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BACKGROUND: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome-wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. OBJECTIVES: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. METHODS: Next-generation sequencing (whole-exome, whole-genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. RESULTS: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7-genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. CONCLUSIONS: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society.
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Parvimonas micra is a gram-positive anaerobic coccus typically found in the human oral cavity, upper respiratory tract and gastrointestinal system. It occasionally causes intra-abdominal abscesses, spondylodiscitis and other infections. There are very few case reports on mycotic aneurysm related to P. micra We describe a rare case of P. micra orbital cellulitis complicated with meningitis, cerebral venous thrombosis and internal carotid artery mycotic aneurysm, which was successfully treated with the combination of endovascular therapy and antibiotics. Additionally, the patient received 6 months of anticoagulation therapy for cerebral venous thrombosis.
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Aneurisma Infectado , Antibacterianos , Celulitis Orbitaria , Humanos , Celulitis Orbitaria/microbiología , Celulitis Orbitaria/complicaciones , Antibacterianos/uso terapéutico , Aneurisma Infectado/complicaciones , Infecciones por Bacterias Grampositivas/complicaciones , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/diagnóstico , Masculino , Firmicutes , Trombosis de la Vena/complicaciones , Trombosis de la Vena/tratamiento farmacológico , Anticoagulantes/uso terapéutico , Trombosis Intracraneal/complicaciones , Trombosis Intracraneal/tratamiento farmacológico , Procedimientos Endovasculares/métodos , FemeninoRESUMEN
A novel homozygous variant in KIFBP was identified in a consanguineous family with four sibs affected by Goldberg-Sphrintzen Syndrome (GOSHS). We report for the first time, early-adulthood-onset progressive ataxia, opthalmoparesis, and hypogonadotropic hypogonadism in GOSHS.
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Ataxia Cerebelosa , Hipogonadismo , Oftalmoplejía , Degeneraciones Espinocerebelosas , Humanos , Adulto , Ataxia Cerebelosa/genética , Hipogonadismo/genética , LinajeRESUMEN
BACKGROUND: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants. OBJECTIVES: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort. METHODS: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes. CONCLUSIONS: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.
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Enfermedad de Parkinson , Humanos , Adulto , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/epidemiología , Pruebas Genéticas , Mutación/genética , Exones , Pueblo Asiatico/genética , Edad de Inicio , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
As the world embarks on mass vaccination against SARS-CoV2 to alleviate the spread of this highly contagious novel coronavirus, there are growing anecdotal reports on immune-related neurological complications following immunisation. Similarly, we encountered 2 cases of central nervous system demyelination at our centre with Comirnaty (BNT162b2), a mRNA-based COVID-19 vaccine. Our first patient had typical clinical-radiological manifestations of acute disseminated encephalomyelitis (ADEM) after his COVID-19 vaccination. This was the sixth reported case to date. Our second patient presented with an unusual complaint of trigeminal neuralgia, with an identifiable demyelinating lesion observed in the pons on neuroimaging. Both cases responded well to immunotherapy. However, larger prospective controlled studies and formal registries are much needed to ascertain a possible relationship between COVID-19 vaccines and acute central nervous system demyelination.
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BACKGROUND: Walking recovery post stroke can be slow and incomplete. Determining effective stroke rehabilitation frequency requires the assessment of neuroplasticity changes. Neurobiological signals from electroencephalogram (EEG) can measure neuroplasticity through incremental changes of these signals after rehabilitation. However, changes seen with a different frequency of rehabilitation require further investigation. It is hypothesized that the association between the incremental changes from EEG signals and the improved functional outcome measure scores are greater in higher rehabilitation frequency, implying enhanced neuroplasticity changes. OBJECTIVE: The purpose of this study is to identify the changes in the neurobiological signals from EEG, to associate these with functional outcome measures scores, and to compare their associations in different therapy frequency for gait rehabilitation among subacute stroke individuals. METHODS: A randomized, single-blinded, controlled study among patients with subacute stroke will be conducted with two groups: an intervention group (IG) and a control group (CG). Each participant in the IG and CG will receive therapy sessions three times a week (high frequency) and once a week (low frequency), respectively, for a total of 12 consecutive weeks. Each session will last for an hour with strengthening, balance, and gait training. The main variables to be assessed are the 6-Minute Walk Test (6MWT), Motor Assessment Scale (MAS), Berg Balance Scale (BBS), Modified Barthel Index (MBI), and quantitative EEG indices in the form of delta to alpha ratio (DAR) and delta-plus-theta to alpha-plus-beta ratio (DTABR). These will be measured at preintervention (R0) and postintervention (R1). Key analyses are to determine the changes in the 6MWT, MAS, BBS, MBI, DAR, and DTABR at R0 and R1 for the CG and IG. The changes in the DAR and DTABR will be analyzed for association with the changes in the 6MWT, MAS, BBS, and MBI to measure neuroplasticity changes for both the CG and IG. RESULTS: We have recruited 18 participants so far. We expect to publish our results in early 2023. CONCLUSIONS: These associations are expected to be positive in both groups, with a higher correlation in the IG compared to the CG, reflecting enhanced neuroplasticity changes and objective evaluation on the dose-response relationship. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/27935.
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INTRODUCTION: The novel Coronavirus Disease 2019 (COVID-19) is an infection caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) which has been spreading rapidly amongst humans and causing a global pandemic. The notorious infection has shown to cause a wide spectrum of neurological syndrome, including autoimmune encephalitis. OBJECTIVE: Here, we systematically review the literature on autoimmune encephalitis that developed in the background of SARS-CoV-2 infections and also the possible pathophysiological mechanisms of auto-immune mediated damage to the nervous system. METHODOLOGY: An exhaustive search was made in Medline/PubMed, Embase, Scopus and other medical databases, and 28 relevant published articles were selected according to the strict inclusion criteria. RESULTS: Autoimmune encephalitis can occur via three possible proposed pathophysiological mechanism and can manifest during or after the acute infection period. It is more common in adult but can also occur in the paediatric patients. There were various spectra of autoantibody panels reported including antineuronal antibody, anti-gangliosides antibody and onconeural antibody. Majority of the patients responded well to the immunomodulating therapy and achieved good recovery. CONCLUSION: In conclusion, SARSCoV-2 infection can induce various spectrum of autoimmune encephalitis. It is a major concern since there is very limited long-term study on the topic. Hence, this review aims to elucidate on the potential long-term complication of SARS-CoV-2 infection and hopefully to improve the management and prognosis of COVID-19.
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COVID-19 , Encefalitis , Enfermedades del Sistema Nervioso , Adulto , Niño , Encefalitis/complicaciones , Humanos , Enfermedades del Sistema Nervioso/epidemiología , Pandemias , SARS-CoV-2RESUMEN
GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.
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Glucosilceramidasa , Enfermedad de Parkinson , Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Glucosilceramidasa/genética , Humanos , Mutación , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/genéticaRESUMEN
Optic nerve demyelination is one of the clinical features of combined central and peripheral demyelination (CCPD), an entity with heterogenous immunopathogenesis and clinical characteristics, overlapping between multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Of interest, earlier studies among patients with CIDP prior to discovery of antibodies against paranodal protein neurofascin 155 (anti-NF 155) also reported optic nerve dysfunction. We aimed to evaluate optic nerve demyelination among anti-NF 155 CIDP patients. We studied 2 patients with anti-NF 155 CIDP using visual-evoked potentials (VEP) and optical coherence tomography (OCT). Both patients had distal acquired demyelinating symmetric (DADS) subtype CIDP. Other common features were prominent sensory ataxia, hand tremors, significantly elevated cerebral spinal fluid protein, high titre anti-NF 155 antibodies and poor response to corticosteroid and intravenous immunoglobulin (IVIg). No central nervous system neuroradiological abnormality detected. Both had normal visual acuity and colour vision, but one had subclinical right relative afferent pupillary defect (RAPD). VEP of both showed bilateral prolonged P100 latencies. OCT for patient with RAPD demonstrated moderate to severe retinal nerve fibre layer (RNFL) thinning. Identification of optic nerve demyelination among subclinical CIDP with anti-NF 155 antibodies expanded the spectrum of demyelination within the subset of CCPD.
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NMDAR encephalitis may be more common among non-Caucasians. A population-based study was conducted to estimate its incidence in Sabah, Malaysia, where the population consists predominantly of Austronesians (84%), and with a Chinese minority. Registries of NMDAR encephalitis at neurology referral centers were reviewed for case ascertainment. The annual incidence was 2.29/million (Austronesians: 2.56/million, Chinese: 1.31/million). Among pediatric population, the incidence was: Austronesians: 3.63/million, Chinese: 2.59/million. Our study demonstrated a higher incidence of NMDAR encephalitis among Austronesians than the predominantly Caucasian populations in Europe (0.5-0.9/million; pediatric: 0.7-1.5/million). Racial and genetic factors may contribute to risks of developing NMDAR encephalitis.
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Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Encefalitis Antirreceptor N-Metil-D-Aspartato/epidemiología , Pueblo Asiatico , Vigilancia de la Población , Población Blanca , Adolescente , Encefalitis Antirreceptor N-Metil-D-Aspartato/genética , Pueblo Asiatico/genética , Niño , Femenino , Humanos , Incidencia , Malasia/epidemiología , Masculino , Vigilancia de la Población/métodos , Población Blanca/genética , Adulto JovenRESUMEN
The rs9958947 single nucleotide polymorphism (SNP) resides in the promoter region of the lipase G (LIPG) gene. This newly discovered SNP increases the risk of stroke in some Asian populations, including Chinese and Korean populations. Stroke is one of the top 5 leading causes of death in Malaysia, so it is of interest to investigate whether this SNP is associated with stroke risk in the Malaysian population. Therefore, this study investigates this association through a case-control study on a Malaysian population along with a comprehensive meta-analysis. Genotyping of LIPG rs9958947 SNP was performed for 241 Malaysians using real-time polymerase chain reaction, and the odds ratios (OR) with 95% confidence intervals were calculated. The meta-analysis was conducted using the software Comprehensive Meta-Analysis ver. 2.2.064. A p value less than 0.05 was considered statistically significant. We observed that the mean age of Malaysian stroke patients was less than that of stroke patients from Korea and China. The meta-analysis showed that the LIPG rs9958947 SNP was significantly associated with an increased risk of ischemic stroke in Asian populations (dominant (CC vs. CT + TT): OR = 1.45, p < 0.001; allelic (C vs. T): OR = 1.21, p = 0.001; heterozygous (CC vs. CT): OR = 1.47, p < 0.001, and homozygous (CC vs. TT): OR = 1.46, p = 0.047). However, there was no evidence to associate this SNP with stroke risk in the Malaysian population (overall CC vs. CT: OR = 1.04, CC vs. TT: OR = 1.25, CC vs. CT + TT, OR = 1.13; all p > 0.05) and blood lipid levels.
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Lipasa/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Malasia , Masculino , Persona de Mediana EdadRESUMEN
Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory disorder of the nervous system which can be potentially debilitating. Its prevalence is estimated to be around 0.5-10 per 100,000 population with predilection towards Asians and females. It can be diagnosed based on core clinical characteristics, serum aquaporin antibodies and neuroimaging features. It is important to pick up the diagnosis of NMOSD as the treatment is different from other demyelinating disease. Here, we illustrate a case of NMOSD presented with intractable vomiting.
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Neuromielitis Óptica , Acuaporina 4 , Autoanticuerpos , Femenino , Humanos , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/diagnóstico por imagen , Vómitos/etiologíaRESUMEN
Thymoma is associated with a wide spectrum of autoimmune paraneoplastic syndromes, though it is uncommon for multiple paraneoplastic syndromes to be present in a single individual. We report a rare case of an elderly gentleman who was found to have thymoma-associated myasthenia gravis and LGI1-encephalitis with myokymia, who presented with nephrotic syndrome (minimal change glomerulopathy) after thymectomy. The latter two paraneoplastic syndromes had manifested when prednisolone was tapered down to low dose. This case serves to remind neurologists that apart from paraneoplastic neurological manifestations, thymoma may also be associated with renal disease. Nephropathy in myasthenia patients with thymoma should be properly evaluated, as it is treatable with immunotherapy, and it may even occur post-thymectomy.
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Encefalitis/etiología , Miastenia Gravis/etiología , Síndrome Nefrótico/etiología , Síndromes Paraneoplásicos/etiología , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Anciano , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas/inmunología , Timectomía , Timoma/cirugía , Neoplasias del Timo/cirugíaRESUMEN
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) occurs worldwide in all ethnicities. Recently, population-based studies have shown that NMOSD is more common among non-White populations. There is scarce data about NMOSD prevalence in South East Asian populations. METHODS: (1) A population-based study was undertaken to estimate NMOSD prevalence in the multi-ethnic Penang Island, Malaysia, comprising Chinese, Malays, and Indians. Medical records of NMOSD patients followed up at the Penang General Hospital (the neurology referral centre in Penang Island) were reviewed. The 2015 diagnostic criteria of the International Panel for NMO Diagnosis were used for case ascertainment. (2) A review of population-based prevalence studies of NMOSD worldwide was carried out. PubMed and conference proceedings were searched for such studies. RESULTS: Of the 28 NMOSD patients, 14 were residents of Penang Island on prevalence day [13 (93%) Chinese and one (7%) Malay]. All 14 patients were females and aquaporin 4 seropositive. The prevalence of NMOSD in Penang Island was 1.99/100,000 population; according to ethnicities, the prevalence in Chinese was significantly higher than in Malays (3.31/100,000 vs 0.43/100,000, respectively, p = 0.0195). CONCLUSION: Based on our and other population-based studies, among Asians, East Asian origin populations (Chinese and Japanese) appear to have higher NMOSD prevalence than other Asian ethnic groups. Worldwide, Blacks seem to have the highest NMOSD prevalence. More studies in different geographical regions and ethnic groups will be useful to further inform about potential factors in NMOSD pathogenesis.