Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders varied in genetic etiologies, clinical presentations, and radiological features. NBIA is an iron homeostasis disorder with progressive iron accumulation in the central nervous systems and is clinically characterized by extrapyramidal movement abnormalities, retinal pigmentary changes, and cognitive impairment. Panthothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease) is the commonest disorder of NBIA with a prevalence of one-three per million. Clinically, it is classified into early-onset childhood, atypical late-onset, and adult-onset type. Adult-onset type is rarer. We report the first case of adult-onset panthothenate kinase-associated neurodegeneration in Hong Kong in a 28-year-old Chinese man who presented with pure young-onset parkinsonism. Magnetic resonance imaging (MRI) of the brain showed the presence of eye-of-the-tiger sign. Two compound heterozygous mutations PANK2 NM_153638.2: c.445G > T; NP_705902.2: p.E149X and PANK2 NM_153638.2: c.1133A > G; NP_705902.2: p.D378G were detected. Parkinsonism per se is a very heterogeneous phenotypic group. In view of the readily available genetic analysis of PANK2, panthothenate kinase-associated neurodegeneration should be considered in adult patients with young-onset parkinsonism with or without the eye-of-the-tiger sign. The exact diagnosis offers a different management approach and genetic counseling. NBIA is likely under- or misdiagnosed in Hong Kong Chinese.

Racial and geographic disparities with gastrostomy tube placement in dementia and parkinsonian disorders.

INTRODUCTION: Many patients with advanced dementia and Parkinson's disease and related disorders (PDRD) are receiving gastrostomy tube (GT) placement annually, despite its lack of proven benefit for preventing aspiration, enhancing nutrition, or prolonging survival. Given clinical practice variability in the care of people with neurodegenerative disorders, we sought to examine racial and geographic disparities in GT placement for these populations in the United States. METHOD: Data were extracted from a publicly-available national database using diagnostic and procedural codes from 2006 to 2010. GT placement rates and odds ratios were calculated for two groups: PDRD and non-parkinsonian dementia (NPD). RESULTS: In the PDRD group, odds of GT placement were higher among patients coded as Black (OR 1.69, CI 0.80-3.56, p = 0.17) and Asian (OR 2.17, CI 0.70-6.78, p = 0.18) than Whites; although these tendencies did not reach statistical significance. In the NPD group, GT placement among Black patients was significantly more likely (OR 2.88, CI 1.90-4.36, p < 0.001) than their white counterparts, while Asian patients were significantly less likely (OR 0.12, CI 0.02-0.91, p = 0.04). Compared to the Northeast region, there were significantly lower odds of GT placement in the Midwest region (OR 0.37, CI 0.24-0.58, p < 0.001) in the NPD group only. No difference in odds was observed between the sexes in both groups. CONCLUSION: This study showed geographic and racial disparities in GT placement among PDRD and NPD patients. Further studies should aim to clarify best practices for GT placement in PDRD and causes of practice differences within and between PDRD and NPD groups.

Frequency of Parkinsonism and Parkinson Disease in African Americans in the Chicago Community.

BACKGROUND: There is paucity of data about African American (AA) patients with Parkinson's disease (PD) and parkinsonism which may precede PD in older adults. Prior studies suggest that there are lower rates of PD in the AA population, with more cognitive impairment in AA with PD. This study aimed to investigate differences in PD, parkinsonism, and cognition between White and AA populations in 3 longitudinal epidemiologic cohort studies of aging. METHODS: This study examined parkinsonism, PD frequency, and cognition of community-dwelling older individuals in 3 longitudinal epidemiologic cohort studies. Parkinsonism was based on an exam utilizing the modified Unified Parkinson's Disease Rating Scale performed by a nurse. PD was based on self-report, medications used for treatment of PD, and examination findings. Cognition was assessed using 19 performance-based tests that assess 5 cognitive domains. RESULTS: AA participants were less likely to have parkinsonism compared to Whites, even with age and gender differences. Frequency of PD was not significant between groups. AA were more likely to have lower cognitive scores as compared to Whites. AA were less likely to have parkinsonism even with controlling for cognitive differences between groups. CONCLUSIONS: Parkinsonian signs are present among AA in the community at lower rates than in White individuals. Cognitive profiles of AA and Whites with parkinsonism may be different, suggesting differing contributions of pathology to cognitive decline and parkinsonism between groups. Additional research is needed to understand the progression of parkinsonism to PD, as well as to understanding the cognitive differences in AA with parkinsonism.

Genotype-phenotype correlates in Taiwanese patients with early-onset recessive Parkinsonism.

We screened for mutations in the PARKIN, DJ-1, and PINK1 genes in a Taiwanese cohort (68 probands; 58 sporadic and 10 familial) with early-onset parkinsonism (EOP, onset <50 years of age). We identified 9 patients harboring mutations in PARKIN (three compound heterozygous and six single heterozygous carriers), 3 patients with heterozygous PINK1 mutations (including two novel substitutions M341I and P209A), and no DJ-1 mutations. Our frequencies of PARKIN (two allele mutation, 4.4%; single allele, 8.8%) and PINK1 (single heterozygous, 4.4%) mutations in Taiwanese-Chinese are similar to those in Caucasian and other Asian EOP patients. Although the role of heterozygosity of recessive genes in EOP remains to be resolved, molecular analysis and functional imaging will play a decisive role in differential diagnosis and determined therapeutic strategy.

A population-based study of parkinsonism in an Amish community.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder with unknown cause. Genetic mutations account for a minority of cases but the role of environmental factors is unclear. METHODS: We performed a population-based screening for PD in subjects in an Amish community over age 60. PD was diagnosed using standard clinical criteria and the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3). Community prevalence was calculated. We constructed a community pedigree and calculated kinship coefficients, a measure of relatedness between 2 subjects, for every pair of subjects in diagnostic categories: clinically definite PD, UPDRS3 score >9, Mini-Mental State Exam (MMSE) score <25, and normal. RESULTS: Of 262 eligible subjects, 213 agreed to participate, 15 had PD, 43 had MMSE <25, 73 had UPDRS3 >9. The prevalence of PD was 5,703/100,000 with increasing prevalence in every decade of age. Excluding first-degree relatives, normal subjects were more related to each other (0.0102, SD = 0.0266) than subjects with clinically definite PD (0.0054, SD = 0.0100; p = 0.00003), subjects with UPDRS >9 (0.0076, SD = 0.0155; p = 0.00001), and subjects with MMSE <25 (0.0090, SD = 0.0180; p = 0.00003). CONCLUSIONS: PD and parkinsonian signs are common in this population and the prevalence increases with age. The finding that subjects with PD were not more related than normal subjects suggests that environmental factors may contribute to the parkinsonian phenotype in this community.

Pseudohypoparathyroidism with basal ganglia calcification: A case report of rare cause of reversible parkinsonism.

RATIONALE: Parkinsonism can be secondary to many internal diseases, in some certain conditions, it seems that the clinical manifestations of parkinsonism presenting reversible. We report a case of patient with parkinsonism secondary to pseudohypoparathyroidism, who improved markedly after the supplement of serum calcium. PATIENT CONCERNS AND DIAGNOSES: A 52-year-old woman with acute parkinsonism was diagnosed as pseudohypoparathyroidism after the conducting of brain computed tomography, laboratory examinations, and gene detection. The son of the patient was also examined and was diagnosed as pseudohypoparathyroidism, who had ever complained of the history of epilepsy. The clinical manifestations of parkinsonism of the patient was reevaluated after the supplement of serum calcium according to the diagnosis. INTERVENTIONS AND OUTCOMES: The brain computed tomography revealed the basal ganglia calcification of the patient, accompanying by serum hypocalcemia and hyperphosphatemia. Loss of function mutation also confirmed the diagnosis. Five days after the therapy targeting at correction of serum hypocalcemia, the patient improved greatly in dyskinesia. LESSONS: This study reported a patient presenting as acute reversible parkinsonism, who was finally diagnosed as pseudohypoparathyroidism. It indicated us that secondary parkinsonism should be carefully differentiated for its dramatic treatment effect. And the family history of seizures might be an indicator for the consideration of pseudohypoparathyroidism.

Parkinsonism Signs and Symptoms in Agricultural Pesticide Handlers in Washington State.

OBJECTIVES: Examine associations between pesticide exposure and signs or symptoms of parkinsonism. METHODS: Prior to the 2014 pesticide spray season, the authors examined 38 active pesticide handlers aged 35 to 65 (median: 43.5) who participated in the State of Washington's cholinesterase monitoring program in the Yakima Valley, where cholinesterase-inhibiting insecticides are applied in fruit orchards. A movement disorder specialist assessed the workers using the Unified Parkinson's Disease Rating Scale (UPDRS) motor subscore 3 (UPDRS3). Participants also self-reported work and medical histories, including the UPDRS activities of daily living subscore 2 (UPDRS2). The authors explored the relation between these scores and lifetime occupational pesticide exposure while accounting for age. RESULTS: All participants were Hispanic men born in Mexico who had worked in agriculture for 4 to 43 years (median: 21 years, including 11 years applying pesticides, mostly in the United States). Ten participants (26%) reported difficulty with one or more UPDRS2 activities of daily living (maximum = 2), and nine (24%) had a UPDRS3 >0 (maximum = 10). The most common symptom and sign, respectively, were excess saliva (n = 6) and action tremor (n = 5). UPDRS2 and UPDRS3 scores were unrelated to the number of years applying pesticides, but UPDRS3, especially action tremor, was positively associated with living on or by a farm. CONCLUSIONS: Symptoms and signs of parkinsonism were absent to mild in this small sample of active workers who apply cholinesterase-inhibiting insecticides in Washington State, USA. Future studies should be larger and examine older, retired workers with greater cumulative exposure to agricultural pesticides at work and home, including other types of agricultural pesticides.

Acute reversible parkinsonism in a diabetic-uremic patient.

Acute movement disorders with basal ganglia lesions have been recently described in diabetic-uremic patients of Asian descent. The process is often reversible, with a favourable clinical outcome. Metabolic (i.e. uremic toxins) and microangiopathic changes have been suggested to be involved in its pathophysiology, even though racial and/or genetic factors might play a role too. In this report, we present a Caucasian diabetic patient with a long-lasting mild uremia in which acute parkinsonism occurred after a steep and unexpected increase of the serum creatinine. The follow-up demonstrated a significant improvement of the neurological signs and symptoms, the creatinine level lowered close to the premorbid levels, and after several months the patient had fully recovered. Our case history suggests that this unusual clinical syndrome is most probably not restricted to Asian patients. Because its potentially favourable outcome, it should be regularly included in the differential diagnosis of acute movement disorders.

RAB39B gene mutations are not linked to familial Parkinson's disease in China.

Recently, RAB39B mutations were reported to be a causative factor in patients with Parkinson's disease (PD). To validate the role of RAB39B in familial PD, a total of 195 subjects consisting of 108 PD families with autosomal-dominant (AD) inheritance and 87 PD families with autosomal-recessive (AR) inheritance in the Chinese Han population from mainland China were included in this study. We did not identify any variants in the coding region or the exon-intron boundaries of the gene by Sanger sequencing method in the DNA samples of 180 patients (100 with AD and 80 with AR). Furthermore, we did not find any variants in the RAB39B gene when Whole-exome sequencing (WES) was applied to DNA samples from 15 patients (8 with AD and 7 with AR) for further genetic analysis. Additionally, when quantitative real-time PCR was used to exclude large rearrangement variants in these patients, we found no dosage mutations in RAB39B gene. Our results suggest that RAB39B mutation is very rare in familial PD and may not be a major cause of familial PD in the Chinese Han Population.

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 Parkinson's 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.

EIF4G1 R1205H and VPS35 D620N mutations are rare in Parkinson's disease from South Africa.

The R1205H mutation in the eukaryotic translation initiation factor 4G1 (EIF4G1) gene and the D620N mutation in the vacuolar protein sorting 35 (VPS35) gene were recently found in patients with autosomal dominant or sporadic forms of Parkinson's disease (PD). In the present study, 418 South African PD patients and 528 control subjects of diverse ethnicities were screened using the KASP (Kompetitive Allele Specific PCR) genotyping assay. The mutations were not found in our study, suggesting that they are not a common cause of PD in South African patients. Further studies are needed on the frequency of these 2 mutations in other sub-Saharan African populations.

Racial and socioeconomic disparities in parkinsonism.

OBJECTIVE: To assess potential racial and socioeconomic disparities in patients with parkinsonism treated at a tertiary Movement Disorders Center. METHODS: Patients with parkinsonism were evaluated for demographics (age, race, annual income, and educational level), medical comorbidities, medication regimen, disability (Older Americans Resources and Services subscale), presence of Parkinson disease, and disease severity (Unified Parkinson Disease Rating Scale). Disability and disease severity measures were compared by race, income, and educational level using analysis of variance for continuous variables and χ(2) tests for dichotomous variables. RESULTS: The sample included 1159 patients with parkinsonism (93.4% white, 6.1% African American, 61.2% who earned more than $50,000 annually, 62.7% who completed college, and 79.2% with a diagnosis of Parkinson disease). Cross-sectional analyses by race, income, and educational level showed greater disability and disease severity in African American compared with white patients (African American vs white Older Americans Resources and Services subscale total score, 29.8 vs 25.3, P = .005; Unified Parkinson's Disease Rating Scale total score, 53.0 vs 42.8; P < .001). African Americans were less likely to be prescribed dopaminergic medications, particularly newer agents (African Americans 20.6% vs whites: 41.1%; P = .01). Lower income and lower educational level were independently associated with greater disease severity and disability (P < .003). CONCLUSION: Racial and socioeconomic disparities exist among patients with parkinsonism being treated at a tertiary Movement Disorders Center. African Americans and those with lower socioeconomic status have greater disease severity and disability than whites. These disparities may be because of problems in diagnosis, access to care, physician referrals, and patient attitudes regarding the appropriate threshold for seeking treatment at a specialized center. Understanding and correction of these disparities may improve outcomes.

Brain volumes in Guam dementia vs Parkinson dementia complex vs aging Chamorro adults.

We sought to determine if Chamorro individuals with a family history of Guam dementia (GD) or Parkinson dementia complex (PDC) exhibit presymptomatic brain MRI changes. Sixty-six Chamorro subjects had neurocognitive assessment and volumetric MRI. MRI brain volumes differed between diagnostic groups (GD, PDC, control) and according to family history. Chamorros with a family history of PDC or dementia may have increased brain atrophy, suggesting a hereditary susceptibility to neurodegenerative disorders.

Prevalence of dementia in Chamorros on Guam: relationship to age, gender, education, and APOE.

OBJECTIVES: To estimate the prevalence of dementia and its clinical subtypes among Chamorros on Guam aged 65 years or older and to examine associations with age, gender, education, and APOE genotype. BACKGROUND: Chamorros, the indigenous people of Guam, had a high incidence of ALS and parkinsonism-dementia complex (PDC), in the 1950s. Over the next 50 years, ALS incidence declined markedly, but PDC only slightly. The prevalence of late life dementia in Chamorros and its relationship to ALS/PDC are unknown. METHODS: Island-wide population-based survey of Chamorros aged 65 years or older as of January 1, 2003. Two-stage assessment: cognitive and motor screening, followed by neurologic and psychometric evaluation. Data were reviewed at consensus conference to make clinical diagnoses. RESULTS: Of 2,789 Chamorros aged 65 years or older, 73% were enrolled; 27% declined participation, died before contact or screening, or moved off Guam. The point prevalence of all-cause dementia on February 1, 2004, was 12.2%. Prevalence data for subtypes were as follows: Guam dementia (clinically equivalent to AD), 8.8%; PDC, 1.5%; pure vascular dementia, 1.3%; other, 0.6%. The prevalence of dementia rose exponentially with age. Low education was significantly associated with dementia, but gender was not. There was a trend toward higher PDC prevalence among men. The APOE epsilon4 allele was not associated with dementia. CONCLUSIONS: The prevalence of dementia among elderly Chamorros is relatively high. Guam dementia is the most common diagnosis and exceeds parkinsonism-dementia complex. Age and low education are strongly associated with dementia, but gender and APOE epsilon4 are not. Incidence studies will allow risk factors for dementia to be clarified.

Cycad exposure and risk of dementia, MCI, and PDC in the Chamorro population of Guam.

OBJECTIVE: To study cycad-derived products as possible risk factors for dementia, mild cognitive impairment (MCI), and parkinsonism-dementia complex (PDC) on Guam. METHODS: Complete risk factor data from in-person interviews of 166 cases of Guam dementia, 50 cases of amnestic MCI, and 21 cases of PDC were compared with 1,581 controls in the base population regarding exposure to cycad-derived products from a traditional food (fadang), consumption of fruit bats, and use of cycad-derived topical medicine. RESULTS: Adjusted odds ratios (ORs) and 95% CIs for picking, processing, and eating fadang in young adulthood ranged from 1.42 (1.05 to 1.91) to 2.87 (1.48 to 5.56) and were consistently elevated and significant across all three diagnostic outcomes. Associations independent of exposure in young adulthood were for picking (OR 0.78, 95% CI 0.64 to 0.96) and processing (OR 0.77, 95% CI 0.63 to 0.94) fadang in childhood with Guam dementia. Men showed stronger and more consistent relations across exposure groups in young adulthood compared with women. No associations were found for consumption of fruit bats or exposure to cycad used as a topical medicine for any of the outcomes. Estimated adjusted population attributable risks suggest that exposure to eating fadang in young adulthood incurred the highest attributable risk percent. CONCLUSIONS: Environmental lifestyle and diet may contribute to the etiology of neurodegenerative diseases in the native population of Guam.

Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism.

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.

Parkin disease in a Brazilian kindred: Manifesting heterozygotes and clinical follow-up over 10 years.

We report on a large Brazilian kindred with young-onset parkinsonism due to either a homozygous or heterozygous mutation in parkin. A total of 6 members were affected: 5 were homozygous and 1 heterozygous for a deletion in exon 4. Two other heterozygotes also had extrapyramidal signs. All affected subjects showed characteristic features of parkin disease with foot dystonia and an excellent response to levodopa complicated by motor fluctuations and dyskinesia within 3 years of therapy. Careful clinical follow-up over 10 years showed the phenotype was similar in all the homozygotes with asymmetrical limb bradykinesia and early walking difficulties. Some acceleration of disability was observed in some of the cases as they entered the third decade of illness, but dementia was absent.

Parkinsonism, FXTAS, and FMR1 premutations.

The presence of late-onset neurological symptoms in male carriers of premutation expansions of the fragile X mental retardation 1 (FMR1) gene has been described recently. One of the clinical symptoms in this fragile X-associated tremor/ataxia syndrome (FXTAS) is parkinsonism. To test the possible association between expanded FMR1 alleles and Parkinson's disease (PD), we determined the size of the FMR1 CGG repeat in 414 male cases of clinically diagnosed parkinsonism, the majority of whom had PD. None of our patients had expanded FMR1 repeats within the premutation range (55-200 CGG repeats). Five patients (1.2%) carry intermediate-size alleles (41-54 CGG repeats). Expansions within the FMR1 gene are not associated with PD in our study.

Mutation analysis of the parkin gene in Russian families with autosomal recessive juvenile parkinsonism.

Autosomal recessive juvenile parkinsonism (AR-JP) is a form of hereditary parkinsonism characterized by variable clinical presentations and caused by mutations in a novel gene, parkin, on chromosome 6q25.2-27. Until now, no Russian cases of parkin-associated AR-JP have been reported on. We recruited 16 patients from 11 Russian families with dopa-responsive movement disorders according to the following criteria: 1) family history compatible with autosomal recessive inheritance; 2) onset of symptoms at A). The majority of our parkin-associated cases were characterized by early-onset dopa-responsive parkinsonism with benign course and slow progression (5 patients from two families have been followed for as long as 18-36 years), and 1 patient had a phenotype of dopa-responsive dystonia. This first description of Russian patients with AR-JP and molecularly proven parkin mutations confirms the widespread occurrence of this polymorphic hereditary extrapyramidal disorder.