Gastrointestinal dysfunction in the synucleinopathies.

Interest in gastrointestinal dysfunction in Parkinson's disease has blossomed over the past 30 years and has generated a wealth of investigation into this non-motor aspect of the disorder, research that has encompassed its pathophysiology, its clinical features, and its impact on quality of life. The question of gastrointestinal dysfunction in the other synucleinopathies has not received nearly as much attention, but information and knowledge are growing. In this review, the current knowledge, controversies, and gaps in our understanding of the pathophysiology of gastrointestinal dysfunction in Parkinson's disease and the other synucleinopathies will be addressed, and extended focus will be directed toward the clinical problems involving saliva management, swallowing, gastric emptying, small intestinal function, and bowel function that are so problematic in these disorders.

Diagnosing Wilson's Disease under the sword of Damocles.

INTRODUCTION: Antos et al. [7] have reported a case of suspected uniparental disomy leading to an initial erroneous diagnosis of Wilson's Disease on the basis of genetic testing. They discuss the usefulness of the 64Cu radioactive copper incorporation test as an often-overlooked diagnostic aid. CLINICAL REFLECTIONS: Wilson's Disease is difficult to diagnose because of its rarity, diverse clinical presentations, and the absence of a single fail-safe diagnostic test. The identification of mutations in the ATP7B gene has been an invaluable aid in the diagnosis, but genetic testing alone is not infallible, and should not be used as the sole diagnostic test in arriving at a diagnosis of Wilson's Disease. CLINICAL IMPLICATIONS: The diagnosis of Wilson's Disease must be based on a combination of findings that includes clinical history, clinical examination, and diagnostic testing. Genetic testing alone is insufficient.

Management of Autonomic Dysfunction in Parkinson's Disease.

Autonomic dysfunction is a frequent and important nonmotor feature of Parkinson's disease (PD). Autonomic dysfunction in PD spans a broad clinical spectrum. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both the patient and the partner. Alterations in sweating and body temperature are not widely recognized, but often are present. The presence of effective treatment for at least some aspects of autonomic dysfunction makes it vitally important that the assessment of autonomic dysfunction be a regular component of the neurologic history and examination for individuals with PD.

Consensus practice recommendations for management of gastrointestinal dysfunction in Parkinson disease.

BACKGROUND: Gastrointestinal (GI) dysfunction is a common non-motor feature of Parkinson disease (PD). GI symptoms may start years before the onset of motor symptoms and impair quality of life. Robust clinical trial data is lacking to guide screening, diagnosis and treatment of GI dysfunction in PD. OBJECTIVE: To develop consensus statements on screening, diagnosis, and treatment of GI dysfunction in PD. METHODS: The application of a modified Delphi panel allowed for the synthesis of expert opinions into clinical statements. Consensus was predefined as a level of agreement of 100 % for each item. Five virtual Delphi rounds were held. Two movement disorders neurologists reviewed the literature on GI dysfunction in PD and developed draft statements based on the literature review. Draft statements were distributed among the panel that included five movement disorder neurologists and two gastroenterologists, both experts in GI dysmotility and its impact on PD symptoms. All members reviewed the statements and references in advance of the virtual meetings. In the virtual meetings, each statement was discussed, edited, and a vote was conducted. If there was not 100 % consensus, further discussions and modifications ensued until there was consensus. RESULTS: Statements were developed for screening, diagnosis, and treatment of common GI symptoms in PD and were organized by anatomic segments: oral cavity and esophagus, stomach, small intestine, and colon and anorectum. CONCLUSIONS: These consensus recommendations offer a practical framework for the diagnosis and treatment of GI dysfunction in PD.

Movement Disorders and the Gut: A Review.

There is a close link between multiple movement disorders and gastrointestinal dysfunction. Gastrointestinal symptoms may precede the development of the neurologic syndrome or may arise following the neurologic presentation. This review will provide an overview of gastrointestinal accompaniments to several well-known as well as lesser known movement disorders. It will also highlight several disorders which may not be considered primary movement disorders but have an overlapping presentation of both gastrointestinal and movement abnormalities.

Gastrointestinal Dysfunction in Parkinson's Disease.

There has been exponential growth in the awareness and understanding of gastrointestinal (GI) dysfunction in Parkinson's disease (PD) over the past 3 decades. The clinical features of GI dysfunction in PD have been clearly identified and innovative research has demonstrated the presence of pathology within the enteric nervous system (ENS) in individuals with PD, leading to suggestions that the GI system may be ground zero for the genesis and the portal of entry of PD pathology, which then ascends via the vagus nerve to the central nervous system (CNS). This theory, as well as the more recent recognition of the association of PD with dysbiosis within the gut microbiota, has been the object of intense study and scrutiny. Since most PD medications are absorbed through the GI system, the need for better understanding of changes within the GI tract that may potentially affect the pattern of response to medications has become evident. In this review, current knowledge of the pathophysiology of changes within the GI tract and the gut microbiome of individuals with PD, including changes that occur with progression of the disease, will be addressed. We focus on common clinical GI problems in PD that can arise from different segments of the GI tract. Relevant diagnostic evaluations and treatment options for each of these problems will be reviewed.

A multinational consensus on dysphagia in Parkinson's disease: screening, diagnosis and prognostic value.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a combination of motor and non-motor dysfunction. Dysphagia is a common symptom in PD, though it is still too frequently underdiagnosed. Consensus is lacking on screening, diagnosis, and prognosis of dysphagia in PD. OBJECTIVE: To systematically review the literature and to define consensus statements on the screening and the diagnosis of dysphagia in PD, as well as on the impact of dysphagia on the prognosis and quality of life (QoL) of PD patients. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or PD conducted a systematic revision of the literature published since January 1990 to February 2021 and reported the results according to PRISMA guidelines. The output of the research was then analyzed and discussed in a consensus conference convened in Pavia, Italy, where the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: Eighty-five papers were used to inform the Panel's statements even though most of them were of Class IV quality. The statements tackled four main areas: (1) screening of dysphagia: timing and tools; (2) diagnosis of dysphagia: clinical and instrumental detection, severity assessment; (3) dysphagia and QoL: impact and assessment; (4) prognostic value of dysphagia; impact on the outcome and role of associated conditions. CONCLUSIONS: The statements elaborated by the Consensus Panel provide a framework to guide the neurologist in the timely detection and accurate diagnosis of dysphagia in PD.

The c.-237_236GA>TT THAP1 sequence variant does not increase risk for primary dystonia.

BACKGROUND: Sequence variants in coding and noncoding regions of THAP1 have been associated with primary dystonia. METHODS: In this study, 1,446 Caucasian subjects with mainly adult-onset primary dystonia and 1,520 controls were genotyped for a variant located in the 5'-untranslated region of THAP1 (c.-237_236GA>TT). RESULTS: Minor allele frequencies were 62/2892 (2.14%) and 55/3040 (1.81%) in subjects with dystonia and controls, respectively (P=0.202). Subgroup analyses by gender and anatomical distribution also failed to attain statistical significance. In addition, there was no effect of the TT variant on expression levels of THAP1 transcript or protein. DISCUSSION: Our findings indicate that the c.-237_236GA>TT THAP1 sequence variant does not increase risk for adult-onset primary dystonia in Caucasians.

Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

Urine levels of the polyglutamine ataxin-3 protein are elevated in patients with spinocerebellar ataxia type 3.

INTRODUCTION: Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. METHODS: We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. RESULTS: PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. CONCLUSION: As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

Consensus on the treatment of dysphagia in Parkinson's disease.

BACKGROUND: Dysphagia is common in Parkinson's disease (PD). The effects of antiparkinsonian drugs on dysphagia are controversial. Several treatments for dysphagia are available but there is no consensus on their efficacy in PD. OBJECTIVE: To conduct a systematic review of the literature and to define consensus statements on the treatment of dysphagia in PD and related nutritional management. METHODS: A multinational group of experts in the field of neurogenic dysphagia and/or Parkinson's disease conducted a systematic evaluation of the literature and reported the results according to PRISMA guidelines. The evidence from the retrieved studies was analyzed and discussed in a consensus conference organized in Pavia, Italy, and the consensus statements were drafted. The final version of statements was subsequently achieved by e-mail consensus. RESULTS: The literature review retrieved 64 papers on treatment and nutrition of patients with PD and dysphagia, mainly of Class IV quality. Based on the literature and expert opinion in cases where the evidence was limited or lacking, 26 statements were developed. CONCLUSIONS: The statements developed by the Consensus panel provide a guidance for a multi-disciplinary treatment of dysphagia in patients with PD, involving neurologists, otorhinolaryngologists, gastroenterologists, phoniatricians, speech-language pathologists, dieticians, and clinical nutritionists.

Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease.

BACKGROUND: Mitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. METHODS: We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. RESULTS: The frequency of affected mothers of the proband with PD (83/167, 49.4%) was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4%) (Odds Ratio 1.22; 95%CI 0.83-1.81). After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. CONCLUSIONS: These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic mDNA mutations, contribute to the risk of familial PD.

Gastrointestinal, urological, and sexual dysfunction in Parkinson's disease.

Recognition has grown regarding the importance of nonmotor dysfunction in the setting of Parkinson's disease. Autonomic involvement, including gastrointestinal, urinary, and sexual dysfunction is frequent and may significantly impair quality of life for affected individuals. Both recognition and attention to appropriate treatment are important for optimum clinical management.

Autonomic Dysfunction in Parkinson's Disease.

Recognition of the importance of nonmotor dysfunction as a component of Parkinson's disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson's disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson's disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained.

Clinical implications of gastric complications on levodopa treatment in Parkinson's disease.

Disorders of the gastrointestinal (GI) tract are common and distressing nonmotor symptoms of Parkinson's disease (PD) that can adversely affect levodopa absorption and lead to OFF periods, also known as motor fluctuations. Gastroparesis, which is primarily defined as delayed gastric emptying (DGE), and Helicobacter pylori infection, which is present with increased frequency in PD, are among the most common and important GI disorders reported in PD that may impair oral levodopa absorption and increase OFF time. Symptoms of gastroparesis include nausea, vomiting, postprandial bloating, fullness, early satiety, abdominal pain, and weight loss. DGE has been reported in a substantial fraction of individuals with PD. Symptoms of H. pylori infection include gastritis and peptic ulcers. Studies have found that DGE and H. pylori infection are correlated with delayed peak levodopa plasma levels and increased incidence of motor fluctuations. Therapeutic strategies devised to minimize the potential that gastric complications will impair oral levodopa absorption and efficacy in PD patients include treatments that circumvent the GI tract, such as apomorphine injection, levodopa intestinal gel delivery, levodopa inhalation powder, and deep brain stimulation. Other strategies aim at improving gastric emptying in PD patients, primarily including prokinetic agents.

Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

High-throughput mutational analysis of TOR1A in primary dystonia.

BACKGROUND: Although the c.904_906delGAG mutation in Exon 5 of TOR1A typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some DeltaGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify TOR1A Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia. METHODS: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known DeltaGAG DYT1 dystonia and 88 subjects with DeltaGAG-negative dystonia. RESULTS: HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A DeltaGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic DeltaGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia. CONCLUSION: First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.

Alpha-synuclein and familial Parkinson's disease.

Whole gene duplications and triplications of alpha-synuclein (SNCA) can cause Parkinson's disease (PD), and variation in the promoter region (Rep1) and 3' region of SNCA has been reported to increase disease susceptibility. Within our cohort, one affected individual from each of 92 multiplex PD families showing the greatest evidence of linkage to the region around SNCA was screened for dosage alterations and sequence changes; no dosage or non-synonymous sequence changes were found. In addition, 737 individuals (from 450 multiplex PD families) that met strict diagnostic criteria for PD and did not harbor a known causative mutation, as well as 359 neurologically normal controls, were genotyped for the Rep1 polymorphism and four SNPs in the 3' region of SNCA. The four SNPs were in high LD (r(2) > 0.95) and were analyzed as a haplotype. The effects of the Rep1 genotype and the 3' haplotype were evaluated using regression models employing only one individual per family. Cases had a 3% higher frequency of the Rep1 263 bp allele compared with controls (OR = 1.54; empirical P-value = 0.02). There was an inverse linear relationship between the number of 263 bp alleles and age of onset (empirical P-value = 0.0004). The 3' haplotype was also associated with disease (OR = 1.29; empirical P-value = 0.01), but not age of onset (P = 0.40). These data suggest that dosage and sequence changes are a rare cause of PD, but variation in the promoter and 3' region of SNCA convey an increased risk for PD.

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.