Trans-Spinal Theta Burst Magnetic Stimulation in Parkinson's Disease and Gait Disorders.

BACKGROUND: Gait disorders in patients with Parkinson's disease (PD) can become disabling with disease progression without effective treatment. OBJECTIVES: To investigate the efficacy of intermittent θ burst trans-spinal magnetic stimulation (TsMS) in PD patients with gait and balance disorders. METHODS: This was a randomized, parallel, double-blind, controlled trial. Active or sham TsMS was applied at third thoracic vertebra with 100% of the trans-spinal motor threshold, during 5 consecutive days. Participants were evaluated at baseline, immediately after last session, 1 and 4 weeks after last session. Primary outcome was Total Timed Up and Go (TUG) values comparing active versus sham phases 1 week after intervention. The secondary outcome measurements consisted of motor, gait and balance scales, and questionnaires for quality of life and cognition. RESULTS: Thirty-three patients were included, average age 68.5 (6.4) years in active group and 70.3 (6.3) years in sham group. In active group, Total TUG mean baseline was 107.18 (95% CI, 52.1-116.1), and 1 week after stimulation was 93.0 (95% CI, 50.7-135.3); sham group, Total TUG mean baseline was 101.2 (95% CI, 47.1-155.3) and 1 week after stimulation 75.2 (95% CI 34.0-116.4), P = 0.54. Similarly, intervention had no significant effects on secondary outcome measurements. During stimulation period, five patients presented with mild side effects (three in active group and two in sham group). DISCUSSION: TsMS did not significantly improve gait or balance analysis in patients with PD and gait disorders. The protocol was safe and well tolerated. © 2024 International Parkinson and Movement Disorder Society.

Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.

High prevalence of self-reported non-motor symptoms and lack of correlation with motor severity in adult patients with idiopathic isolated dystonia.

BACKGROUND: Although abnormal movements and postures are the hallmark of dystonia, non-motor symptoms (NMS) are common and negatively affect quality of life. OBJECTIVES: The aim of this study was to screen dystonia patients for NMS and analyze their association with clinical parameters, including motor disability. METHODS: Adult patients with idiopathic isolated dystonia were interviewed and examined. Dystonia severity was evaluated with the Fahn-Marsden Dystonia Rating Scale and the presence of NMS was assessed using a list of 29 complaints. RESULTS: A hundred and two patients (63.7% female) were enrolled. Dystonia began after 20 years of age in 61.8% and was focal or segmental in 82.8% of patients. Only eight patients (7.8%) had no NMS and 59.8% reported more than five. The most prevalent NMS were pain (72.5%) and anxiety (63.7%), followed by difficulty recalling information (44.1%), sadness/anhedonia (41.2%), and difficulty falling asleep (38.2%). No correlation was found between the total number of NMS and dystonia severity (p = 0.18) or regular botulinum toxin use (p = 0.66). The majority of NMS domains correlated with each other. CONCLUSIONS: Our results confirm a high prevalence of NMS among dystonia patients, even in those with mild motor disability. The pathophysiology of NMS in dystonia remains to be completely understood.

FDG-PET Patterns Predict Amyloid Deposition and Clinical Profile in Corticobasal Syndrome.

BACKGROUND: Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. OBJECTIVE: To investigate if individual brain [18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [11 C]Pittsburgh Compound-B (PIB)-PET. METHODS: Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PET-magnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. RESULTS: CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. CONCLUSION: FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition. © 2020 International Parkinson and Movement Disorder Society.

Freezing of gait (FOG) in Parkinson's disease patients-the contribution of Garcin and Melaragno.

Raymond Garcin, professor of neurology in Paris, France, and his Brazilian assistant, Professor Roberto Melaragno described in 1948 the phenomenon defined as "bégaiement de la mise en route du mouvement" in patients with Parkinson's disease. This was one of the first descriptions of freezing of gait (FOG) in the world.

Rescue Subthalamic Deep Brain Stimulation for Refractory Meige Syndrome.

Meige syndrome is a segmental form of dystonia. It is a disabling disease, especially when refractory to treatment with botulinum toxin. A well-established therapeutic option is deep brain stimulation (DBS), and the target in bilateral globus pallidus internus (GPi DBS) demonstrated satisfactory short- and long-term efficacy. However, some patients present minor or suboptimal responses after GPi DBS, and in those cases, rescue DBS may be appropriate. The present case illustrates a good outcome after subthalamic nucleus (STN) and not after GPi DBS (considering that both were well positioned and had adequate programming). The larger dimension of the GPi and its somatotopic organization, with the stimulation outside the "face region," could explain our outcomes.

Loss of presynaptic inhibition for step initiation in parkinsonian individuals with freezing of gait.

KEY POINTS: Individuals with freezing of gait (FoG) due to Parkinson's disease (PD) have small and long anticipatory postural adjustments (APAs) associated with delayed step initiation. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs due to supraspinal dysfunction. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, it may be deficient in freezers during APAs. We show that freezers presented PSI in quiet stance (control task), but they presented loss of PSI (i.e. higher ratio of the conditioned H-reflex relative to the test H-reflex) during APAs before step initiation (functional task), whereas non-freezers and healthy control individuals presented PSI in both the tasks. The loss of PSI in freezers was associated with both small APA amplitudes and FoG severity. We hypothesize that loss of PSI during APAs for step initiation in freezers may be due to FoG. ABSTRACT: Freezing of gait (FoG) in Parkinson's disease involves deficient anticipatory postural adjustments (APAs), resulting in a cessation of step initiation due to supraspinal dysfunction. Individuals with FoG ('freezers') may require functional reorganization of spinal mechanisms to perform APAs. As presynaptic inhibition (PSI) is centrally modulated to allow execution of supraspinal motor commands, here we hypothesized a loss of PSI in freezers during APA for step initiation, which would be associated with FoG severity. Seventy individuals [27 freezers, 22 non-freezers, and 21 age-matched healthy controls (HC)] performed a 'GO'-commanded step initiation task on a force platform under three conditions: (1) without electrical stimulation, (2) test Hoffman reflex (H-reflex) and (3) conditioned H-reflex. They also performed a control task (quiet stance). In the step initiation task, the H-reflexes were evoked on the soleus muscle when the amplitude of the APA exceeded 10-20% of the mean baseline mediolateral force. PSI was quantified by the ratio of the conditioned H-reflex relative to the test H-reflex in both the tasks. Objective assessment of FoG severity (FoG-ratio) was performed. Freezers presented lower PSI levels during quiet stance than non-freezers and HC (P < 0.05). During step initiation, freezers presented loss of PSI and lower APA amplitudes than non-freezers and HC (P < 0.05). Significant correlations were only found for freezers between loss of PSI and FoG-ratio (r = 0.59, P = 0.0005) and loss of PSI and APA amplitude (r = -0.35, P < 0.036). Our findings suggest that loss of PSI for step initiation in freezers may be due to FoG.

A Randomized, Controlled Trial of Exercise for Parkinsonian Individuals With Freezing of Gait.

BACKGROUND: Exercises with motor complexity induce neuroplasticity in individuals with Parkinson's disease (PD), but its effects on freezing of gait are unknown. The objective of this study was to verify if adapted resistance training with instability - exercises with motor complexity will be more effective than traditional motor rehabilitation - exercises without motor complexity in improving freezing-of-gait severity, outcomes linked to freezing of gait, and brain function. METHODS: Freezers were randomized either to the adapted resistance training with instability group (n = 17) or to the active control group (traditional motor rehabilitation, n = 15). Both training groups performed exercises 3 times a week for 12 weeks. The primary outcome was the New Freezing of Gait Questionnaire. Secondary outcomes were freezing of gait ratio (turning task), cognitive inhibition (Stroop-III test), motor signs (Unified Parkinson's Disease Rating Scale part-III [UPDRS-III]), quality of life (PD Questionnaire 39), anticipatory postural adjustment (leg-lifting task) and brain activation during a functional magnetic resonance imaging protocol of simulated anticipatory postural adjustment task. Outcomes were evaluated before and after interventions. RESULTS: Only adapted resistance training with instability improved all the outcomes (P < 0.05). Adapted resistance training with instability was more effective than traditional motor rehabilitation (in improving freezing-of-gait ratio, motor signs, quality of life, anticipatory postural adjustment amplitude, and brain activation; P < 0.05). Our results are clinically relevant because improvement in the New Freezing of Gait Questionnaire (-4.4 points) and UPDRS-III (-7.4 points) scores exceeded the minimally detectable change (traditional motor rehabilitation group data) and the moderate clinically important difference suggested for PD, respectively. The changes in mesencephalic locomotor region activation and in anticipatory postural adjustment amplitude explained the changes in New Freezing of Gait Questionnaire scores and in freezing-of-gait ratio following adapted resistance training with instability, respectively. CONCLUSIONS: Adapted resistance training with instability is able to cause significant clinical improvement and brain plasticity in freezers. © 2020 International Parkinson and Movement Disorder Society.

DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.

OBJECTIVE: DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). METHODS: The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. RESULTS: We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. INTERPRETATION: Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis.

Substantia nigra fractional anisotropy is not a diagnostic biomarker of Parkinson's disease: A diagnostic performance study and meta-analysis.

OBJECTIVES: Our goal was to estimate the diagnostic accuracy of substantia nigra fractional anisotropy (SN-FA) for Parkinson's disease (PD) diagnosis in a sample similar to the clinical setting, including patients with essential tremor (ET) and healthy controls (HC). We also performed a systematic review and meta-analysis to estimate mean change in SN-FA induced by PD and its diagnostic accuracy. METHODS: Our sample consisted of 135 subjects: 72 PD, 21 ET and 42 HC. To address inter-scanner variability, two 3.0-T MRI scans were performed. MRI results of this sample were pooled into a meta-analysis that included 1,432 subjects (806 PD and 626 HC). A bivariate model was used to evaluate diagnostic accuracy measures. RESULTS: In our sample, we did not observe a significant effect of disease on SN-FA and it was uninformative for diagnosis. The results of the meta-analysis estimated a 0.03 decrease in mean SN-FA in PD relative to HC (CI: 0.01-0.05). However, the discriminatory capability of SN-FA to diagnose PD was low: pooled sensitivity and specificity were 72 % (CI: 68-75) and 63 % (CI: 58-70), respectively. There was high heterogeneity between studies (I2 = 91.9 %). CONCLUSIONS: SN-FA cannot be used as an isolated measure to diagnose PD. KEY POINTS: • SN-FA appears insufficiently sensitive and specific to diagnose PD. • Radiologists must be careful when translating mean group results to clinical practice. • Imaging protocol and analysis standardization is necessary for developing reproducible quantitative biomarkers.

Modified Pfeffer Questionnaire for Functional Assessment in Parkinson Disease.

INTRODUCTION: It was proposed to modify the Pfeffer questionnaire (PQ) for functional assessment in patients with Parkinson disease (PD). AIM: To determine the cutoff score for diagnosis of functional impairment in patients with PD by modified PQ (mPQ). METHODS: A total of 110 patients with PD were enrolled into the study, and a neuropsychological test battery was performed to assess their cognitive status. Regarding functional assessment, the mPQ has been applied, and their results were compared to the functional assessment by Informant Questionnaire on Cognitive Decline in the Elderly adapted for use in Brazil (IQCODE-BR). The statistical analysis was accomplished through receiver operating characteristic (ROC) curve with evaluation of the area under the curve, sensitivity, and specificity of the new cutoff point. RESULTS: Eighty-nine patients with PD were evaluated with a mean age of 63.69 ± 9.14 years. Cognitive status categorization was 28.10% as normal, 44.94% as mild cognitive impairment, and 26.96% of patients as dementia associated with PD. The average score on PQ was 3.49 ± 4.79 and on the mPQ 2.56 ± 3.49. In IQCODE-BR, the average score was 6.75 ± 32.72. The ROC curve for the new cutoff point presented 47.4% sensitivity, 88.10% specificity, and 0.757 of area under the curve, with a standard deviation of 0.055 (95% confidence interval: 0.650-0.864). CONCLUSION: 3.5 is proposed as the cutoff point to define functional impairment in patients with PD by mPQ.

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.

BACKGROUND: ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. METHODS: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. RESULTS: The first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. CONCLUSIONS: The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.

Spinal cord stimulation for Parkinson's disease: a systematic review.

Axial symptoms are a late-developing phenomenon in the course of Parkinson's disease (PD) and represent a therapeutic challenge given their poor response to levodopa therapy and deep brain stimulation. Spinal cord stimulation (SCS) may be a new therapeutic approach for the alleviation of levodopa-resistant motor symptoms of PD. Our purpose was to systematically review the effectiveness of SCS for the treatment of motor symptoms of PD and to evaluate the technical and pathophysiological mechanisms that may influence the outcome efficacy of SCS. A comprehensive literature search was conducted using electronic databases for the period from January 1966 through April 2014. The methodology utilized in this work follows a review process derived from evidence-based systematic review and meta-analysis of randomized trials described in the PRISMA statement. Reports examining SCS for the treatment of PD are limited. Eight studies with a total of 24 patients were included in this review. The overall motor score of the Unified Parkinson's Disease Rating Scale in the on/off-stimulation condition remained unchanged in 6 patients and improved in 18 patients after SCS. SCS appears to yield positive results for PD symptoms, especially for impairments in gait function and postural stability. However, evidence is limited and long-term prospective studies will be required to identify the optimal candidates for SCS and the best parameters of stimulation and to fully characterize the effects of stimulation on motor and nonmotor symptoms of PD.

Randomized controlled trial protocol: balance training with rhythmical cues to improve and maintain balance control in Parkinson's disease.

BACKGROUND: Postural instability is a particularly incapacitating disorder, whose loss of motor independence by Parkinson´s Disease (PD) patients marks a significant stage of disease onset. Evidence suggests that deficits in automatic motor control, sensory integration and attention are associated with the lack of balance in PD. Physiotherapy together with medication play an important role in the treatment of this state, although no consensus has been reached on the best treatment modality. The aim of this randomized controlled trial protocol is to evaluate the effects of balance training with rhythmical (BRT), which is a motor program to improve balance associated with rhythmical auditory cues (RACs). This study is ongoing in the stage 1. METHODS AND DESIGN: A total of 150 PD patients at H&Y stages II-III and asymptomatic for depression and dementia are enrolled in a single-blind randomized study. Randomization is achieved via a computer-generated random-sequence table. All patients should also present a fall history. They will be assigned into one of three groups, and their balance and gait will be assessed before and after 10 training sessions, and after 4 and 30 weeks subsequent to the end of the training. The BRT group will receive a motor program to improve balance associated with RACs, the MT group will perform motor training with the same aims as those in the BRT group but without RACs, and the control group (CG) will be trained only in orientations. The exercise program specific to balance is of 5 weeks' duration with two sessions per week, 45 min each, and consists of general physiotherapy exercises. Each session will be divided into five warm-up minutes-30 min for the main part and 10 min for the cool down. The training progresses and intensifies each week depending on the individual's performance. The subjects should be able to execute 10 repetitions of the exercise sequences correctly to progress to the next movement. DISCUSSION: This randomized study protocol will evaluate the effects of a motor program designed to improve balance associated with RACs, and will also assess whether balance training leads to activation of balance reactions at the appropriate time. We hypothesize that if this motor program is maintained long-term, it will prevent falls. TRIAL REGISTRATION: Clinicaltrials.gov NCT02488265 ; Ethics Committee of the University of São Paulo Faculty of Medicine Clinics Hospital 1.102.464.

Correlation between impulsivity and executive function in patients with Parkinson disease experiencing depression and anxiety symptoms.

BACKGROUND: Depression and anxiety are comorbidities often associated with Parkinson disease (PD). Recent studies debate on how affective disorders can influence the cognition of patients with PD. This study sought to investigate how depression and anxiety affect specific executive functions and impulsivity traits in these patients. METHODS: Twenty-eight patients with advanced PD and 28 closely matched healthy volunteers (HV) were assessed for depressive and anxiety symptoms, impulsivity, executive function and control attention and behavioral response. RESULTS: Compared to the HV group, the PD group showed significantly higher perseverative responses and slowness to adapt to changes in environmental stimuli and longer reaction time for inter-stimulus interval change. Depression symptoms were significantly correlated to motor impulsivity score and total Barratt Impulsiveness Scale (BIS -11) score. Moreover, there was also significant correlation between anxiety symptoms and attentional impulsivity score and total BIS-11 score. Correlation analysis between impulsivity and control attention indicated a positive correlation in commission and a negative correlation in reaction time and detectability in the PD group. CONCLUSIONS: The present results suggest that depression and anxiety were highly correlated to impulsivity but not to executive functions changes in these PD patients.

Complex Exercises Improve Cognition in People With Parkinson's Disease and Freezing of Gait.

BACKGROUND: Evidence has suggested that cognitive decline may be a risk factor for freezing of gait (FOG) in Parkinson's disease (PD). Complex and challenging exercises have been suggested as potential rehabilitation strategies to decrease FOG severity and improve cognition; however, it is unknown whether improvement in cognition would explain decreased FOG severity following exercise. OBJECTIVE: In this secondary analysis, we evaluated the effects of the adapted resistance training with instability (ARTI-complex and challenging exercises) compared with traditional motor rehabilitation (TMR-without challenging exercises) on cognitive function in people with FOG of PD. We also verified whether cognitive improvement explains the decrease in FOG previously published. METHODS: Participants were randomized to either the experimental group (ARTI, n = 17) or the active control group (TMR, n = 15). Both training groups exercised 3 times a week for 12 weeks (80-90 minute each session). FOG severity (FOG ratio from inertial sensors during a 360° turning-in-place task), frontal lobe function (Frontal Assessment Battery [FAB]), global cognition (Montreal Cognitive Assessment [MoCA]), and attention and psychomotor speed (Digit Symbol Substitution Test [DSST]) were evaluated before and after interventions. RESULTS: Only the ARTI group improved FAB, MoCA, and DSST scores at posttraining. In addition, ARTI was more effective than TMR in improving FAB scores at posttraining. The changes in FAB scores explained the changes in FOG ratio following ARTI (R2 = .43, P < .01). CONCLUSIONS: This pilot study suggests that ARTI, a complex and challenging training, improves cognition in people with FOG of PD. Improvements in frontal lobe function with ARTI help explain decreased FOG severity.

X-Linked Levodopa-Responsive Parkinsonism-Epilepsy Syndrome: A Novel PGK1 Mutation and Literature Review.

BACKGROUND: Genetic underpinnings in Parkinson's disease (PD) and parkinsonian syndromes are challenging, and recent discoveries regarding their genetic pathways have led to potential gene-specific treatment trials. CASES: We report 3 X-linked levodopa (l-dopa)-responsive parkinsonism-epilepsy syndrome cases due to a hemizygous variant in the phosphoglycerate kinase 1 (PGK1) gene. The likely pathogenic variant NM_000291.4 (PGK1):c.950G > A;p.(Gly317Asp) was identified in a hemizygous state. LITERATURE REVIEW: Only 8 previous cases have linked this phenotype to PGK1, a gene more commonly associated with hemolytic anemia and myopathy. The unusual association of epilepsy, psychiatric symptoms, action tremor, limb dystonia, cognitive symptoms, and l-dopa-responsive parkinsonism must draw attention to PGK1 mutations, especially because this gene is absent from most commercial hereditary parkinsonism panels. CONCLUSIONS: This report aims to shed light on an overlooked gene that causes hereditary parkinsonian syndromes. Further research regarding genetic pathways in PD may provide a better understanding of its pathophysiology and open possibilities for new disease-modifying trials, such as SNCA, LRRK2, PRKN, PINK1, and DJ-1 genes.

Wilson disease: the diagnostic challenge and treatment outcomes in a series of 262 cases.

BACKGROUND: Wilson disease (WD) is an autosomal recessive disorder that leads to organ toxicity due to copper overload. Early diagnosis is complicated by the rarity and diversity of manifestations. OBJECTIVE: To describe the diagnostic features and response to treatment in our cohort of WD patients. METHODS: This was a retrospective analysis of 262 WD patients stratified by clinical presentation, complementary exams, ATP7B genotyping, and response to treatment. RESULTS: Symptoms occurred at an average age of 17.4 (7-49) years, and patients were followed up for an average of 9.6 (0-45) years. Patients presented mainly with hepatic (36.3%), neurologic (34.7%), and neuropsychiatric (8.3%) forms. Other presentations were hematologic, renal, or musculoskeletal, and 16.8% of the patients were asymptomatic. Kayser-Fleischer rings occurred in 78.3% of the patients, hypoceruloplasminemia in 98.3%, and elevated cupruria/24h in 73.0%, with an increase after D-penicillamine in 54.0%. Mutations of the ATP7B gene were detected in 84.4% of alleles. Brain magnetic resonance imaging showed abnormalities in the basal ganglia in 77.7% of patients. D-penicillamine was the first choice in 93.6% of the 245 patients, and 21.1% of these patients were switched due to adverse effects. The second-line therapies were zinc and trientine. The therapeutic response did not differ significantly between the drugs (p = 0.2). Nine patients underwent liver transplantation and 82 died. CONCLUSION: Wilson disease is diagnosed at a late stage, and therapeutic options are limited. In people under 40 years of age with compatible manifestations, WD could be considered earlier in the differential diagnosis. There is a need to include ATP7B genotyping and therapeutic alternatives in clinical practice.

ANTECEDENTES: A doença de Wilson (DW) é um distúrbio autossômico recessivo caracterizado por acúmulo de cobre lesivo aos órgãos. O diagnóstico precoce é dificultado pela raridade e diversidade de apresentações. OBJETIVO: Descrever características ao diagnóstico e resposta ao tratamento em uma coorte de DW. MéTODOS: Análise retrospectiva de 262 casos de DW quanto à apresentação clínica, exames complementares, genotipagem e resposta ao tratamento. RESULTADOS: Os sintomas surgiram em uma média aos 17,4 (7­49) anos, e os pacientes foram acompanhados por uma média de 9,6 (0­45) anos. Os pacientes apresentaram principalmente formas hepáticas (36,3%), neurológicas (34,7%) e neuropsiquiátricas (8,3%). Outras apresentações foram hematológicas, renais e musculoesqueléticas. Apenas 16,8% eram assintomáticos. Anéis de Kayser-Fleischer ocorreram em 78,3% dos pacientes, hipoceruloplasminemia em 98,3%, e cuprúria elevada/24h em 73,0%, com aumento após D-penicilamina em 54,0%. Mutações do gene ATP7B foram detectadas em 84,4% dos alelos pesquisados. A ressonância magnética cerebral mostrou alterações em gânglios da base em 77,7% dos pacientes. O tratamento com D-penicilamina foi a escolha inicial em 93,6% dos 245 casos e foi trocado em 21,1% devido a efeitos adversos. Terapias de segunda linha foram zinco e trientina. A resposta terapêutica não diferiu significativamente entre os medicamentos (p = 0,2). Nove pacientes receberam transplante hepático e 82 faleceram. CONCLUSãO: O diagnóstico da DW ainda ocorre em estágios tardios, e as opções terapêuticas são limitadas. A DW deve ser considerada precocemente no diagnóstico diferencial de pessoas com menos de 40 anos com manifestações compatíveis. É necessário incorporar na prática clínica a genotipagem do ATP7B e alternativas terapêuticas à penicilamina.

Resolution of Wing-Beating Tremor and Magnetic Resonance Imaging Lesions in Wilson's Disease Following Penicillamine.

Background: The wing-beating tremor, characteristic of Wilson's disease (WD), is a disabling symptom that can be resistant to anti-copper and anti-tremor medications. Phenomenology Shown: This video illustrates severe bilateral wing-beating tremor, moderate head and lower limb tremors, mild cervical dystonia, and subtle cerebellar ataxia, with nearly resolution after penicillamine treatment. Educational Value: This case highlights a typical aspect of WD, emphasizing the importance of early detection and treatment, and its correlation with MRI findings. Highlights: This case highlights the typical wing-beating tremor in Wilson's disease and its correlation with the involvement of the dentato-rubro-thalamic pathway. The early diagnosis and initiation of treatment with penicillamine resulted in an excellent clinical and radiological response.