Objective
Peripheral neuropathy (PN) is thought to be coincidental in patients with idiopathic Parkinson disease (IPD). We sought to examine the prevalence of PN in a population of IPD patients and a ...potential relationship to levodopa use and fasting methylmalonic acid (MMA) levels.
Methods
In a prospective cohort study, IPD patients randomly selected from a comprehensive database were compared to control subjects regarding the presence and severity of PN using clinical and electrophysiological measures. IPD severity was determined using the Unified Parkinson's Disease Rating Scale (UPDRS). We determined the relation of levodopa use with serum levels of cobalamin, MMA, and homocysteine (Hcy). We also explored the association between presence and severity of PN and age, duration of IPD, cumulative levodopa dosing, cobalamin, MMA, and Hcy levels.
Results
Fifty‐eight randomly selected IPD patients were compared to 58 age‐ and sex‐matched controls. PN was present in 55% of IPD patients and 9% of controls. Patients with IPD had greater prevalence of PN and fasting MMA/Hcy levels than controls. IPD patients with PN were older and exhibited higher UPDRS scores, fasting MMA/Hcy levels, and cumulative levodopa exposure. PN severity in IPD subjects positively correlated with both levodopa exposure and MMA levels.
Interpretation
IPD patients have a higher prevalence of PN than controls. Although causality is not established, levodopa exposure is associated with MMA elevation and sensorimotor neuropathy in IPD patients. Cobalamin replacement concurrent with levodopa therapy should be considered to protect against development of PN in IPD patients. ANN NEUROL 2010;67:28–36
Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. ...Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 SPG76). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.
Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with ...autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T p.Thr703Met) and one from the Netherlands (c.563A>C p.Asn188Thr). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.
Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective treatment for generalized dystonia. Its role in the management of other types of dystonia is uncertain. ...Therefore we performed a prospective, single-blind, multicentre study assessing the efficacy and safety of bilateral GPi-DBS in 10 patients with severe, chronic, medication-resistant cervical dystonia. Two blinded neurologists assessed patients before surgery and at 6 and 12 months post-operatively using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). The primary outcome measure was the severity subscore (range 0–30, higher scores indicating greater impairment). Secondary outcomes included disability (0 to 30), pain (0 to 40) subscores and total scores of the TWSTRS, Short Form-36 and Beck depression inventory. Swallowing and neuropsychological assessment were also performed at baseline and 12 months. One-way repeated measures analysis of variance was used to analyse the data. The TWSTRS severity score improved from a mean (SD) of 14.7 (4.2) before surgery to 8.4 (4.4) at 12 months post-operatively (P = 0.003). The disability and pain scores improved from 14.9 (3.8) and 26.6 (3.6) before surgery, to 5.4 (7.0) and 9.2 (13.1) at 12 months, respectively (both P < 0.001). General health and physical functioning as well as depression scores improved significantly. Complications were mild and reversible in four patients. Some changes in neuropsychological tests were observed, although these did not impact daily life or employment. Our results support the efficacy and safety of GPi-DBS for the treatment of patients with severe and prolonged cervical dystonia who have failed medical management.
To improve our understanding of sex differences in the clinical characteristics of Parkinson's Disease, we sought to examine differences in the clinical features and disease severity of men and women ...with early treated Parkinson's Disease (PD) enrolled in a large-scale clinical trial.
Analysis was performed of baseline data from the National Institutes of Health Exploratory Trials in Parkinson's Disease (NET-PD) Long-term Study-1, a randomized, multi-center, double-blind, placebo-controlled study of 10 grams of oral creatine/day in individuals with early, treated PD. We compared mean age at symptom onset, age at PD diagnosis, and age at randomization between men and women using t-test statistics. Sex differences in clinical features were evaluated, including: symptoms at diagnosis (motor) and symptoms at randomization (motor, non-motor, and daily functioning).
1,741 participants were enrolled (62.5% male). No differences were detected in mean age at PD onset, age at PD diagnosis, age at randomization, motor symptoms, or daily functioning between men and women. Differences in non-motor symptoms were observed, with women demonstrating better performance compared to men on SCOPA-COG (Z = 5.064, p<0.0001) and Symbol Digit Modality measures (Z = 5.221, p<0.0001).
Overall, men and women did not demonstrate differences in clinical motor features early in the course of PD. However, the differences observed in non-motor cognitive symptoms suggests further assessment of the influence of sex on non-motor symptoms in later stages of PD is warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional ...outcomes for patients with HSP.
We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics. The main outcome measure for a subset of the cohort (n = 48) was the Spastic Paraplegia Rating Scale. We also used the SPATAX-EUROSPA disability stage (disability score) to assess disability (n = 65).
A total of 526 patients were identified with HSP across the country, and 150 patients had a confirmed genetic diagnosis. Mutations were identified in 15 different genes; the most common were
(SPG4, 48%),
(SPG3A, 16%),
(8%),
(7%), and
(SPG8, 5%). The diagnosis of SPG4 was associated with older age at symptom onset (
= 0.0017). SPG4 and SPG3A were less associated with learning disabilities compared to other subtypes of HSP, and SPG11 was strongly associated with progressive cognitive deficits (odds ratio 87.75, 95% confidence interval 14.04-548.24,
< 0.0001). SPG3A was associated with better functional outcomes compared to other HSP subtypes (
= 0.04) on multivariate analysis. The strongest predictor of significant disability was abnormal brain MRI (
= 0.014).
The most important predictors of disability in our HSP cohort were
mutations and abnormal brain MRI. Accurate molecular characterization of well-phenotyped cohorts and international collaboration are essential to establish the natural history of these rare neurodegenerative disorders.
This study explored the viability and efficacy of integrating cadence-matched, salient music into a walking intervention for patients with Parkinson's disease (PD). Twenty-two people with PD were ...randomised to a control (CTRL, n=11) or experimental (MUSIC, n=11) group. MUSIC subjects walked with an individualised music playlist three times a week for the intervention period. Playlists were designed to meet subject's musical preferences. In addition, the tempo of the music closely matched (±10–15 bpm) the subject's preferred cadence. CTRL subjects continued with their regular activities during the intervention. The effects of training accompanied by “walking songs” were evaluated using objective measures of gait score. The MUSIC group improved gait velocity, stride time, cadence, and motor symptom severity following the intervention. This is the first study to demonstrate that music listening can be safely implemented amongst PD patients during home exercise.
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