ALS Regional Variants (Brachial Amyotrophic Diplegia and Amyotrophic Leg Diplegia): Still A Diagnostic Challenge in Neurology.

PURPOSE: We illustrate three patients with regional amyotrophic lateral sclerosis (ALS) variants and hope to improve accuracy in diagnosis for this scarce group of diseases. CASE REPORT: Amyotrophic lateral sclerosis (ALS) represents a broad spectrum of acquired and inherited neurodegenerative conditions involving the upper and motor neurons. Typical ALS remains a clinical diagnosis that is not hard to diagnose. Still, when it comes to atypical forms of ALS, the physicians may face some difficulties differentiating between atypical forms of ALS and other neurological diseases, such as multifocal motor neuropathy, chronic inflammatory demyelinating polyneuropathy, and spinal muscular atrophy. Both brachial amyotrophic diplegia (BAD) and leg amyotrophic diplegia (LAD) are considered regional variants of ALS. We are here to report two cases of BAD and one case of LAD. All these 3 cases showed progression of the disease after longitudinal follow- up for approximately two years. However, after two years, their disease progressions were slow and confined to their 'regions' of upper or lower limbs. CONCLUSION: BAD and LAD are unique regional variants of ALS with a significantly better prognosis than typical ALS. The phenotypic characteristics of regional ALS variants must be recognized when physicians are to tailor advice on disease progression, disease outcome, drug therapy, and end-of-life planning for patients with ALS or ALS variants.

Case-control study of hypertension and Parkinson's disease.

We evaluate the association of hypertension with PD in an Asian population and performed a meta-analysis on similar studies to address the effect of hypertension on PD risk. A matched case-control study involving 1342 Chinese subjects (671 PD and 671 age and gender-matched controls (with a mean age of 63.9 ± 9.7 and 63.5 ± 9.8 years, and identical proportion of gender distribution) was conducted. Hypertension increases PD risk by 1.9 times [OR 1.86 (1.46-2.38)]. The literature search identified 618 studies initially; however, only three matched case-control studies (all in Caucasians) met the inclusion criteria for meta-analysis. Overall analysis showed that hypertension decreases PD risk by 0.2 times [OR 0.80 (0.66-0.96)]. Hypertension increases PD risk by 1.9 times in our Asian population. However, a meta-analysis comprising of Caucasian populations showed a protective effect of hypertension suggesting that ethnic differences or other genetic or environmental factors may contribute to the divergent observation. Early diagnosis and treatment of hypertension may potentially reduce the risk of PD, at least in our population.

Association of NOTCH2NLC Repeat Expansions With Parkinson Disease.

Importance: The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. Objective: To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. Design, Setting, and Participants: This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. Main Outcomes and Measures: Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. Results: A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P < .001). None of the patients with PD were carriers of known PD-associated genes. Ten patients with PD carried a GGC expansion of between 41 and 64 repeats (1% of patients with sporadic PD; mean [SD], 49.4 [9.2] repeats). The other 3 patients carried GGC repeats of 79 or more units, 2 with 122 and 79 repeats, respectively, exhibited typical parkinsonism and were responsive to small dosages of levodopa over many years, with no clinical or imaging features of NIID. The other patient with PD, who had 130 repeats, only developed cognitive impairment before death. Within the GGC expansions, there was no GGA interruptions (mean [SD] GGA percentage in the 3 patients with PD vs patients with NIID, 0% vs 12% [9%]), and the frequency of AGC interruptions was 3 times higher in these patients with PD than patients with NIID (mean [SD], 25% [12%] vs 8% [8%]). Conclusions and Relevance: This study demonstrated that individuals with sporadic PD who carried pathogenic NOTCH2NLC GGC repeat expansions can present with typical parkinsonism, requiring only low dosages of levodopa, without displaying other clinical or imaging features of NIID even after several years of follow-up. None of the patients with PD had GGA interruptions within their GGC expansions, and the frequency of AGC interruptions was much higher than that of patients with NIID. The functional significance of a higher moderate repeat expansion in patients with PD compared with healthy controls needs to be further investigated.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

High-density electromyographic data during isometric contractions of the ankle joint in children with cerebral palsy pre and post BoNT-A treatment.

Understanding the underlying mechanisms leading to progressive muscle pathologies in spastic Cerebral Palsy remains a challenging field of research. Furthermore, Botulinum Neurotoxin-A (BoNT-A) is a frequent intervention to treat spasticity in CP but its effects on neuromuscular properties are not yet fully explored. High-density Electromyographic (HD-EMG) data have been collected before and after BoNT-A injections from children aged 5-15 years during isometric contractions of the ankle joint together with torque output, clinical assessments and demographic details. Data collected from a total of 13 children with and 29 children without spastic CP allow for between-group comparisons and are made available using Mendeley Data (https://doi.org/10.17632/3sbptrk54c.2 and https://doi.org/10.17632/3b98g5fyff.1).

Genes and Nonmotor Symptoms in Parkinson's Disease.

Published data on genetic risk factors of nonmotor symptoms (NMS) are relatively lacking since the first mutation responsible for Parkinson's disease (PD) being reported in 1996. This chapter provides a concise summary of genetic links to common individual NMS such as cognitive impairment, depression, psychosis, olfactory dysfunction, pain, and sleep disorders. Although some genetic variants such as apolipoprotein E and glucocerebrosidase demonstrate consistent links with certain NMS, it is difficult to draw definitive conclusions. A concerted effort involving standardized protocol in multiple centers and multiethnic groups will be useful to further investigate the association. With the help of high-throughput genomic techniques, more causative genes and novel genes will be discovered in the future and this will contribute further to the understanding of genetic susceptibility of NMS in PD.