Gastrointestinal disorders are one of the most significant non-motor problems affecting people with Parkinson disease (PD). Pathogenetically, the gastrointestinal tract has been proposed to be the initial site of pathological changes in PD. Intestinal inflammation and alterations in the gut microbiota may contribute to initiation and progression of pathology in PD. However, the mechanisms underlying this “gut-brain” axis in PD remain unclear. PD patients can display a large variety of gastrointestinal symptoms, leading to reduced quality of life and psychological distress. Gastrointestinal disorders can also limit patients’ response to medications, and consequently negatively impact on neurological outcomes. Despite an increasing research focus, gastrointestinal disorders in PD remain poorly understood and their clinical management often suboptimal. This review summarises our understanding of the relevance of the “gut-brain” axis to the pathogenesis of PD, discusses the impact of gastrointestinal disorders in patients with PD, and provides clinicians with practical guidance to their management.
A BS TRACT: Myoclonus-dystonia is a clinical syndrome characterized by a typical childhood onset of myoclonic jerks and dystonia involving the neck, trunk, and upper limbs. Psychiatric symptomatology, namely, alcohol dependence and phobic and obsessive-compulsive disorder, is also part of the clinical picture. Zonisamide has demonstrated effectiveness at reducing both myoclonus and dystonia, and deep brain stimulation seems to be an effective and long-lasting therapeutic option for medication-refractory cases. In a subset of patients, myoclonus-dystonia is associated with pathogenic variants in the epsilon-sarcoglycan gene, located on chromosome 7q21, and up to now, more than 100 different pathogenic variants of the epsilon-sarcoglycan gene have been described. In a few families with a clinical phenotype resembling myoclonus-dystonia associated with distinct clinical features, variants have been identified in genes involved in novel pathways such as calcium channel regulation and neurodevelopment. Because of phenotypic similarities with epsilon-sarcoglycan gene-related myoclonus-dystonia, these conditions can be collectively classified as "myoclonusdystonia syndromes." In the present article, we present myoclonus-dystonia caused by epsilon-sarcoglycan gene mutations, with a focus on genetics and underlying disease mechanisms. Second, we review those conditions falling within the spectrum of myoclonus-dystonia syndromes, highlighting their genetic background and involved pathways. Finally, we critically discuss the normal and pathological function of the epsilon-sarcoglycan gene and its product, suggesting a role in the stabilization of the dopaminergic membrane via regulation of calcium homeostasis and in the neurodevelopmental process involving the cerebello-thalamo-pallido-cortical network.
Variants in the glucocerebrosidase (GBA) gene are the most common genetic risk factor for Parkinson disease (PD). These include pathogenic variants causing Gaucher disease (GD) (divided into “severe,” “mild,” or “complex”—resulting from recombinant alleles—based on the phenotypic effects in GD) and “risk” variants, which are not associated with GD but nevertheless confer increased risk of PD. As a group, GBA-PD patients have more severe motor and nonmotor symptoms, faster disease progression, and reduced survival compared with noncarriers. However, different GBA variants impact variably on clinical phenotype. In the heterozygous state, “complex” and “severe” variants are associated with a more aggressive and rapidly progressive disease. Conversely, “mild” and “risk” variants portend a more benign course. Homozygous or compound heterozygous carriers usually display severe phenotypes, akin to heterozygous “complex” or “severe” variants carriers. This article reviews genotype–phenotype correlations in GBA-PD, focusing on clinical and nonclinical aspects (neuroimaging and biochemical markers), and explores other disease modifiers that deserve consideration in the characterization of these patients.
Importance: The effects of dopaminergic treatment on speech in patients with Parkinson's disease (PD) are often mixed and unclear. The aim of this study was to better elucidate those discrepancies.Methods: Full retrospective data from advanced PD patients before and after an acute levodopa challenge were collected. Acoustic analysis of spontaneous monologue and sustained phonation including several quantitative parameters [i.e., maximum phonation time (MPT); shimmer local dB] as well as the Unified Parkinson's Disease Rating Scale (UPDRS) (total scores, subscores, and items) and the Clinical Dyskinesia Rating Scale (CDRS) were performed in both the defined-OFF and -ON conditions. The primary outcome was the changes of speech parameters after levodopa intake. Secondary outcomes included the analysis of possible correlations of motor features and levodopa-induced dyskinesia (LID) with acoustic speech parameters. Statistical analysis included paired t-test between the ON and OFF data (calculated separately for male and female subgroups) and Pearson correlation between speech and motor data.Results: In 50 PD patients (male: 32; female: 18), levodopa significantly increased the MPT of sustained phonation in female patients (p < 0.01). In the OFF-state, the UPDRS part-III speech item negatively correlated with MPT (p = 0.02), whereas in the ON-state, it correlated positively with the shimmer local dB (p = 0.01), an expression of poorer voice quality. The total CDRS score and axial subscores strongly correlated with the ON-state shimmer local dB (p = 0.01 and p < 0.01, respectively).Conclusions: Our findings emphasize that levodopa has a poor effect on speech acoustic parameters. The intensity and location of LID negatively influenced speech quality.
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