Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes.

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.

The role of clinical and neuroimaging features in the diagnosis of CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study. For each patient, demographic and clinical data were collected. MRI images were centrally analysed for the presence of lacunar infarcts, microbleeds, temporal lobe involvement, global atrophy and white matter hyperintensities. RESULTS: 128 patients (mean age 56.3 ± 12.4 years) were included. A NOTCH3 mutation was found in 12.5% of them. A family history of stroke, the presence of dementia and external capsule lesions on MRI were the only features significantly associated with the diagnosis of CADASIL. Although thalamic, temporal pole gliosis and severe white matter hyperintensities were less specific for CADASIL diagnosis, the combination of a number of these factors together with familial history for stroke result in a higher positive predictive value and specificity. CONCLUSIONS: A careful familial history collection and neuroradiological assessment can identify patients in whom NOTCH3 genetic testing has a higher yield.

Clinical Pregenetic Screening for Stroke Monogenic Diseases: Results From Lombardia GENS Registry.

BACKGROUND AND PURPOSE: Lombardia GENS is a multicentre prospective study aimed at diagnosing 5 single-gene disorders associated with stroke (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Fabry disease, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes], hereditary cerebral amyloid angiopathy, and Marfan syndrome) by applying diagnostic algorithms specific for each clinically suspected disease METHODS: We enrolled a consecutive series of patients with ischemic or hemorrhagic stroke or transient ischemic attack admitted in stroke units in the Lombardia region participating in the project. Patients were defined as probable when presenting with stroke or transient ischemic attack of unknown etiopathogenic causes, or in the presence of <3 conventional vascular risk factors or young age at onset, or positive familial history or of specific clinical features. Patients fulfilling diagnostic algorithms specific for each monogenic disease (suspected) were referred for genetic analysis. RESULTS: In 209 patients (57.4±14.7 years), the application of the disease-specific algorithm identified 227 patients with possible monogenic disease. Genetic testing identified pathogenic mutations in 7% of these cases. Familial history of stroke was the only significant specific feature that distinguished mutated patients from nonmutated ones. The presence of cerebrovascular risk factors did not exclude a genetic disease. CONCLUSIONS: In patients prescreened using a clinical algorithm for monogenic disorders, we identified monogenic causes of events in 7% of patients in comparison to the 1% to 5% prevalence reported in previous series.

Intensive rehabilitation treatment in early Parkinson's disease: a randomized pilot study with a 2-year follow-up.

BACKGROUND: Although physical exercise improves motor aspects of Parkinson's disease (PD), it is not clear whether it may also have a neuroprotective effect. Objective. In this 2-year follow-up study, we determined whether intensive exercise in the early stages of the disease slows down PD progression. METHODS: Forty newly diagnosed patients with PD were treated with rasagiline and randomly assigned to 2 groups: MIRT Group (two 28-day multidisciplinary intensive rehabilitation treatments [MIRT], at 1-year interval) and Control Group (only drug). In both groups, Unified Parkinson's Disease Rating Scale Section II (UPDRS II), UPDRS III, 6-minute walking test (6MWT), Timed Up-and-Go test (TUG); PD Disability Scale (PDDS), and l-dopa equivalents were assessed at baseline (T0), 6 months (T1), 1 year (T2), 18 months (T3), and 2 years (T4) later. RESULTS: Over 2 years, UPDRS II, UPDRS III, TUG, and PDDS differentially progressed in the 2 groups: In the MIRT Group, all scores at T4 were better than at T0 (all Ps < .03). No changes were noted in the Control Group. l-dopa equivalent dosages increased significantly only in the Control Group (P = .0015), with a decrease in the percentages of patients in monotherapy (T1 40%; T2, T3, and T4 20%). In the MIRT Group, the percentages of such patients remained higher (T1 and T2 100%; T3 89%; T4 75%). CONCLUSIONS: These results suggest that MIRT might slow down the progression of motor decay, it might delay the need for increasing drug treatment, and thus, it might have a neuroprotective effect.

Intensive rehabilitation increases BDNF serum levels in parkinsonian patients: a randomized study.

BACKGROUND: Exercise may decrease the risk of Parkinson's disease (PD) in humans and reduce PD symptoms in animal models. The beneficial effects have been linked to increased levels of neurotrophic factors. OBJECTIVE: We examined whether intensive rehabilitation treatment reduces motor disability in patients in the early stages of PD and increases brain-derived neurotrophic factor (BDNF) serum levels. METHODS: Thirty participants in the early stages of PD treated with rasagiline were randomly assigned to 3 hours of rehabilitation treatment that included aerobic exercise for 28 days (Group 1) or to not therapy (control; Group 2). BDNF serum levels were assessed at time T0 (baseline, before treatment), T1 (10 days), T2 (20 days), and T3 (28 days). At T0 and T3, we assessed the Unified Parkinson's Disease Rating Scale (UPDRS) III in both groups, as well as the UPDRS II and total, Berg Balance Scale, and 6-minute walking test only in Group 1. RESULTS: BDNF levels significantly increased at T1 in Group 1, an increase that was maintained throughout the treatment period. At T3 compared to T0, UPDRS III scores significantly improved in Group 1 along with scores for UPDRS II, total, Berg Balance Scale, and 6-minute walking test. CONCLUSIONS: Intensive rehabilitation treatment increases the BDNF levels and improves PD signs in patients in the early stages of the disease. These results are in line with studies on animal models of PD and healthy subjects.

Short- and long-term efficacy of intensive rehabilitation treatment on balance and gait in parkinsonian patients: a preliminary study with a 1-year followup.

Parkinson's disease (PD) is a neurodegenerative disease in which gait and balance disturbances are relevant symptoms that respond poorly to pharmacological treatment. The aim of this study was to investigate whether a 4-week inpatient multidisciplinary intensive rehabilitation treatment (MIRT) is effective in improving balance and gait and whether improvements persist at a one-year followup. We studied 20 PD inpatients (stage 3 Hoehn-Yahr) who underwent a MIRT. Outcome measures were UPDRS items for balance (30), falls (13), and walk (29), Berg Balance Scale, six-minute walking test, Timed Up and Go Test, and Comfortable-Fast gait speeds. Patients were evaluated at admission, at the end of the 4-week treatment, and at a 1-year followup. Pharmacological therapy was unchanged during MIRT and follow-up. All outcome measures improved significantly at the end of treatment. At 1-year follow-up control, UPDRS walk and Comfortable-Fast gait speeds still maintained better values with respect to admission (P = 0.009, P = 0.03, and P = 0.02, resp.), while the remaining scales did not differ significantly. Our results demonstrate that the MIRT was effective in improving balance and gait and that the improvement in gait performances was partially maintained also after 1 year.

Effectiveness of intensive inpatient rehabilitation treatment on disease progression in parkinsonian patients: a randomized controlled trial with 1-year follow-up.

BACKGROUND: Rehabilitation treatments have acute beneficial effects in Parkinson's disease (PD) patients, but whether the effects persist over time is unclear. OBJECTIVE: To assess whether an intensive rehabilitation treatment (IRT) is effective in improving motor performance compared with a control group in a 12-month follow-up, to investigate whether a second cycle administered after 1 year has the same efficacy as the first treatment, and to determine whether IRT reduces the need for increasing levodopa dosage. METHODS: A total of 50 PD patients were randomly assigned to 2 groups; 25 participants had 4 weeks of inpatient physical therapy that included treadmill and stabilometric platform training. At discharge, these patients were invited to continue doing the learned exercises. After 12 months, the same treatment was repeated. The control group of 25 patients received only pharmacological treatment and was invited to practice generic physical exercise at home. The rating scales used for the clinical evaluation were the Unified Parkinson's Disease Rating Scale Sections II and III (UPDRS II and III) and total (UPDRS tot). RESULTS: The authors found that the beneficial effects of IRT persisted over time. A second rehabilitation cycle administered after 1 year was as effective as the first treatment. At the end of the study, daily medication dosage was reduced in treated patients, whereas it was significantly increased in control patients. CONCLUSION: These findings suggest that the natural worsening of symptoms associated with PD can be effectively counteracted by a properly designed IRT.

Rehabilitation in Parkinson's disease: assessing the outcome using objective metabolic measurements.

Objective measurements to assess the efficacy of rehabilitation treatment in Parkinson's disease, suitable to be carried out routinely in the clinical setting, are lacking. Metabolic parameters, reflecting the recruitment and co-ordination of muscle fibers, might be simple instrumental measurements suitable for use as outcome markers. Twenty parkinsonian patients underwent a 4-week rehabilitation treatment. Functional evaluation was based on Unified Parkinson's Disease Rating Scale Motor Section (UPDRS III), Berg's scale, 6-minute walking test (6MWT), and the metabolic data recorded during the 6MWT namely the active energy expenditure (AEE), the kinetics of the energy consumption curve, and the peak value of energy consumption. Both rating scales and gait improved significantly (UPDRS III decreased by 32%, Berg increased by 21% and the 6MWT increased by 17%). We observed significant improvements also in metabolic measurements (35, 18, and 15 improvement in the kinetics of the energy consumption, AEE, and peak value of energy consumption, respectively). Hence, the rehabilitation protocol improved functional characteristics of the patients and these improvements were clearly reflected also by the metabolic measurements. The improvement in clinical scores corresponded with an increase in energy consumption during the 6MWT, indicating greater speed in the recruitment of motor units and of a capacity to maintain this recruitment over time.

Rehabilitation treatment of gait in patients with Parkinson's disease with freezing: a comparison between two physical therapy protocols using visual and auditory cues with or without treadmill training.

Freezing is a disabling symptom in patients with Parkinson's disease. We investigated the effectiveness of a new rehabilitation strategy based on treadmill training associated with auditory and visual cues. Forty Parkinsonian patients with freezing were randomly assigned to two groups: Group 1 underwent a rehabilitation program based on treadmill training associated with auditory and visual cues, while Group 2 followed a rehabilitation protocol using cues and not associated with treadmill. Functional evaluation was based on the Unified Parkinson's Disease Rating Scale Motor Section (UPDRS III), Freezing of Gait Questionnaire (FOGQ), 6-minute walking test (6MWT), gait speed, and stride cycle. Patients in both the groups had significant improvements in all variables considered by the end of the rehabilitation program (all P = 0.0001). Patients treated with the protocol including treadmill, had more improvement than patients in Group 2 in most functional indicators (P = 0.007, P = 0.0004, P = 0.0126, and P = 0.0263 for FOGQ, 6MWT, gait speed, stride cycle, respectively). The most striking result was obtained for 6MWT, with a mean increase of 130 m in Group 1 compared with 57 m in Group 2. Our results suggest that treadmill training associated with auditory and visual cues might give better results than more conventional treatments. Treadmill training probably acts as a supplementary external cue.

Mirtazapine in the treatment of essential tremor: an open-label, observer-blind study.

INTRODUCTION: Essential tremor (ET) is the most common movement disorder in the adult population. At present ET treatment shows limited efficacy, particularly in patients with severe and disabling symptoms. This study evaluates the clinical efficacy of mirtazapine in an untreated ET patient population. MATERIALS AND METHODS: 30 ET patients (female/male = 19/11; average age = 71.4 +/- 8.3 years) were examined by clinical criteria, electromyographic (EMG), and apomorphine tests to study the cortical silent period. The patients were all treated with mirtazapine 30 mg daily. RESULTS: Mirtazapine proved to be a good control agent for tremor symptomatology in 23/27 patients (85%) who completed 1 month of treatment, with a marked reduction of tremor; the benefit was maintained during the 12-month follow-up. No significant variation in EMG parameters was observed aside from two prevalent and distinct frequencies of tremors (5-6 Hz and 7-8 Hz) and a group of selected patients whose cortical silent period (SP) was markedly reduced. There were no clinical differences between the two subgroups. All apomorphine-tested patients showed an SP with no significant modifications. CONCLUSIONS: Mirtazapine proved to be an efficacious drug treatment for tremor symptoms in patients suffering from ET. It had limited side effects and excellent overall tolerability, could be used as daily monotherapy, and did not interfere with any of the many other medications being taken simultaneously by the patients.