5 families with PDC. One marker, D20S103, generated a logarithm of odds score of greater than 1.5. Multipoint association analysis also highlighted 2 other areas on chromosome 14q (adjacent to D14S592, 59.2 megabases [M]) and chromosome 20 (adjacent to D20S470, 17.4 M) with multipoint association logarithm of the odds scores of greater than 2. The areas around D20S103, D14S592, and D20S470 were further analyzed by association using additional microsatellite markers and by conventional linkage analysis. This did not provide further evidence for the role of these areas in PDC. CONCLUSIONS: This study has not identified a single gene locus for PDC, confirming the impression of a geographic disease isolate with a complex genetic, a genetic/environmental etiology, or a purely environmental etiology.

Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.

BACKGROUND: Mutations in the PTEN-induced kinase (PINK1) gene located within the PARK6 locus on chromosome 1p35-p36 have recently been identified in patients with recessive early-onset Parkinson disease. OBJECTIVE: To assess the prevalence of PINK1 mutations within a series of early- and late-onset Parkinson disease patients living in North America. DESIGN: All coding exons of the PINK1 gene were sequenced in a series of 289 Parkinson disease patients and 80 neurologically normal control subjects; the mutation frequencies were evaluated in additional controls (100 white and 50 Filipino subjects). RESULTS: We identified 27 variants, including the first reported compound heterozygous mutation (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-onset Parkinson disease patients. CONCLUSION: Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease.

Analysis of familial and sporadic restless legs syndrome in age of onset, gender, and severity features.

Restless Legs Syndrome is characterized by the irresistible, often indescribable unpleasant urge to move the limbs while resting. It has an estimated prevalence of approximately 29.3 % in US private practice. Restless Legs Syndrome often has a familial component; whether the familial and non-familial forms differ in terms of clinical features has previously been investigated, with the only significant factor emerging as younger age at onset in familial cases. Our study further explores a possible underlying difference between familial and sporadic forms of RLS by comparing familial RLS with sporadic RLS in terms of demographic and clinical features including subject gender, age of onset, and severity measures based an the IRLSSG severity scale. Both gender and family history are significant predictors of onset age in an overall model and also significant when analyzed independently. Participants who reported more severe RLS symptoms were significantly younger in age and progressed more rapidly. Two variables from the IRLSSG severity scale were significantly associated with age of onset when tested independently: discomfort and the urge to move the limb for relief. Our analysis supports the prevailing hypothesis that RLS is divided into earlier onset disease with a clear genetic component and later onset disease with unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.

Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study.

We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients.