Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders.

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Genetic Polymorphisms in the HMGCR Gene and Associations with Cognitive Decline in Parkinson's Disease Patients.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor and non-motor symptoms including cognitive impairment and dementia. The etiopathogenesis of PD, as well as its protective and susceptibility factors, are still elusive. 3-Hydroxy-3-methyglutaryl coenzyme A reductase (HMGCR) is an enzyme regulating cholesterol synthesis. Single-nucleotide polymorphisms (SNPs) in the gene coding HMGCR have recently been correlated with the risk of Alzheimer's disease. Alternative splicing of exon 13 of the HMGCR transcript and its strongly associated HMGCR haplotype 7 (H7: rs17244841, rs3846662, rs17238540) may downregulate protein activity and cholesterol synthesis, with lower low-density lipoprotein cholesterol (LDL) levels associated with PD that may affect cognitive abilities. We genotyped three SNPs in the H7 HMGCR gene in 306 PD patients divided into three groups-without cognitive decline, with mild cognitive impairment (MCI), and with PD dementia-and in 242 healthy participants. A correlation between the rs17238540 genotype and PD susceptibility as well as a minor association between rs3846662 and cognitive status in PD patients was observed; however, the two-sided analysis of these groups did not reveal any significance. We observed a statistically significant elevated high-density lipoprotein cholesterol (HDL) plasma level in the minor allele carriers of rs17238540 and rs17244841 among PD patients. This study should be replicated in a larger population.

Ultrasonographically measured atrophy of vagus nerve in Parkinson's Disease: clinical and pathogenetic insights plus systematic review and meta-analysis.

INTRODUCTION: According to the current Parkinson's Disease (PD) pathogenesis hypotheses, the vagus nerve (VN) is essential for disease development. It has been identified as a main entry point for misfolded α-synuclein to the central nervous system, and surgical vagotomy appears to limit disease progress both in animal models and in humans. A recent approach tried to assess VN size in PD patients via neck ultrasonography, but the clinical value of this method is yet to be established. STATE OF THE ART: A systematic search of the MEDLINE, Scopus, and Web of Science databases was conducted, and 12 case- -control studies were included. Meta-analysis revealed a modest reduction in VN size in PD (effect size - 0.79 SD (95%CI [-1.34, -0.25] p = 0.004)). The atrophy was more pronounced on the right side, and the nerve was smaller in females. In PD patients, VN reduction correlated with cardiac parasympathetic function decline and with advances in motor ratings. The discrimination potential for PD diagnosis, and any association with other non-motor domains, remains unclear. CLINICAL IMPLICATIONS: VN atrophy in PD could be detected by ultrasound imaging. However, the clinical significance of this phenomenon has yet to be clarified. Size reduction is not readily apparent and is individually variable. However, it may be considered a promising means to improve early PD diagnosis and the recognition of autonomic dysfunction. FUTURE DIRECTIONS: With more extensive research, VN sonography could provide useful evidence regarding disease origins. Imaging should be performed together with a profound clinical assessment and biomarker testing to establish the role to be played by this method in future practice.

Reflexive and voluntary saccadic eye movements as biomarker of Huntington's Disease.

INTRODUCTION: Subtle abnormalities in the preclinical stage of Huntington's Disease (HD) can be detected using saccadic eye movement assessment reflecting disease progression. This study was aimed to evaluate abnormalities in saccade parameters in asymptomatic carriers and symptomatic HD patients at various stages of HD. MATERIAL AND METHODS: The study enrolled 104 participants, including 14 asymptomatic carriers of HTT mutations, 44 symptomatic HD patients, and 46 control subjects. HD severity was measured using the Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) and Total Functional Capacity Scale (TFC). The evaluation of rapid eye movements (reflexive saccades, anti-saccades, memory-guided saccades) was carried out using 'Saccadometer Research'. RESULTS: Measures of reflexive and volitional saccades did not differ between the asymptomatic carriers and controls. Significant latency prolongation and increased physiological variability of latency times, as well as higher error rates among HD patients, were found in all saccade tasks (p < 0.001) compared to the controls. Abnormalities in saccade parameters were more pronounced in the advanced stages of the disease. Latency of saccades and error rate of volitional saccades correlated with the UHDRS-TMS and TFC scores. CONCLUSIONS: The saccade parameters in asymptomatic HD carriers with a long time to disease development were similar to those in the control group. Saccade abnormalities appeared in symptomatic patients at the beginning of the disease, and correlated with HD severity.

Tools and criteria to select patients with advanced Parkinson's disease for device-aided therapies: a narrative review.

This article provides an overview of the various screening and selection tools which have been developed over the past 25 years to identify patients with Parkinson's disease (PD) possibly eligible for device-aided therapies (DATs). For the available screening tools, we describe the target therapies (subtypes of DAT), development methods, validation data, and their use in clinical practice. In addition, the historical background and potential utility of these screening tools are discussed. The challenges in developing and validating these tools are also addressed, taking into account the differences in population, the local health care organization, and resource availability.

Hyperkinetic movement disorders following SARS-CoV-2 infection and vaccination - an update.

The aim of this review was to summarise current knowledge regarding hyperkinetic movement disorders related to SARS-CoV-2 infection and vaccination in terms of phenomenology, epidemiology, pathogenesis and treatment. After a thorough review of the PubMed and Google Scholar databases (2020-2022), we identified myoclonus and ataxia sometimes accompanied by opsoclonus (AMS) as the two most frequent COVID-19 sequelae, with chorea, tremor and dystonia being very rare. The pathogenesis seems to be variable, but in the majority of AMS cases it was autoimmunological, with good response and recovery after corticosteroids or intravenous immunoglobulins infusions. Vaccination may be complicated by hyperkinetic movement disorders (e.g. tremor, dystonia), but this is very rare. Patients with Deep Brain Simulation depletion should not be postponed due to lockdowns as this may result in fatal outcomes.

Incidence and characteristics of post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease mainly affecting the respiratory system; however, a significant prevalence of neurological symptoms has been noted. OBJECTIVES: To investigate the incidence and characteristics of post-COVID-19 parkinsonism and to study dyskinesia related to COVID-19 vaccines. MATERIAL AND METHODS: The MEDLINE, PubMed, Scopus, and Web of Science databases were searched for all manuscripts relevant to post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines. Subsequently, we extracted and analysed data from the manuscripts in a structured manner. RESULTS: We found 24 patients with post-COVID-19 parkinsonism, with a mean onset age of 58 years after a mean of 30 days from the COVID-19 onset. Akinetic-rigid (n = 11) and mixed (n = 6) subtypes were the most common. Asymmetry was present in 13/15 patients. Brain MRI was unremarkable in 11/19, whereas dopaminergic system imaging was abnormal in 8/8 patients. Responsiveness to dopaminergic treatment was observed in 12/15 patients. Four patients improved after immunomodulatory therapy. Comorbidities were present in 9/24, encephalopathy symptoms in 11/24, and loss of smell in 9/13 patients. Most patients (n = 14) suffered serious COVID-19- related complications and three were treated with haloperidol. Parkinsonism improved (n = 5) or resolved (n = 4) during the follow-up. Five patients, with a mean age of 52, developed dyskinesia at a mean of 25 hours after receiving the COVID-19 mRNA vaccines. One patient had a history of neuropsychiatric symptoms and developed functional dyskinesia of the tongue. Four patients had a previous history of Parkinson's Disease (PD) with a mean duration of 10 years and developed dyskinesia and dystonia, which resolved (n = 2) or improved (n = 2) during the follow-up. CONCLUSIONS: Post-COVID-19 parkinsonism is a very rare complication, and it is likely that this is an umbrella syndrome that includes many different etiologies. Dyskinesia due to COVID-19 vaccines is exceedingly rare and probably has the same pathophysiological basis as in other conditions with exacerbation of PD symptoms.

Acute/subacutae demyelinating polyneuropathy in Parkinson's Disease patients on levodopa-carbidopa intestinal gel therapy: systematic review with new case report.

Polyneuropathy (PNP) is a known complication of levodopa-carbidopa intestinal gel (LCIG) therapy of advanced Parkinson's Disease (PD). The overall prevalence of PNP in PD is estimated to be 42.1% (as shown in a review by Romagnolo et al. 2018), and the most common type is chronic axonal polyneuropathy. There is a group of acute/subacute onset demyelinating polyneuropathies, which is far less common, although it seems to be an important factor leading to the rapid discontinuation of LCIG treatment. In this systematic review, we present data on demyelinating polyneuropathy with acute/subacute onset; we identified nine papers including prospective assessments and case reports, with detailed information on 15 patients. In all patients, despite treatment with corticosteroids, intravenous immunoglobulins (IVIG) or plasma exchange (PE), the LCIG therapy was terminated. We also present a case of subacute demyelinating polyneuropathy with effective treatment and continuation of LCIG therapy.

First families with spinocerebellar ataxia type 7 in Poland.

INTRODUCTION: We present the first two Polish families diagnosed with spinocerebellar ataxia type 7 (SCA7) and draw attention to cardiac involvement as a new potential manifestation of this disease. MATERIAL AND METHODS: Two well-documented kindreds are presented. RESULTS: The proband from Family 1 presented aged 54 years with vision worsening followed by progressive imbalance. Brain MRI demonstrated cerebellar atrophy. Genetic testing confirmed CAG repeat expansion (42/10) in ATXN7 gene. The proband from Family 2 developed imbalance at age 20, followed by progressive deterioration of vision. Brain MRI revealed cerebellar atrophy. Additionally, she developed chronic congestive heart failure and, at age 38, had cardiomyopathy with an ejection fraction of 20% and significant mitral and tricuspid regurgitation. Genetic analysis found abnormal CAG expansion in the ATXN7 (46/10). CONCLUSIONS AND CLINICAL IMPLICATIONS: Vision loss due to pigmentary retinal degeneration is the distinguishing feature of SCA7 and often the initial manifestation. Although SCA7 is one of the most common SCAs in Sweden, it has never been reported in neighbouring Poland. Until now, cardiac abnormalities have only been described in infantile-onset SCA7 with large CAG repeats. The observed cardiac involvement in Family 2 may be coincidental, albeit a new possible manifestation of SCA7 cannot be excluded.

Expanding the phenotype of DNAJC30-associated Leigh syndrome.

Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.