The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations

Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS

Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey

Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved

Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

OBJECTIVE: To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS: Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS: Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS: This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Sleep, Sleep Structure and Sleep Disorders in a Cohort of Patients Affected by ALS

Amyotrophic Lateral Sclerosis is a neurodegenerative disease, mostly due to progressive loss of motor neurons, with poor prognosis. Although motor involvement is predominant, other systems may be altered, and, among these, also sleep. The aim of this study is to evaluate sleep in a cohort of patients affected by ALS. We consecutively enrolled 48 patients, whom underwent to clinical and instrumental evaluation, including a full night video-PSG. They were compared to 15 control subjects. Respect to controls, patients had fragmented sleep, with poor sleep efficiency, higher amount of WASO and N1 sleep stage, and lower percentage of N2 and REM sleep stages, despite they perceived a sleep of good quality. Moreover, 33% of patients underwent video-PSG was diagnosed with OSAS, and 14, 28% with nocturnal respiratory insufficiency. Start NIV early is known to raise QOL, prolong life expectancy, and improve compliance to subsequent 24h NIV and tracheal ventilation. Furthermore, sleep of bad quality is a cardiovascular risk factor. In conclusion, in patients with ALS, instrumental assessment of sleep in early stages of the disease should be mandatory

Functional brain connectivity analysis in amyotrophic lateral sclerosis: an EEG source-space study

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, which affects domains outside of the motor system. Recent findings have suggested that scalp electroencephalography (EEG) analysis may represent a useful tool for the monitoring of the disease. Here, we investigated functional connectivity in a set of ALS patients using source-reconstructed EEG time series comparing the results to age-matched healthy controls. Source based functional connectivity was estimated using a measure of amplitude envelope correlation (AEC) after performing orthogonalisation procedure in the time domain. The results of this study show that alpha band functional connectivity at source level discloses different patterns of inter-regional synchronization in ALS patients compared to healthy subjects. These findings suggest that ALS induces a strong frequency-specific reduction of functional connectivity patterns and that these changes are not limited to motor connections

Isolated rapid eye movement sleep without atonia in amyotrophic lateral sclerosis

Objective: The aim of this study was to quantitatively analyze, with the most recent and advanced tools, the presence of periodic leg movements during sleep (PLMS) and/or rapid eye movement (REM) sleep without atonia (RSWA), in a group of patients with amyotrophic lateral sclerosis (ALS), and to assess their eventual correlation with the clinical severity of the disease. Methods: Twenty-nine ALS patients were enrolled (mean age 63.6 years) along with 28 age-matched "normal" controls (mean age 63.8 years). Functional impairment due to ALS was evaluated using the ALS-Functional Rating Scale-Revised (ALS-FRS) and the ALS severity scale (ALSSS). Full video polysomnographic night recordings were obtained, and PLMS were analyzed by considering their number/hour of sleep and periodicity index, the distribution of intermovement intervals, and the distribution during the night. The characteristics of the chin electromyogram (EMG) amplitude during REM sleep were analyzed by means of the automatic atonia index and the number of chin EMG activations (movements). Results: The ALS patients showed longer sleep latency than the controls, together with an increase in number of stage shifts, increased sleep stage 1, and decreased sleep stage 2. None of the leg PLMS parameters were different between the ALS patients and controls. The REM atonia index was significantly decreased in the ALS patients, and the number of chin movements/hour tended to increase. Both REM atonia index and number of chin movements/hour correlated significantly with the ALS-FRS; REM atonia was higher and chin movements were less in ALS patients with more preserved function (higher scores on the ALS-FRS). Conclusion: Abnormal REM sleep atonia seemed to be a genuine effect of ALS pathology per se and correlated with the clinical severity of the disease. It is unclear if this might constitute the basis of a possible risk for the development of REM sleep behavior disorder or represent a form of isolated RSWA in ALS

Pisa-Like Syndrome Under Baclofen in a Patient With Spastic Hemiparesis due to Ischemic Stroke

In its original description, Pisa syndrome was reported as an iatrogenic dystonia of the trunk caused by neuroleptic drugs. However, sometimes, not dystonic lateral flexion of the trunk is described as Pisa syndrome. These observations support the possibility of a drug-induced lateral flexion of the trunk with clinical presentation similar to Pisa syndrome, although with a different etiology and pathophysiology. Here, we describe the case of a male patient, with a previous ischemic stroke and residual spastic hemiparesis to the right side, who subacutely developed a dramatic lateral flexion of trunk (approximately 45° to the right) a few days after the introduction of Baclofen (5 mg 3 times per day). After the discontinuation of baclofen, a full recovery of the correct posture was obtained. In this respect, our case is paradigmatic: it is drug-induced but not clearly dystonic in its manifestation. Baclofen reduces the spasticity depressing the monosinaptic and polisinaptic reflex in the spinal cord by stimulating Gamma-aminobutyric acid B (GABA-B) receptors, which inhibit the release of excitatory amino acids, glutamate and aspartate. We believe that the definition of Pisa syndrome for these forms, not clearly dystonic, might be not completely appropriate, but they should be defined more correctly as Pisa-like syndromes