ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules

Infantile-onset Ascending Hereditary Spastic Paralysis, Juvenile Primary Lateral Sclerosis and Juvenile Amyotrophic Lateral Sclerosis are all motor neuron diseases related to mutations on the ALS2 gene, encoding for a 1657 amino acids protein named Alsin. This ~185 kDa multi-domain protein is ubiquitously expressed in various human tissues, mostly in the brain and the spinal cord. Several investigations have indicated how mutations within Alsin’s structured domains may be responsible for the alteration of Alsin’s native oligomerization state or Alsin’s propensity to interact with protein partners. In this review paper, we propose a description of differences and similarities characterizing the above-mentioned ALS2-related rare neurodegenerative disorders, pointing attention to the effects of ALS2 mutation from molecule to organ and at the system level. Known cases were collected through a literature review and rationalized to deeply elucidate the neurodegenerative clinical outcomes as consequences of ALS2 mutations.

ParaCom An IoT based affordable solution enabling people with limited mobility to interact with machines

There are many people in this world who don’t have the ability to communicate with others due to some unforeseen accident. User’s who are paralyzed and/or suffering from different Motor Neuron Diseases (MND) like Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis etc, by making them more independent. Patients suffering from these diseases are not able to move their arms and legs, lose their body balance and the ability to speak. Here we propose an IoT based communication controller using the concept of Morse Code Technology which controls the smartphone of the user. This paper proposes a solution to give the user ability to communicate to other people using machine as an intermediator. The device will require minimal inputs from the user.

Blenderized Tube Feeding and Enterostomy Tube Occlusions Among Adults with Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis

Adults with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) may develop swallowing difficulties and elect to receive an enterostomy feeding tube for nutrition support. Blenderized tube feeding (BTF) appeals to those interested in a homemade enteral nutrition option, but there are concerns of feeding tube occlusion and limited research on this potential risk. Therefore, our purpose was to determine the frequency of, and risk factors for, feeding tube occlusions among adults with ALS or PLS who use BTF. For this retrospective study, the electronic medical records of tube-fed adults with ALS or PLS who received outpatient care at a provincial ALS clinic during a two-year period were reviewed (n = 651). There were 97 tube-fed patients identified, of which 20 (21%) used BTF. Average duration of BTF use was 11.25 ± 7.5 months. Seven subjects (35%) used BTF exclusively, while 13 (65%) used a combination of BTF and commercial enteral formula. All received BTF by gastrostomy tube, sized 14 to 24 French. BTF administration methods and compliance with water flush recommendations varied. Despite the perceived risk of feeding tube occlusions with blenderized tube feeding, no occlusions were found to have occurred in this study.

Presenilin-1 Mutations Are a Cause of Primary Lateral Sclerosis-Like Syndrome

Background and PurposePrimary lateral sclerosis (PLS) is a progressive upper motor neuron (UMN) disorder. It is debated whether PLS is part of the amyotrophic lateral sclerosis (ALS) spectrum, or a syndrome encompassing different neurodegenerative diseases. Recently, new diagnostic criteria for PLS have been proposed. We describe four patients of two pedigrees, meeting definite PLS criteria and harboring two different mutations in presenilin 1 (PSEN1).MethodsPatients underwent neurological and neuropsychological examination, MRI, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid-related biomarkers, and next-generation sequencing (NGS) testing.ResultsFour patients, aged 25–45 years old, presented with a progressive UMN syndrome meeting clinical criteria of definite PLS. Cognitive symptoms and signs were mild or absent during the first year of the disease but appeared or progressed later in the disease course. Brain MRI showed microbleeds in two siblings, but iron-related hypointensities in the motor cortex were absent. Brain FDG-PET showed variable areas of hypometabolism, including the motor cortex and frontotemporal lobes. Amyloid deposition was confirmed with either cerebrospinal fluid (CSF) or imaging biomarkers. Two heterozygous likely pathogenic mutations in PSEN1 (p.Pro88Leu and p.Leu166Pro) were found in the NGS testing.ConclusionClinically defined PLS is a syndrome encompassing different neurodegenerative diseases. The NGS testing should be part of the diagnostic workup in patients with PLS, at least in those with red flags, such as early-onset, cognitive impairment, and/or family history of neurodegenerative diseases.

SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis

ObjectiveTo assess the association between copy number (CN) variation in the survival motor neuron (SMN) locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of SMN1 and SMN2 CN with MMN, PMA, and PLS disease course.MethodsIn this monocenter study, we used multiplex ligation-dependent probe amplification to determine SMN1 and SMN2 CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for SMN1 and SMN2 CN. We analyzed SMN1 and SMN2 exons 1–6, intron 6, and exon 8 CN to study the genetic architecture of SMN1 duplications.ResultsSMN1 and SMN2 CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in SMN1 or SMN2. By contrast, patients with PMA more often than controls carried SMN1 duplications (≥3 SMN1 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43–4.91), p 0.0020). SMN1 and SMN2 CN status was not associated with MMN, PLS, or PMA disease course. In case of SMN1 exon 7 duplications, exons 1–6, exon 8, and introns 6 and 7 were also duplicated, suggesting full SMN1 duplications.ConclusionsSMN1 duplications are associated with PMA, but not with PLS and MMN. SMN1 duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered SMN CN on lower motor neurons.

Early Versus Delayed Mobilization Post-Operative Protocols for Primary Lateral Ankle Ligament Reconstruction: A Systematic Review and Meta-Analysis

Introduction. Lateral ankle instability represents a common orthopaedic diagnosis. Nonoperative treatment through focused physical therapy provides satisfactory results in most patients. However, some patients experience persistent chronic lateral ankle instability despite appropriate nonoperative treatment. These patients may require stabilization which can include primary lateral ligament reconstruction with a graft to restore ankle stability. Optimal post-operative rehabilitation of lateral ankle ligament reconstruction remains unknown, as surgeons vary in how long they immobilize their patients post-operatively. The aim of this review is to provide insight into early mobilization (EM) versus delayed mobilization (DM) post-operative protocols in patients undergoing primary lateral ankle ligament reconstructions to determine if an optimal evidence-based post-operative rehabilitation protocol exists in the literature. Methods. Following PRIMSA criteria, a systematic review/meta-analysis using the PubMed/Ovid Medline database was performed (10/11/1947-1/28/2020). Manuscripts that were duplicates, non-lateral ligament repair, biomechanical and non-English language were excluded. Protocols were reviewed and divided into two categories; early mobilization (within 3 weeks of surgery) and delayed mobilization (after 3 weeks of surgery). Functional outcome scores (AOFAS, Karlsson scores), radiographic measurements (anterior drawer, talar tilt) and complications evaluated using weighted mean differences (pre- and post-operative scores) and mixed-effect models. Results. After our search, we found 12 out of 1,574 studies that met the criteria for the final analysis, representing 399 patients undergoing lateral ankle reconstruction. Using weighted mean differences the DM group showed superior AOFAS functional scores compared to the EM group; 28.0 (5.5) vs. 26.3 (0.0) respectively, p < 0.001; although sample size was small. Conversely, no significant differences were found for Karlsson functional score (p = 0.246). With regards to radiographic outcome, no significant differences were observed; anterior drawer was p = 0.244 and talar tilt was p = 0.937. A meta-analysis using mixed-effects models confirmed these results, although heterogeneity was high. Conclusions. While there were some conflicting results, findings suggest that EM post-operative protocols for patients undergoing lateral ankle ligament reconstruction may not compromise functional outcomes or post-operative stability. Because heterogeneity was high, future studies are still needed to evaluate these protocols in less diverse patient groups and/or more consistent techniques for lateral ankle ligament reconstruction.