BACKGROUND:LAMA2-related dystrophies (LAMA2-RDs) represent one of the most common forms of congenital muscular dystrophy and have historically been classified into two subtypes: complete or partial deficiency of laminin-211 (merosin). Patients with LAMA2-RD with the typical congenital phenotype manifest severe muscle weakness, delayed motor milestones, joint contractures, failure to thrive, and progressive respiratory insufficiency. OBJECTIVE:While a comprehensive prospective natural history study has been performed in LAMA2-RD patients over 5 years of age, the early natural history of patients with LAMA2-RD 5 years and younger has not been comprehensively characterized. METHODS:We extracted retrospective data for patients with LAMA2-RD ages birth through 5 years via the Congenital Muscle Disease International Registry (CMDIR). We analyzed the data using a phenotypic classification based on maximal motor milestones to divide patients into two phenotypic groups: "Sit" for those patients who attained that ability to remain seated and "Walk" for those patients who attained the ability to walk independently by 3.5 years of age. RESULTS:Sixty patients with LAMA2-RD from 10 countries fulfilled the inclusion criteria. Twenty-four patients had initiated non-invasive ventilation by age 5 years. Hospitalizations during the first years of life were often related to respiratory insufficiency. Feeding/nutritional difficulties and orthopedic issues were commonly reported. Significant elevations of creatine kinase (CK) observed during the neonatal period declined rapidly within the first few months of life. CONCLUSIONS:This is the largest international retrospective early natural history study of LAMA2-RD to date, contributing essential data for understanding early clinical findings in LAMA2-RD which, along with the data being collected in international, prospective early natural history studies, will help to establish clinical trial readiness. Our proposed nomenclature of LAMA2-RD1 for patients who attain the ability to sit (remain seated) and LAMA2-RD2 for patients who attain the ability to walk independently is aimed at further improving LAMA2-RD classification.

Congenital muscular dystrophies (CMDs) are congenital onset muscular dystrophies with laminin alpha-2 (LAMA2) and collagen VI (COL6)-related dystrophies (RD) being the most common subtypes. Symptoms include hypotonia, progressive muscle weakness, respiratory insufficiency and joint contractures. With multiple promising therapies in development for LAMA2-RD and COL6-RD, the validation of motor outcome measures in young children is essential, given their likely inclusion in future clinical trials. The Motor Function Measure-20 (MFM20) is a 20-item standardized scale used to measure motor function and has been validated in children 2-6 years of age with congenital muscle diseases. The Neuromuscular Gross Motor Outcome (NM GRO) is a 50-item scale, developed by Nationwide Children's Hospital for use in patients from birth onward. The goal of the scale is to assess motor function across the years and reduce the burden of testing. Initial validation studies have been completed in individuals with spinal muscular atrophy (SMA), a motor neuron disease. This exploratory analysis aims to compare MFM20 and NM GRO assessments from the baseline visit of CMD participants younger than 6 years of age. MFM20 and NM GRO were administered to 14 participants: 5 with LAMA2-RD (35.7%) and 9 with COL6-RD (64.3%). Of the 14 participants, 11 were male with the mean age of 3.84 ± 1.11 years. Using Spearman's rank correlation, there was a statistically significant correlation between the MFM20 percentage and NM GRO score (ρ = 0.97, p < 0.001). When individually examining each subgroup, both the COL6-RD group and LAMA2-RD retained statistical significance between the MFM20 percentage and NM GRO score (ρ = 0.94, p < 0.001) and (ρ = 0.87, p = 0.05), respectively. Additional studies, with a larger sample size, are needed to validate the NM GRO as a comprehensive assessment tool for patients with LAMA2-RD and COL6-RD. Congenital muscular dystrophies (CMDs) are congenital onset muscular dystrophies with laminin alpha-2 (LAMA2) and collagen VI (COL6)-related dystrophies (RD) being the most common subtypes. Symptoms include hypotonia, progressive muscle weakness, respiratory insufficiency and joint contractures. With multiple promising therapies in development for LAMA2-RD and COL6-RD, the validation of motor outcome measures in young children is essential, given their likely inclusion in future clinical trials. The Motor Function Measure-20 (MFM20) is a 20-item standardized scale used to measure motor function and has been validated in children 2-6 years of age with congenital muscle diseases. The Neuromuscular Gross Motor Outcome (NM GRO) is a 50-item scale, developed by Nationwide Children's Hospital for use in patients from birth onward. The goal of the scale is to assess motor function across the years and reduce the burden of testing. Initial validation studies have been completed in individuals with spinal muscular atrophy (SMA), a motor neuron disease. This exploratory analysis aims to compare MFM20 and NM GRO assessments from the baseline visit of CMD participants younger than 6 years of age. MFM20 and NM GRO were administered to 14 participants: 5 with LAMA2-RD (35.7%) and 9 with COL6-RD (64.3%). Of the 14 participants, 11 were male with the mean age of 3.84 ± 1.11 years. Using Spearman's rank correlation, there was a statistically significant correlation between the MFM20 percentage and NM GRO score (ρ = 0.97, p < 0.001). When individually examining each subgroup, both the COL6-RD group and LAMA2-RD retained statistical significance between the MFM20 percentage and NM GRO score (ρ = 0.94, p < 0.001) and (ρ = 0.87, p = 0.05), respectively. Additional studies, with a larger sample size, are needed to validate the NM GRO as a comprehensive assessment tool for patients with LAMA2-RD and COL6-RD.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. We have evaluated participants with GAN in an ongoing natural history study (NCT01568658). Additionally, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438) is ongoing. This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes by dot blot, with concomitant immunomodulation. Cross-sectional and longitudinal ophthalmologic data are presented, including best corrected visual acuity (LogMAR) and retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) (SD-OCT: Cirrus HD-OC) from participants with GAN in natural history and in participants following gene transfer. Participants with GAN, especially those with a more aggressive form of the disease, frequently have abnormalities in average RNFL thickness (defined as < 80 μm) and progressive decline in visual acuity. Prior to gene transfer, 9 participants (64%) had abnormal RNFL thickness at baseline in the right (OD) and left eye (OS) (range: 56 - 100 μm). In follow up to 6 years, we observe trends towards stabilization in visual acuity as assessed by slope post gene transfer as compared to lead in natural history data. Concomitant trends in RNFL measurements following gene transfer were reviewed, taking into account the measurable range of RNFL thickness. Potential stabilization in visual acuity over long term follow up suggests an impact at the level of the optic nerve with IT administration of AAV9 mediated gene transfer in GAN at the vector genome doses administered in this trial. Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. We have evaluated participants with GAN in an ongoing natural history study (NCT01568658). Additionally, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438) is ongoing. This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes by dot blot, with concomitant immunomodulation. Cross-sectional and longitudinal ophthalmologic data are presented, including best corrected visual acuity (LogMAR) and retinal nerve fiber layer thickness as measured by optical coherence tomography (OCT) (SD-OCT: Cirrus HD-OC) from participants with GAN in natural history and in participants following gene transfer. Participants with GAN, especially those with a more aggressive form of the disease, frequently have abnormalities in average RNFL thickness (defined as < 80 μm) and progressive decline in visual acuity. Prior to gene transfer, 9 participants (64%) had abnormal RNFL thickness at baseline in the right (OD) and left eye (OS) (range: 56 - 100 μm). In follow up to 6 years, we observe trends towards stabilization in visual acuity as assessed by slope post gene transfer as compared to lead in natural history data. Concomitant trends in RNFL measurements following gene transfer were reviewed, taking into account the measurable range of RNFL thickness. Potential stabilization in visual acuity over long term follow up suggests an impact at the level of the optic nerve with IT administration of AAV9 mediated gene transfer in GAN at the vector genome doses administered in this trial.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. Based on an ongoing natural history study (NCT01568658), we report on electrophysiologic data on motor and sensory amplitude responses in 40 participants with GAN with at least one nerve conduction study recording. We report on single time point and longitudinal trends in motor and sensory nerve amplitude as compared to age. Electrical impedance myography of four upper and four lower limb muscles has also been obtained. Concurrently, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for the treatment of GAN was initiated (NCT02362438). This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes, with concomitant immunosuppression. Findings for up to six years post gene transfer included stable or re-emerging sensory amplitudes for digit II median sensory (n=5) and digit V ulnar sensory (n=6) nerves. Of note, the stability or recovery as was seen in upper extremity sensory responses contrasts with more variability that was observed in motor responses. Post gene transfer, the following additional measures were reported: electrical impedance myography, nerve pathology (regenerative cluster density), and epidermal nerve fiber layer density. Together, these data suggest dose, age, and length dependent nerve restoration following IT AAV9 gene therapy and suggest that additional evidence of positive clinical impact could be expected if patients were treated at a younger age or earlier in disease course. Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease of the central, peripheral and autonomic nervous systems caused by deficiency or complete loss-of-function of gigaxonin, leading to accumulation of intermediate filaments. GAN clinically manifests with progressive axonal sensorimotor, orthopedic complications, CNS involvement, and optic neuropathy, and in its more aggressive form leads to respiratory failure with death by the third decade of life. There are no approved therapies for the treatment of GAN. Based on an ongoing natural history study (NCT01568658), we report on electrophysiologic data on motor and sensory amplitude responses in 40 participants with GAN with at least one nerve conduction study recording. We report on single time point and longitudinal trends in motor and sensory nerve amplitude as compared to age. Electrical impedance myography of four upper and four lower limb muscles has also been obtained. Concurrently, a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for the treatment of GAN was initiated (NCT02362438). This is an ongoing single site, phase I/II, open-label, dose-escalation, non-randomized trial with lead-in data from the GAN natural history data. Fourteen trial participants (6-14 years of age) have received a single IT dose of scAAV9-JeT-GANopt, ranging from 3.5e13 to 3.5e14 total vector genomes, with concomitant immunosuppression. Findings for up to six years post gene transfer included stable or re-emerging sensory amplitudes for digit II median sensory (n=5) and digit V ulnar sensory (n=6) nerves. Of note, the stability or recovery as was seen in upper extremity sensory responses contrasts with more variability that was observed in motor responses. Post gene transfer, the following additional measures were reported: electrical impedance myography, nerve pathology (regenerative cluster density), and epidermal nerve fiber layer density. Together, these data suggest dose, age, and length dependent nerve restoration following IT AAV9 gene therapy and suggest that additional evidence of positive clinical impact could be expected if patients were treated at a younger age or earlier in disease course.

Skeletal muscle ultrasound (MUS) is a non-invasive ancillary tool for evaluation of neuromuscular conditions that can enhance the physical exam and complement electrodiagnostic studies. While MUS is more extensively studied in primary myopathies, it can also enhance the diagnostic evaluation of patients with neuropathies. Neurogenic disease typically results in heterogenous "streaky" echogenicity in skeletal muscle while myopathic disease typically appears as homogenously increased echogenicity in a granular pattern. In addition, the superiority of MUS in detecting fasciculations compared to EMG is reported in amyotrophic lateral sclerosis, which is likely due to the higher volume of sampled muscle with MUS. Here, we describe MUS findings and EMG/NCS correlates in a cohort of 17 individuals with genetically confirmed childhood onset neuropathies and neuronopathies evaluated at the National Institutes of Health. MUS was graded using the modified Heckmatt scale (MHS) and a description of increased echogenicity as "streaky" or "granular" by three independent reviewers. In 17 patients evaluated, there was a length-dependent pattern of increased echogenicity. Tibialis anterior and gastrocnemius were most affected, and deltoid, triceps and biceps were most spared. "Streaky" appearance was seen in most muscles but was more difficult to appreciate in muscles with low echogenicity scores (grade 0 MHS) or in "end-stage" muscle (grade 3 MHS). MUS was more sensitive at detecting fasciculations than EMG in this setting. No clear pattern emerged to differentiate specific genetic etiologies of neuropathy/neuronopathy from one another via MUS. This study demonstrates the utility of muscle ultrasound in detecting neuropathic disease.

Giant axonal neuropathy (GAN) is a rare and fatal pediatric neurodegenerative disorder affecting the central and peripheral nervous system. Recessive variants in the GAN gene cause dysfunction of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure with death by the second to third decade of life. We are conducting a first-in-human intrathecal (IT) AAV9-mediated gene transfer trial for GAN (NCT02362438). This is an ongoing single site, phase I, non-randomized, open label dose escalation trial with lead-in and GAN natural history data serving for comparison. Fourteen GAN participants ages 6 years to 14 years old have received a single IT dose of scAAV9-JeT-GANopt (ranging from 3.5x1013 vector genomes (vg) to 3.5x1014 vg total dose) with concomitant immunomodulation protocols. Safety is the primary outcome measure with follow-up data spanning 24-72 months post gene transfer. Secondary outcome measures include the motor function measure (MFM)-32, nerve conduction studies, and nerve pathology. Here we review safety and immunologic findings related to dose, genotype, baseline AAV9 seropositivity, and the use of T-cell immune modulation. We present preliminary efficacy results on change in MFM-32 at one year post gene transfer compared to lead-in and our GAN natural history data as well as MFM-32 trajectories in long-term follow-up. Neurophysiologic (CMAP and SNAP amplitude) and nerve pathology findings are also reviewed. This study highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer and demonstrates the ability of IT gene transfer to positively modify the expected rate of decline and progression in GAN. Importantly, this study serves as proof of concept for IT gene transfer with targeted immune modulation as a successful strategy for gene replacement in disorders affecting the central and peripheral nervous system.