Genetic landscape of ALS in Malta based on a quinquennial analysis.

Genetic risk for amyotrophic lateral sclerosis (ALS) is highly elevated in genetic isolates, like the island population of Malta in the south of Europe, providing a unique opportunity to investigate the genetics of this disease. Here we characterize the clinical phenotype and genetic profile of the largest series of Maltese ALS patients to date identified throughout a 5-year window. Cases and controls underwent neuromuscular assessment and analysis of rare variants in ALS causative or risk genes following whole-genome sequencing. Potentially damaging variants or repeat expansions were identified in more than 45% of all patients. The most commonly affected genes were ALS2, DAO, SETX and SPG11, an infrequent cause of ALS in Europeans. We also confirmed a significant association between ATXN1 intermediate repeats and increased disease risk. Damaging variants in major ALS genes C9orf72, SOD1, TARDBP and FUS were however either absent or rare in Maltese ALS patients. Overall, our study underscores a population that is an outlier within Europe and one that represents a high percentage of genetically explained cases.

Occupation and amyotrophic lateral sclerosis risk: a case-control study in the isolated island population of Malta.

Objective: Amyotrophic lateral sclerosis (ALS) is a mostly sporadic neurodegenerative disease. The role of environmental factors has been extensively investigated but associations remain controversial. Considering that a substantial proportion of adult life is spent at work, identifying occupations and work-related exposures is considered an effective way to detect factors that increase ALS risk. This process may be further facilitated in population isolates due to environmental and genetic homogeneity. Our study investigated occupations and occupational exposures potentially associated with ALS risk in the isolated island population of Malta, using a case-control study design. Methods: Patients with ALS and randomly identified matched controls (1:1) were recruited throughout a four-year window, from 2017 through 2020. Data on educational level, residence, main occupation, smoking, and alcohol history were collected. Results: We found that compared to controls (44.4%), a higher percentage (73.7%) of ALS patients reported a blue-collar job as their main occupation (OR 2.04, 95% CI 1.2-3.72; p = 0.0072). Through regression analysis, craft and related trades occupations such as carpentry and construction (ISCO-08 major group 7), were found to be positively associated with ALS, with patients in this occupational category found to be more prone to develop bulbar-onset ALS (p = 0.0297). Overall, patients with ALS reported a significantly higher exposure to work-related strenuous physical activity (OR 2.35, 95% CI 1.53-3.59; p = 0.0002). Conclusion: Our findings suggest that manual workers particularly those working in the carpentry and construction industries have an increased ALS risk, possibly due to a history of intense or sustained physical activity.

Genetic analysis of ALS cases in the isolated island population of Malta.

Genetic isolates are compelling tools for mapping genes of inherited disorders. The archipelago of Malta, a sovereign microstate in the south of Europe is home to a geographically and culturally isolated population. Here, we investigate the epidemiology and genetic profile of Maltese patients with amyotrophic lateral sclerosis (ALS), identified throughout a 2-year window. Cases were largely male (66.7%) with a predominant spinal onset of symptoms (70.8%). Disease onset occurred around mid-age (median age: 64 years, men; 59.5 years, female); 12.5% had familial ALS (fALS). Annual incidence rate was 2.48 (95% CI 1.59-3.68) per 100,000 person-years. Male-to-female incidence ratio was 1.93:1. Prevalence was 3.44 (95% CI 2.01-5.52) cases per 100,000 inhabitants on 31st December 2018. Whole-genome sequencing allowed us to determine rare DNA variants that change the protein-coding sequence of ALS-associated genes. Interestingly, the Maltese ALS patient cohort was found to be negative for deleterious variants in C9orf72, SOD1, TARDBP or FUS genes, which are the most commonly mutated ALS genes globally. Nonetheless, ALS-associated repeat expansions were identified in ATXN2 and NIPA1. Variants predicted to be damaging were also detected in ALS2, DAO, DCTN1, ERBB4, SETX, SCFD1 and SPG11. A total of 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci. This warrants further studies to elucidate novel genes that cause ALS in this unique population isolate.

Bilateral painful tic convulsif.

'Painful tic convulsif' (PTC) describes the coexistence of hemifacial spasm and trigeminal neuralgia. In this report, we describe a unique presentation of bilateral PTC in a man with bilateral hemifacial spasm and trigeminal neuralgia secondary to neurovascular conflict of all four cranial nerves. Following failed medical and radiofrequency therapy, microvascular decompression of three of the four involved nerves was performed, where the offending vessels were mobilised and Teflon used to prevent conflict recurrence. He continues to respond to Botox for right hemifacial spasm. Since surgery, he remains pain free bilaterally and spasm free on the left.

Brain Symmetry Index in Healthy and Stroke Patients for Assessment and Prognosis.

Objective. Quantitative neurophysiological signal parameters are of value in predicting motor recovery after stroke. The novel role of EEG-derived brain symmetry index for motor function prognostication in the subacute phase after stroke is explored. Methods. Ten male stroke patients and ten matched healthy controls were recruited. Motor function was first assessed clinically using the MRC score, its derivative Motricity Index, and the Fugl-Meyer assessment score. EEG was subsequently recorded first with subjects at rest and then during hand grasping motions, triggered by visual cues. Brain symmetry index (BSI) was used to identify the differences in EEG-quantified interhemispheric cortical power asymmetry observable in healthy versus cortical and subcortical stroke patients. Subsequently, any correlation between BSI and motor function was explored. Results. BSI was found to be significantly higher in stroke subjects compared to healthy controls (p = 0.023). The difference in BSI was more pronounced in the cortical stroke subgroup (p = 0.016). BSI showed only a mild general decrease on repeated monthly recording. Notably, a statistically significant correlation was observed between early BSI and Fugl-Meyer score later in recovery (p < 0.050). Conclusions. Brain symmetry index is increased in the subacute poststroke phase and correlates with motor function 1-2 months after stroke.

An Adult Case of Acute EBV Cerebellitis.

Acute neurological manifestations of infectious mononucleosis are uncommon and have been predominantly reported in the paediatric population. We report a case of acute Epstein-Barr virus cerebellitis in an adult in whom spontaneous resolution of symptoms and signs occurred after 2 weeks of supportive treatment. An infective cause for an acute cerebellar syndrome in an adult must always be considered in the differential diagnosis when appropriate. LEARNING POINTS: A high index of suspicion is needed in adults who present with a febrile syndrome and cerebellar signs.An acute cerebellar syndrome may be the only manifestation of Epstein-Barr virus infection.In certain cases, conservative management may be sufficient depending on the clinical severity.