Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy.

Background and Objectives: Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes and assesses the effect of 19 novel or nonpreviously clinically characterized VCP variants identified in 28 patients (26 unrelated families) in the retrospective VCP International Multicenter Study. Methods: A 6-item clinical score was developed to evaluate the phenotypic level of evidence to support the pathogenicity of the novel variants. Each item is allocated a value, a score ranging from 0.5 to 5.5 points. A receiver-operating characteristic curve was used to identify a cutoff value of 3 to consider a variant as high likelihood disease associated. The scoring system results were confronted with results of in vitro ATPase activity assays and with in silico analysis. Results: All variants were missense, except for one small deletion-insertion, 18 led to amino acid changes within the N and D1 domains, and 13 increased the enzymatic activity. The clinical score coincided with the functional studies in 17 of 19 variants and with the in silico analysis in 12 of 19. For 12 variants, the 3 predictive tools agreed, and for 7 variants, the predictive tools disagreed. The pooled data supported the pathogenicity of 13 of 19 novel VCP variants identified in the study. Discussion: This study provides data to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. METHODS: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. RESULTS: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. CONCLUSIONS: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis.

BACKGROUND: Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord. METHODS: We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section. RESULTS: We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics. CONCLUSIONS: Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.

ALS is a disease affecting the brain and spinal cord which leads to weakness and muscle wasting. It is important to be able to measure disease-related changes whilst clinical trials are ongoing to assess whether the treatments being tested are working. We imaged the brain and spinal cord of people with and without ALS at 3 time points over a year. We found changes in the brain and spine over time. This study demonstrates that brain imaging could be potentially used to assess changes in disease progression during clinical trials, giving an indication of whether the treatments being tested are having an effect.

Randomized trial of inosine for urate elevation in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Higher urate levels are associated with improved ALS survival in retrospective studies, however whether raising urate levels confers a survival advantage is unknown. In the Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (SURE-ALS) trial, inosine raised serum urate and was safe and well-tolerated. The SURE-ALS2 trial was designed to assess longer term safety. Functional outcomes and a smartphone application were also explored. METHODS: Participants were randomized 2:1 to inosine (n = 14) or placebo (n = 9) for 20 weeks, titrated to serum urate of 7-8 mg/dL. Primary outcomes were safety and tolerability. Functional outcomes were measured with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). Mobility and ALSFRS-R were also assessed by a smartphone application. RESULTS: During inosine treatment, mean urate ranged 5.68-6.82 mg/dL. Treatment-emergent adverse event (TEAE) incidence was similar between groups (p > .10). Renal TEAEs occurred in three (21%) and hypertension in one (7%) of participants randomized to inosine. Inosine was tolerated in 71% of participants versus placebo 67%. Two participants (14%) in the inosine group experienced TEAEs deemed related to treatment (nephrolithiasis); one was a severe adverse event. Mean ALSFRS-R decline did not differ between groups (p = .69). Change in measured home time was similar between groups. Digital and in-clinic ALSFRS-R correlated well. DISCUSSION: Inosine met pre-specified criteria for safety and tolerability. A functional benefit was not demonstrated in this trial designed for safety and tolerability. Findings suggested potential utility for a smartphone application in ALS clinical and research settings.

Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease.

OBJECTIVE: To determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1. METHODS: This phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests. RESULTS: In Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs. CONCLUSIONS: Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Phase 2B randomized controlled trial of NP001 in amyotrophic lateral sclerosis: Pre-specified and post hoc analyses.

INTRODUCTION/AIMS: ALS is a heterogeneous disease that may be complicated or in part driven by inflammation. NP001, a regulator of macrophage activation, was associated with slowing disease progression in those with higher levels of the plasma inflammatory marker C-reactive protein (CRP) in phase 2A studies in ALS. Here, we evaluate the effects of NP001 in a phase 2B trial, and perform a post hoc analysis with combined data from the preceding phase 2A trial. METHODS: The phase 2B trial enrolled 138 participants within 3 y of symptom onset and with plasma hs-CRP values >1.13 mg/L. They were randomized 1:1 to receive either placebo or NP001 for 6 mo. Change from baseline ALSFRS-R scores was the primary efficacy endpoint. Secondary endpoints included vital capacity (VC) change from baseline and percentage of participants showing no decline of ALSFRS-R score over 6 mo (non-progressor). RESULTS: The phase 2B study did not show significant differences between placebo and active treatment with respect to change in ALSFRS-R scores, or VC. The drug was safe and well tolerated. A post hoc analysis identified a 40- to 65-y-old subset in which NP001-treated patients demonstrated slower declines in ALSFRS-R score by 36% and VC loss by 51% compared with placebo. A greater number of non-progressors were NP001-treated compared with placebo (p = .004). DISCUSSION: Although the phase 2B trial failed to meet its primary endpoints, post hoc analyses identified a subgroup whose decline in ALSFRS-R and VC scores were significantly slower than placebo. Further studies will be required to validate these findings.

Harnessing the power of the electronic health record for ALS research and quality improvement: CReATe CAPTURE-ALS and the ALS Toolkit.

The electronic health record (EHR) is designed principally to support the provision and documentation of clinical care, as well as billing and insurance claims. Broad implementation of the EHR, however, also yields an opportunity to use EHR data for other purposes, including research and quality improvement. Indeed, effective use of clinical data for research purposes has been a long-standing goal of physicians who provide care for patients with ALS, but the quality and completeness of clinical data, as well as the burden of double data entry into the EHR and into a research database, have been persistent barriers. These factors provided motivation for the development of the ALS Toolkit, a set of interactive digital forms within the EHR that enable easy, consistent, and structured capture of information relevant to ALS patient care (as well as research and quality improvement) during clinical encounters. Routine use of the ALS Toolkit within the context of the CReATe Consortium's institutional review board-approved Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study protocol, permits aggregation of structured ALS patient data, with the goals of empowering research and driving quality improvement. Widespread use of the ALS Toolkit through the CAPTURE-ALS protocol will help to ensure that ALS clinics become a driving force for collecting and aggregating clinical data in a way that reflects the true diversity of the populations affected by this disease, rather than the restricted subset of patients that currently participate in dedicated research studies.

A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. METHODS: In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. RESULTS: High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: - 0.37 points; 97.5% CI [- 0.68 to - 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. CONCLUSION: The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot-Marie-Tooth disease type 1A.

Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations (PAIN-CONTRoLS): Bayesian Adaptive Comparative Effectiveness Randomized Trial.

Importance: Cryptogenic sensory polyneuropathy (CSPN) is a common generalized slowly progressive neuropathy, second in prevalence only to diabetic neuropathy. Most patients with CSPN have significant pain. Many medications have been tried for pain reduction in CSPN, including antiepileptics, antidepressants, and sodium channel blockers. There are no comparative studies that identify the most effective medication for pain reduction in CSPN. Objective: To determine which medication (pregabalin, duloxetine, nortriptyline, or mexiletine) is most effective for reducing neuropathic pain and best tolerated in patients with CSPN. Design, Setting, and Participants: From December 1, 2014, through October 20, 2017, a bayesian adaptive, open-label randomized clinical comparative effectiveness study of pain in 402 participants with CSPN was conducted at 40 neurology care clinics. The trial included response adaptive randomization. Participants were patients with CSPN who were 30 years or older, with a pain score of 4 or greater on a numerical rating scale (range, 0-10, with higher scores indicating a higher level of pain). Participant allocation to 1 of 4 drug groups used the utility function and treatment's sample size for response adaptation randomization. At each interim analysis, a decision was made to continue enrolling (up to 400 participants) or stop the whole trial for success (80% power). Patient engagement was maintained throughout the trial, which helped guide the study and identify ways to communicate and disseminate information. Analysis was performed from December 11, 2015, to January 19, 2018. Interventions: Participants were randomized to receive nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). Main Outcomes and Measures: The primary outcome was a utility function that was a composite of the efficacy (participant reported pain reduction of ≥50% from baseline to week 12) and quit (participants who discontinued medication) rates. Results: Among the 402 participants (213 men [53.0%]; mean [SD] age, 60.1 [13.4] years; 343 White [85.3%]), the utility function of nortriptyline was 0.81 (95% bayesian credible interval [CrI], 0.69-0.93; 34 of 134 [25.4%] efficacious; and 51 of 134 [38.1%] quit), of duloxetine was 0.80 (95% CrI, 0.68-0.92; 29 of 126 [23.0%] efficacious; and 47 of 126 [37.3%] quit), pregabalin was 0.69 (95% CrI, 0.55-0.84; 11 of 73 [15.1%] efficacious; and 31 of 73 [42.5%] quit), and mexiletine was 0.58 (95% CrI, 0.42-0.75; 14 of 69 [20.3%] efficacious; and 40 of 69 [58.0%] quit). The probability each medication yielded the highest utility was 0.52 for nortriptyline, 0.43 for duloxetine, 0.05 for pregabalin, and 0.00 for mexiletine. Conclusions and Relevance: This study found that, although there was no clearly superior medication, nortriptyline and duloxetine outperformed pregabalin and mexiletine when pain reduction and undesirable adverse effects are combined to a single end point. Trial Registration: ClinicalTrials.gov Identifier: NCT02260388.

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

The genetic landscape of axonal neuropathies in the middle-aged and elderly: Focus on MME.

OBJECTIVE: To test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years. METHODS: We recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin. RESULTS: In the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance. CONCLUSIONS: A detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.

The NEALS primary lateral sclerosis registry.

BACKGROUND AND OBJECTIVE: Primary lateral sclerosis (PLS) is a neurodegenerative disease characterized by progressive upper motor neuron dysfunction. Because PLS patients represent only 1 to 4% of patients with adult motor neuron diseases, there is limited information about the disease's natural history. The objective of this study was to establish a large multicenter retrospective longitudinal registry of PLS patients seen at Northeast ALS Consortium (NEALS) sites to better characterize the natural progression of PLS. Methods: Clinical characteristics, electrophysiological findings, laboratory values, disease-related symptoms, and medications for symptom management were collected from PLS patients seen between 2000 and 2015. Results: The NEALS registry included data from 250 PLS patients. Median follow-up time was 3 years. The mean rate of functional decline measured by ALSFRS-R total score was -1.6 points/year (SE:0.24, n = 124); the mean annual decline in vital capacity was -3%/year (SE:0.55, n = 126). During the observational period, 18 patients died, 17 patients had a feeding tube placed and 7 required permanent assistive ventilation. Conclusions: The NEALS PLS Registry represents the largest available aggregation of longitudinal clinical data from PLS patients and provides a description of expected natural disease progression. Data from the registry will be available to the PLS community and can be leveraged to plan future clinical trials in this rare disease.

Tract-specific analysis improves sensitivity of spinal cord diffusion MRI to cross-sectional and longitudinal changes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease that causes progressive degeneration of motor neurons in the brain and the spinal cord. Corticospinal tract degeneration is a defining feature of ALS. However, there have been very few longitudinal, controlled studies assessing diffusion MRI (dMRI) metrics in different fiber tracts along the spinal cord in general or the corticospinal tract in particular. Here we demonstrate that a tract-specific analysis, with segmentation of ascending and descending tracts in the spinal cord white matter, substantially increases the sensitivity of dMRI to disease-related changes in ALS. Our work also identifies the tracts and spinal levels affected in ALS, supporting electrophysiologic and pathologic evidence of involvement of sensory pathways in ALS. We note changes in diffusion metrics and cord cross-sectional area, with enhanced sensitivity to disease effects through a multimodal analysis, and with strong correlations between these metrics and spinal components of ALSFRS-R.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Rituximab in refractory chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this. METHODS: Baseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP. RESULTS: The MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy. DISCUSSION: Our study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.

Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study.

Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.

Investigating the Feasibility of a Modified Quantitative Sensory Testing Approach to Profile Sensory Function and Predict Pain Outcomes Following Intrathecal Baclofen Implant Surgery in Cerebral Palsy.

OBJECTIVES: Intrathecal baclofen (ITB) pumps used to manage spasticity in children with cerebral palsy (CP) also improve pain outcomes for some but not all patients. The purpose of this clinical feasibility study was to explore whether a quantitative sensory testing approach could a) be modified and used to subgroup individuals into sensory profiles and b) test whether the profiles were related to postimplant pain outcomes (i.e., pain responsive or pain persistent). SUBJECTS: A purposeful clinical sample of nine children with CP (mean age = 12.5 years, male = 56%) and complex communication needs participated. METHODS: A prospective within-subject design was used to measure proxy-reported pain before and after ITB implant. Pain response status was determined by proxy-reported pain intensity change (>50% change in maximum rated intensity). A modified quantitative sensory testing (mQST) procedure was used to assess behavioral responsivity to an array of calibrated sensory (tactile/acute nociceptive) stimuli before surgery. RESULTS: Seven individuals with presurgical pain had mQST differentiated sensory profiles in relation to ITB pain outcomes and relative to the two individuals with no pain. Presurgically, the ITB pain responsive subgroup (N = 3, maximum rated pain intensity decreased >50% after ITB implant) showed increased behavioral reactivity to an acute nociceptive stimulus and cold stimulus, whereas the ITB pain persistent subgroup (N = 4) showed reduced behavioral reactivity to cold and repeated von Frey stimulation relative to the no pain individuals. CONCLUSION: Implications for patient selection criteria and stratification to presurgically identify individuals with CP "at risk" for persistent postprocedure pain are discussed.