Jonathan Marra

Observational study of spinal muscular atrophy type I and implications for clinical trials

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 Childrens 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.

Prospective cohort study of spinal muscular atrophy types 2 and 3

Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.

Observational Study of Spinal Muscular Atrophy Type 2 and 3: Functional Outcomes Over 1 Year

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.

Reliability of telephone administration of the PedsQL Generic Quality of Life Inventory and Neuromuscular Module in spinal muscular atrophy (SMA).

Clinical research visits are challenging for people with SMA because of limited mobility and intercurrent illnesses. Missing data threaten the validity of research results. Obtaining outcomes remotely would represent a solution. To evaluate reliability of telephone administration of the PedsQL Pediatric Generic Core Quality of Life Inventory 4.0 (Generic) and Neuromuscular Module 3.0 (NM) in SMA, we recruited 21 participants of a Natural History Study for telephone administration of both modules no more than 7 days before or after an in-person study visit. We found excellent reliability between telephone and in-person administration of both modules with the NM slightly better than the Generic. Reliability of the child and parent forms was similar. We concluded that both modules can be administered reliably over the telephone to SMA patients and caregivers, expanding the utility of these tools in clinical trials. Notably, telephone administration is reliable in children as young as 8 years.

Six-minute walk test is reliable and valid in spinal muscular atrophy.

Introduction: The Six‐Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. Methods: Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. Results: Test–retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand‐held dynamometry, and inversely with 10‐m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. Conclusions: This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836–842, 2016

Identification of a novel nemaline myopathy-Causing mutation in the troponin T1 (TNNT1) gene: A case outside of the old order amish

Introduction: Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2–3 months of life. Methods: We describe an Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing. Results: Direct sequencing revealed that he is homozygous for a pathogenic nonsense variant c.323C>G (p.S108X) in exon 9 of the TNNT1 gene. Conclusions: This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy‐causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry. Muscle Nerve 51:767–772, 2015

The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy

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.

An integrated motion capture system for evaluation of neuromuscular disease patients

There currently exist a variety of methods for evaluating movement in patients suffering from neuromuscular diseases (NMD). These tests are primarily performed in the clinical setting and evaluated by highly trained individuals, rather than evaluating patient in their natural environments (i.e., home or school). Currently available automated motion capture modalities offer a highly accurate means of assessing general motion, but are also limited to a highly controlled setting. Recent advances in MEMS technology have introduced the possibility of robust motion capture in uncontrolled environments, while minimizing user interference with self-initiated motion, especially in weaker subjects. The goal of this study is to design and evaluate a MEMS-sensor-based system for motion capture in the NMD patient population. The highly interdisciplinary effort has led to significant progress toward the implementation of a new device, which is accurate, clinically relevant, and highly affordable.

Design and evaluation of a hybrid passive and active gravity neutral orthosis (GNO)

Neuromuscular diseases (NMD), including Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD), result in progressive muscular weakness that often leaves patients functionally dependent on caregivers for many activities of daily living (ADL) such as eating, bathing, grooming (touching the face and head), reaching (grabbing for objects), and dressing. In severe cases, patients are unable to perform even the simplest of activities from exploring their 3D space to touching their own face. The ability to move and initiate age appropriate tasks, such as playing and exploration, are considered to be of vital importance to both their physical and cognitive development. Therefore, to improve quality of life and reduce dependence on caregivers in children and young adults with NMD, we designed, built and evaluated an assistive, active orthosis to support arm function. The goal of this project is the development and evaluation of a mechanical arm orthosis to both encourage and assist functional arm movement while providing the user a sense of independence and control over one’s own body.

715. Giant Axonal Neuropathy - The Role of Natural History Studies in Gene Transfer Therapy Trial Design

OBJECTIVE: Giant axonal neuropathy (GAN) is a rare childhood onset autosomal recessive neurodegenerative disorder affecting the central and peripheral nervous system. Mutations in the GAN gene cause loss of function of gigaxonin, a cytoskeletal regulatory protein, clinically leading to progressive sensorimotor neuropathy and neuropathy, reduced coordination, slurred speech, seizures, and progressive respiratory failure leading to death by the 2nd to 3rd decade of life. We are in the midst of a first-in-human intrathecal AAV9 mediated gene transfer trial for GAN. Given the ultra-rare nature of the disease, it is critical to build disease appropriate outcome measures and have lead in safety and outcome data to feed into the clinical trial. Our aim here was to identify and develop targeted quantitative markers of disease severity in GAN. METHODS: This natural history study evaluated measures of motor, neurophysiologic, and ophthalmologic function as well as exploratory neuroimaging markers in genetically confirmed GAN patients seen at the National Institutes of Health (NIH). The primary aim was to correlate a quantitative motor scale (MFM32) with a semi-quantitative Neuropathy Impairment Score (NIS) in cross sectional analysis of GAN patients. Secondary aims included evaluation of strength (myometry) and motor nerve amplitude (nerve conduction) compared to motor function (MFM32). Quantitative ophthalmologic testing included retinal nerve fiber layer thickness analysis correlated to visual acuity, MFM32, and motor nerve amplitude. Additional exploratory measures of spinal cord volume, brain DTI, quantitative MR spectroscopy, and biochemical (in serum and CSF) measures are underway. RESULTS: 15 GAN patients were evaluated at the NIH. Data analysis (Pearson correlation) showed the following: 1) NIS and MFM32 are significantly correlated (p<0.0001); 2) Muscle strength of knee extension, knee flexion, hip abduction, and hand grip each correlate significantly with MFM32 (p values from <0.0001 to 0.039) ; 3) Median motor nerve amplitude correlates significantly with MFM32 (p=0.0016). There was no significant correlation between elbow extension or elbow flexion strength and MFM32. Retinal nerve fiber layer corresponds strongly with MFM32 and the median motor nerve amplitude (p<0.0001 and p=0.005, respectively). CONCLUSIONS: The phase I intrathecal gene transfer study for GAN is a novel clinical trial, and will set a precedent by proof of principle for future gene transfer trials for neurodegenerative disorders. The primary outcome is safety, but given that the trial entails administration of a presumed effective dose, careful selection to outcome measures was essential in the protocol design. Through this natural history study, we have identified markers such as the MFM32, NIS, median motor amplitude, and retinal nerve fiber layer thickness, as well as spinal cord volumetric data that clearly correlate with disease progression. These markers are being followed longitudinally in natural history and were designed into the phase I trial. Such broad data capture allows for the incorporation of more targeted disease specific clinically meaningful outcome measures and data on natural rate of progression of such markers over short durations of follow up. Such models of trial design will be crucial to the development of genetic therapeutic trials for rare neurodegenerative disorders.