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The cell membrane protein, dystroglycan, plays a crucial role in connecting the cytoskeleton of a variety of mammalian cells to the extracellular matrix. The α-subunit of dystroglycan (αDG) is characterized by a high level of glycosylation, including a unique O-mannosyl matriglycan. This specific glycosylation is essential for binding of αDG to extracellular matrix ligands effectively. A subset of muscular dystrophies, called dystroglycanopathies, are associated with aberrant, dysfunctional glycosylation of αDG. This defect prevents myocytes from attaching to the basal membrane, leading to contraction-induced injury. Here, we describe a novel Western blot (WB) assay for determining levels of αDG glycosylation in skeletal muscle tissue. The assay described involves extracting proteins from fine needle tibialis anterior (TA) biopsies and separation using SDS-PAGE followed by WB. Glycosylated and core αDG are then detected in a multiplexed format using fluorescent antibodies. A practical application of this assay is demonstrated with samples from normal donors and patients diagnosed with LGMD2I/R9. Quantitative analysis of the WB, which employed the use of a normal TA derived calibration curve, revealed significantly reduced levels of αDG in patient biopsies relative to unaffected TA. Importantly, the assay was able to distinguish between the L276I homozygous patients and a more severe form of clinical disease observed with other FKRP variants. Data demonstrating the accuracy and reliability of the assay are also presented, which further supports the potential utility of this novel assay to monitor changes in ⍺DG of TA muscle biopsies in the evaluation of potential therapeutics., (© 2024. ML Bio Solutions Inc., a BridgeBio Pharma, Inc. Company.)

Spinal muscular atrophy type 1 (SMA1) is a debilitating neurodegenerative disease resulting from survival motor neuron 1 gene (SMN1) deletion/mutation. Onasemnogene abeparvovec (formerly AVXS-101) is a gene therapy that restores SMN production via one-time systemic administration. The present study demonstrates widespread biodistribution of vector genomes and transgenes throughout the central nervous system (CNS) and peripheral organs, after intravenous administration of an AAV9-mediated gene therapy. Two symptomatic infants with SMA1 enrolled in phase III studies received onasemnogene abeparvovec. Both patients died of respiratory complications unrelated to onasemnogene abeparvovec. One patient had improved motor function and the other died shortly after administration before appreciable clinical benefit could be observed. In both patients, onasemnogene abeparvovec DNA and messenger RNA distribution were widespread among peripheral organs and in the CNS. The greatest concentration of vector genomes was detected in the liver, with an increase over that detected in CNS tissues of 300-1,000-fold. SMN protein, which was low in an untreated SMA1 control, was clearly detectable in motor neurons, brain, skeletal muscle and multiple peripheral organs in treated patients. These data support the fact that onasemnogene abeparvovec has effective distribution, transduction and expression throughout the CNS after intravenous administration and restores SMN expression in humans., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy., Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10 14 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed)., Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus)., Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1., Funding: Novartis Gene Therapies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background : Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective : To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design : We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective : USA/Commercial payer Participants : Children aged <2 years with SMA1. Interventions : Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure : Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results : Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion : This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY)., Competing Interests: Rebecca Dean, Ivar Jensen, Phil Cyr and Beckley Miller are employees of PRECISIONheor and PRECISIONheor received funding for the analysis from Novartis Gene Therapies. Benit Maru and Thomas Wiesner are employees of SSI Strategy, who were contracted to support Novartis Gene Therapies. Douglas M. Sproule, Douglas E. Feltner are former employees of Novartis Gene Therapies. Omar Dabbous, Matthias Bischof and Walter Toro are employees of Novartis Gene Therapies. Daniel C. Malone is a consultant to Novartis., (© The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1)., Methods: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3)., Results: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months)., Conclusions: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with spinal muscular atrophy (SMA) have high healthcare resource use (HRU) due to respiratory and nutritional complications resulting from progressive muscle atrophy. While previous studies estimate the direct costs to be US$113,000 to US$121,682 per year in the US, they potentially understate costs for type 1 SMA (SMA1). This study analyzed HRU in hospitalizations with a diagnosis of SMA1 and compared it with hospitalizations with complex chronic conditions (CCC) other than SMA1 or those with no CCC., Methods: This retrospective analysis of a defined subset of the 2012 Kids' Inpatient Database (KID) compared a nationally estimated number of hospitalizations of children (aged < 3 years) categorized into three groups: (1) SMA1 (n = 237 admissions), (2) no CCC (n = 632,467 admissions), and (3) other CCC (n = 224,953 admissions)., Results: Mean total charges were higher for SMA1 admissions compared with admissions with no CCC (US$150,921 vs US$19,261 per admission, respectively; costs: US$50,190 vs $5862 per admission, respectively; both p < 0.0001). A larger proportion of SMA1 admissions were billed for one or more procedure codes (81.9%) than in the no CCC group (39.4%) or other CCC group (70.1%; both p ≤ 0.0003). SMA1 admissions had a longer length of stay compared with admissions with no CCC (15.1 vs 3.4, respectively; p < 0.0001)., Conclusions: The average total charges for a single SMA1 admission were higher than those of the no CCC group. Because most infants with SMA1 require multiple hospitalizations per year, previous estimates may dramatically underestimate the direct costs associated with HRU. Further studies are required to determine the indirect costs and societal impacts of SMA1.

Background : Spinal muscular atrophy type 1 (SMA1) is a devastating genetic disease for which gene-replacement therapy may bring substantial survival and quality of life benefits. Objective : This study investigated the cost-effectiveness of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Study design : A Markov model was used to estimate the incremental cost-effectiveness ratio (ICER), expressed as cost/quality-adjusted life year ($/QALY), of AVXS-101 versus nusinersen over a lifetime. Survival, healthcare costs and QALYs were estimated using natural history data for SMA patients who achieved motor milestones (sitting/walking). Health utility weights were obtained from the CHERISH trial. Setting : USA; commercial payer perspective Participants : SMA1 infants Interventions : AVXS-101 was compared to nusinersen. Main outcome measure : The primary outcome was the ICER. Results : Expected survival (undiscounted) over a lifetime predicted by the model was 37.20 life years for AVXS-101 and 9.68 for nusinersen (discounted QALYs, 15.65 and 5.29, respectively). Using a potential AVXS-101 price range ($2.5-5.0M/treatment), the average lifetime cost/patient was $4.2-6.6M for AVXS-101 and $6.3M for nusinersen. The ICER range was (-$203,072) to $31,379 per QALY gained for AVXS-101 versus nusinersen, indicating that AVXS-101 was cost-effective with prices of ≤$5M. Conclusion : Single-dose AVXS-101 was cost-effective compared to chronic nusinersen for SMA1 patients.

Introduction: Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1., Methods: Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches., Results: Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1-12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1-1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0-3.6) and RR was 1.6 (95% CI 1.4-1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6-5.3) and RR was 1.4 (95% CI 1.2-1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1-1.9), 1.5 (95% CI 1.1-2.5), and 1.2 (95% CI 1.0-1.5); RRs 4.2 (95% CI 2.6-6.7), 7.8 (95% CI 3.6-17.0), and 11.2 (95% CI 5.1-24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach., Conclusion: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones., Funding: AveXis.

Background: Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy., Methods: Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function., Results: All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently., Conclusions: AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy., Trial Registration: ClinicalTrials.gov number, NCT02122952., (© 2018 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

Background: Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are emerging., Objective: This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants., Methods: Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events., Results: Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively)., Conclusions: In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.

Background: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease., Methods: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10 13 vg per kilogram of body weight), and 12 received a high dose (2.0×10 14 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts)., Results: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone., Conclusions: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).

As part of a natural history study of giant axonal neuropathy, we hypothesized that the Friedreich Ataxia Rating Scale and the Gross Motor Function Measure would show a significant change over 6 months, reflecting subjects' decline in motor function. The Friedreich Ataxia Rating Scale was performed on 11 subjects and the Gross Motor Function Measure was performed on 10 subjects twice with a six-month interval. A paired two-tailed t-test was used to assess the difference in each subject's score. Significant changes were found over six months of 11.7 ± 11.0 (P = 0.006) for the Friedreich Ataxia Rating Scale and -10.0 ± 13.5 (P = 0.043) for the Gross Motor Function Measure, reflecting subjects' decline in motor function on examination and by report. These standardized assessments of clinical function are the first to be validated in giant axonal neuropathy and will be used in an upcoming gene therapy clinical trial., (© The Author(s) 2014.)

Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the "giant" axons caused by accumulations of intermediate filaments. The disease is progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot-Marie-Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as "giant axonal neurodegeneration.", (Copyright © 2014 Wiley Periodicals, Inc.)

Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I)., Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered., Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02)., Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design., (© 2014 American Academy of Neurology.)

Introduction: The purpose of this study was to measure and analyze motor unit number estimation (MUNE) values longitudinally in spinal muscular atrophy (SMA)., Methods: Sixty-two children with SMA types 2 and 3 were observed prospectively for up to 42 months. Longitudinal electrophysiological data were collected, including compound motor action potential (CMAP), single motor unit action potential (SMUP), and MUNE., Results: Significant motor neuron loss and compensatory collateral reinnervation were noted at baseline. Over time, there was a significant mean increase in MUNE (4.92 units/year, P = 0.009), a mean decrease in SMUP amplitude (-6.32 μV/year, P = 0.10), and stable CMAP amplitude., Conclusions: The unexpected longitudinal results differ from findings in amyotrophic lateral sclerosis studies, perhaps indicating that compensatory processes in SMA involve new motor unit development. A better understanding of the mechanisms of motor unit decline and compensation in SMA is important for assessing novel therapeutic strategies and for providing key insights into disease pathophysiology., (Copyright © 2013 Wiley Periodicals, Inc.)

Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p=0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot-Marie-Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot-Marie-Tooth Disease type 2., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Spinal muscular atrophy is an autosomal recessive neurodegenerative disease caused by homozygous mutation to the survival motor neuron 1 (SMN1) gene. Historically, spinal muscular atrophy has been considered to almost exclusively affect the function and survival of alpha motor neurons of the spinal cord and brainstem. With the development of animal models of spinal muscular atrophy, the presence of widespread systemic abnormalities affecting the brain, heart, and pancreas has been repeatedly noted among animals with diminished survival motor neuron protein expression. While these observations suggest similar possible effects in humans, reports of primary systemic disease manifestations among humans affected by spinal muscular atrophy are strikingly lacking. Here we report a case of a 29-year-old man with genetically confirmed spinal muscular atrophy type II who presented with new onset diabetes mellitus and diabetic ketoacidosis.

Weakness and fatigue are captured by the 6-minute walk test, but the relationship between these symptoms is uncertain. Comparison across neuromuscular diseases has not been examined. A cohort study of 114 patients with spinal muscular atrophy, Duchenne/Becker muscular dystrophy, myasthenia gravis, and energy failure syndromes were included. Percent-predicted distance on the 6-minute walk test was computed from normative values to determine weakness. Fatigue was determined by the decrement in distance from the first to sixth minute. Weakness was seen across all groups (61.9%) but significant fatigue was seen only in spinal muscular atrophy (21.0%). Other groups showed little fatigue. Correlation between weakness and fatigue was significant only in spinal muscular atrophy (R = -0.71; P < .001). Longitudinally, distance walked declined only in Duchenne/Becker muscular dystrophy. In spinal muscular atrophy, weakness did not change, but fatigue increased significantly. These findings suggest independent mechanisms underlying weakness and fatigue in diverse neuromuscular conditions.

Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills.

Objectives: Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS)., Methods: BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores., Results: 12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures., Conclusions: Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.

Growth failure is nearly universal in spinal muscular atrophy type 1 and common in type 2, although acuity is often underappreciated at initial diagnosis. We reviewed 44 consecutive spinal muscular atrophy patients (28 type 1, 16 type 2) under 3 years at initial presentation. Growth failure was conventionally defined: weight below the fifth percentile or dropping 2 major percentiles over 6 months. Growth failure differed among subjects stratified by age at disease onset using the Kaplan-Meier method (P = 0.011). Median time to growth failure among subjects with onset between 0 to 3 months of age was 5 months; Only 1 of 22 avoided failure by 22 months of age. Median time to failure with disease onset between 4 to 6 months was 15 months. Most late onset (> 6 months) subjects avoided growth failure. Early clinical symptoms predict feeding dysfunction and growth failure. Immediate, proactive nutritional intervention is indicated for patients with early symptom onset.

Spinal muscular atrophy is a relatively stable chronic disease. Patients may gradually experience declines in muscle strength and motor function over time. However, functional progression is difficult to document, and the mechanism remains poorly understood. An 11-year-old girl was diagnosed at 19 months and took a few steps without assistance at 25 months. She was evaluated for 54 months in a prospective multicenter natural history study. Outcome measures were performed serially. From 6 to 7.5 years, motor function improved. From 7.5 to 11 years, motor function declined with increasing growth. Manual muscle testing scores minimally decreased. Motor unit number estimation studies gradually increased over 4.5 years. Compared to the published natural history of spinal muscular atrophy type III, our patient lost motor function over time. However, she walked with assistance 2 years longer than expected. Our report highlights possible precipitating factors that could affect the natural history of spinal muscular atrophy type III.

Changes in thigh muscle volume over 6 months were assessed using magnetic resonance imaging in 11 subjects aged 6 to 47 years with spinal muscular atrophy (4 type 2 and 7 type 3; 4 ambulatory and 3 nonambulatory). Muscle volume with normal and abnormal signal was measured using blinded, semiautomated analysis of reconstructed data. Volumes at baseline and 6 months were correlated with clinical function at each epoch. There was minimal increase in normal (0.3 ± 1.4 mL/cm) and total (0.1 ± 1.3 mL/cm) muscle. Muscle volume correlated closely with clinical function. Minimal interval change in muscle volume is consistent with the established clinical history of minimal disease progression over intervals shorter than 1 year. Relative constancy of muscle volume estimation and correlation with established functional measures suggest a role for segmental magnetic resonance imaging as a biomarker of treatment effect in future therapeutic trials.

Objective: To characterize the short-term course of spinal muscular atrophy (SMA) in a genetically and clinically well-defined cohort of patients with SMA., Design: A comprehensive multicenter, longitudinal, observational study., Setting: The Pediatric Neuromuscular Clinical Research Network for SMA, a consortium of clinical investigators at 3 clinical sites., Participants: Sixty-five participants with SMA types 2 and 3, aged 20 months to 45 years, were prospectively evaluated., Intervention: We collected demographic and medical history information and determined the SMN 2 copy number., Main Outcome Measures: Clinical outcomes included measures of motor function (Gross Motor Function Measure and expanded Hammersmith Functional Motor Scale), pulmonary function (forced vital capacity), and muscle strength (myometry). Participants were evaluated every 2 months for the initial 6 months and every 3 months for the subsequent 6 months. We evaluated change over 12 months for all clinical outcomes and examined potential correlates of change over time including age, sex, SMA type, ambulatory status, SMN2 copy number, medication use, and baseline function., Results: There were no significant changes over 12 months in motor function, pulmonary function, and muscle strength measures. There was evidence of motor function gain in ambulatory patients, especially in those children younger than 5 years. Scoliosis surgery during the observation period led to a subsequent decline in motor function., Conclusions: Our results confirm previous clinical reports suggesting that SMA types 2 and 3 represent chronic phenotypes that have relatively stable clinical courses. We did not detect any measurable clinical disease progression in SMA types 2 and 3 over 12 months, suggesting that clinical trials will have to be designed to measure improvement rather than stabilization of disease progression.