Melissa Hanson

Early-onset Parkinson's disease caused by a compound heterozygous DJ-1 mutation.

Mutations in DJ‐1 have been linked to an autosomal recessive form of early‐onset parkinsonism. To identify mutations causing Parkinsons disease (PD), we sequenced exons 1 through 7 of DJ‐1 in 107 early‐onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ‐1 are a rare cause of early‐onset PD.

Profile of families with parkinsonism‐predominant spinocerebellar ataxia type 2 (SCA2)

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism‐predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinsons disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.

The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population.

We investigated the association of Parkinsons disease (PD) with tau gene H1 haplotypes in the Norwegian population. In a sample of 96 unrelated PD cases and 68 control subjects, we observed an increased risk of PD for persons with the tau H1 haplotype (odds ratio=5.52; 95% confidence interval: 2.64-11.10; P=2.17x10(-6)). Findings provide evidence that tau participates in the PD pathogenic process and demonstrate the value of isolated populations in mapping complex traits.

Glucocerebrosidase mutations are also found in subjects with early-onset parkinsonism from Venezuela

We read with interest the publications by Clark and colleagues1 and Sato and associates2 regarding their pilot association studies of glucocerebrosidase mutations and Parkinson’s disease. Clearly, several different research findings now support an association between altered glucocerebrosidase and parkinsonism. Initially, parkinsonian manifestations were noted in a rare subset of patients with Gaucher disease, the inherited deficiency of glucocerebrosidase.3,4 Subsequently, neuropathological examination of brains from patients with Gaucher disease and early-onset, treatment-refractory parkinsonism found Lewy bodies in regions specifically affected in Gaucher disease, including layers CA4–CA2 of the hippocampus.5 Family studies complemented these observations, revealing a greater than anticipated incidence of parkinsonism among Gaucher disease carriers.6 Thus, both clinical observations and neuropathological data suggested that alterations in glucocerebrosidase may contribute to a vulnerability to the development of parkinsonian symptoms. To explore this association, the glucocerebrosidase gene (GBA) has been examined by different screening techniques in five different cohorts with parkinsonism. Initially, GBA was sequenced in 57 brain samples from subjects with a primary diagnosis of Parkinson’s disease, obtained from five different North American tissue banks.7 Alterations in GBA were identified in 12 samples (21%); 4 with polymorphisms (T369M or E326K) and 8 with Gaucher mutations (N370S, L444P, K198T, R329C), of which 2 were N370S homozygotes. All eight Gaucher carriers or homozygotes were among the 28 younger Parkinson subjects who died before age 75 (27%). Sequencing of GBA in 44 controls from the same brain banks revealed no mutations, although polymorphisms were identified in 2 subjects (4.5%). Subsequently, another series of 26 brain samples from British subjects diagnosed with Parkinson’s disease between 42 and 78 years were obtained from the Parkinson’s Disease Society Tissue Bank of the Imperial College, United Kingdom (registered charity 948776). Sequencing revealed two (8%) carried GBA mutations (D140H E326K, RecNciI).8 In a third series, investigators from Israel screened 99 Ashkenazi Jewish probands with Parkinson’s disease for six known glucocerebrosidase mutations.9 They identified 31 patients (31.3%) with mutations N370S or c.84insG, including 3 N370S homozygotes. This frequency was considerably higher than the 10.7% incidence of mutation N370S reported in a similar cohort of 160 Jewish subjects with parkinsonism from New York City.1 In a fifth series, a group from Toronto screened for seven glucocerebrosidase mutations in 88 unrelated Caucasian subjects of Canadian origin with clinically diagnosed parkinsonism, selected for an early age of onset or a positive family history.2 They identified mutations in 5.6% of this Canadian cohort, as opposed to 0.8% in their screened normal controls. We have now screened an ethnically different group of 33 subjects diagnosed with early-onset Parkinson’s disease, who were seen at the Movement Disorder Unit at the Hospital Universitario in Caracas, Venezuela. In this cohort, the age at symptom onset ranged from 24 to 50 years, with a mean of 36 years. None of the probands had Ashkenazi Jewish ancestry. All exons and most flanking intronic regions of GBA were sequenced from lymphocyte DNA as previously described.10 Four unrelated probands (12%) carried GBA mutations L444P, N370S, or RecNciI, a recombinant allele that comprises alterations L444P, A456P, and V460V (Table 1). Because three different mutant alleles were identified, this finding was unlikely to be due to a founder effect. All 4 probands were at least initially levodopa responsive, and only 1 had a positive family history of Parkinson’s disease. We subsequently sequenced DNA from a series of 31 adult patients (over age 40) with no clinical signs of parkinsonism, who were seen at the Research Institute Fundación Instituto de Estudios Avanzados in Caracas, Venezuela. This control group included Venezuelan citizens of mixed ethnic backgrounds, including some with Italian, Peruvian, Spanish, or Colombian ancestry. All exons were examined in 29 of the controls, but in 2, sequencing of exons 1 to 4 was incomplete. One control (3.2%) carried an alteration in exon 10, D443N, but no other mutations were identified in the control group. D443N, which has not been described previously, is predicted to be located in Domain II of glucocerebrosidase, on the outer surface of the enzyme.11 These studies demonstrate that GBA mutations are observed with an increased frequency not only among Ashkenazi Jews with Parkinson’s disease but also among subjects with parkinsonism from diverse ethnic backgrounds. This study, in particular, replicates this finding in a cohort with early-onset Parkinson’s disease. It provides further evidence that altered glucocerebrosidase may serve as a risk factor for the development of parkinsonian symptoms. By unraveling the relationship between altered glucocerebrosidase and parkinsonism, we may advance our understanding of the etiology, genetics, and pathogenesis of Parkinson’s 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 Parkinsons 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.

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 ~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 wich unclear etiology, and that one or more endophenotypes might exist within the disorder which could further characterize these subjects for future genetic studies.

Accurate determination of ataxin-2 polyglutamine expansion in patients with intermediate-range repeats.

Spinocerebellar ataxia, type 2 (SCA2), results from an expansion of a stretch of polyglutamine repeats within the coding sequence of the ataxin-2 gene (ATX2), localized to chromosome 12q23-24. Recent studies have widened the clinical phenotype, notably for individuals with repeats of intermediate size, from 32 to 35 glutamine residues. This narrow range necessitates precise determination of repeat size. Diagnostic laboratories most often perform direct genotyping of ATX2 from polymerase chain-amplified patient DNA with subsequent sizing utilizing slab gel polyacrylamide gel electrophoresis (PAGE) or capillary electrophoresis. Using cloning and sequencing methods, we have constructed a ladder of ATX2 alleles of known size and sequence composition. This freely available size ladder will facilitate future quantification of expansions of the ATX2 locus.

A consanguineous Turkish family with early-onset Parkinson's disease and an exon 4 parkin deletion

The importance of parkin in early‐onset Parkinsons disease in Japan, Europe, and the United States is well established. The contribution of this gene to the risk of Parkinsons disease in other populations is less well known. To explore the importance of parkin in those of Turkish ancestry, we studied familial cases from that country, and identified a consanguineous family with early‐onset Parkinsons disease due to a homozygous mutation in parkin.

Exercise-induced dystonia as a preceding symptom of familial Parkinson's disease†

Paroxysmal exercise‐induced dystonia can occur with Parkinsons disease (PD), and in rare cases, this can also be the presenting symptom. We report on 2 second cousins (no known consanguinity) who presented with paroxysmal exercise‐induced dystonia who later developed clinical features of PD. Although autosomal recessive inheritance was suggested, and the dystonic features further suggest parkin as a possible cause, ssequencing for parkin mutations was negative and this family may represent a genetic variant of PD. Further genotype–phenotype studies in this and similar families may give clues to pre‐symptomatic symptoms in PD and may reflect a particular phenotype of interest for genetics studies in the future.

Mutation at the SCA17 locus is not a common cause of parkinsonism

Spinocerebellar ataxia (SCA) 17 is a dominant, progressive, neurodegenerative disorder. The disease is caused by a triplet repeat expansion mutation within TATA-binding protein (TBP). Ataxia, dementia, parkinsonism and dystonia are common features. We have previously shown in several pedigrees that SCA-2 and SCA-3 can cause both parkinsonism and typical Parkinsons disease in the absence of prominent ataxia; a finding which has been confirmed by others. Given these previous findings and the description of parkinsonism as a common feature of SCA-17 we examined this locus in a series of probands from families with 2 or more members affected with parkinsonism (n=51) and a group of sporadic parkinsonism patients (n=59). We did not find any repeat sizes in the pathogenic range. The repeats we observed ranged from 29 to 41 (mean 36.8; median 37). We conclude that SCA-17 repeat expansion mutations are not a common cause of familial parkinsonism.