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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. [ABSTRACT FROM AUTHOR]

BACKGROUND Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin. METHODS We conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope. RESULTS One of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants -- 3.5 x 1013 total vector genomes (vg) (in 2 participants), 1.2 x 1014 vg (in 4), 1.8 x 1014 vg (in 5), and 3.5 x 1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5 x 1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2 x 1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8 x 1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5 x 1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8. CONCLUSIONS Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

PIEZO2 is a large stretch-gated ion channel highly expressed in specific sensory neurons which mediates human mechanosensation. Individuals with biallelic loss of function (LOF) variants in the PIEZO2 gene highlight the impact of the congenital absence of specific mechanotransduction-dependent senses, including proprioception aspects of touch and interception. We report on twelve unrelated individuals (except one sibling pair), ranging in age from 4 years to 42 years old with biallelic PIEZO2 LOF, and report on detailed neurological examination, neurophysiology, and evaluations of pulmonary, gastrointestinal and urinary function. We identified common early neonatal and developmental consequences of PIEZO2 LOF including: reduced fetal movements (n=6), hypotonia (n=12), neonatal respiratory distress (n=9), and feeding difficulty (n=11). The age at achievement of independent ambulation (n=8) was markedly delayed (5-16 years old). Pseudoathetosis was frequently clinically observed. Orthopedic and systemic findings included: congenital hip dysplasia (n=11), arthrogryposis (n=12), early progressive scoliosis (n=12), constipation (n=11), reduced voiding frequency (n=10). The findings in these participants with LOF in PIEZO2 recapitulates what is observed in preclinical models, and highlights the developmental, motor functional, systemic, and orthopedic consequences of absent mechanotransduction and proprioception. Initially slow but improving functional gains over time suggest that these maturational processes may rely on emerging executive and motor planning skills combined with visual compensatory input. This expanded series represents the largest cohort of individuals with PIEZO2 LOF across a wide age range. Recognizing and elucidating this PIEZO2-related phenotype improves our understanding of human sensory perception and allows for development of rehabilitative measures aimed at compensatory recruitment of intact sensory modalities to optimize function. [ABSTRACT FROM AUTHOR]

Collagen XII-related disease (COL12 -RD), also classified as myopathic Ehlers-Danlos syndrome (EDS), is a congenital onset disorder with overlapping connective tissue and muscle involvement. Biallelic loss-of-function (LoF), as well as dominantly acting monoallelic variants in COL12A1 , have been recognized to cause COL12 -RD. While there have been additional reports of patients with dominant COL12A1 variants, fewer cases of the presumed more severe recessive COL12 -RD have been documented. We present clinical, immunocytochemical, and imaging data on eight additional patients from seven families, with biallelic variants in COL12A1. All patients presented with a consistent constellation of symptoms including congenital onset disease characterized by hypotonia, dysmorphic features including most notably gingival hypertrophy, prominent distal joint hyperlaxity with co-occurring contractures of large joints, and muscle involvement of variable degrees, evident both clinically and on muscle imaging. Five patients presented with a severe congenital phenotype manifesting with profound weakness, significantly delayed or minimal attainment of motor milestones, respiratory insufficiency, and feeding difficulties. Three patients presented with milder disease manifesting with mild to moderate muscle weakness and delayed milestones but were able to achieve independent ambulation. Patients were found to have biallelic LoF COL12A1 variants, except for one family with compound heterozygosity for a missense variant (p.I1393Ffs*11/ p.A1110D). Consistent with the variable clinical spectrum, in vitro collagen XII immunocytochemistry analysis in fibroblasts ranged from complete absence of collagen XII expression in a patient with severe disease, to a mild reduction in a patient with milder disease. This series aids to further establish COL12A1 as a recessive myopathic EDS gene and to expand the clinical spectrum to include a milder EDS phenotype. [ABSTRACT FROM AUTHOR]

SRPK3-TTN -related myopathy was recently established as a neuromuscular disorder inherited through digenic transmission. Here, we present clinical findings from four new pediatric cases (age range: 3-9 years; all males) diagnosed with SRPK3-TTN -related myopathy with a truncating TTN -variant and a concomitant pathogenic variant in the X-chromosomal SRPK3. All four newly identified patients presented before birth with reduced fetal movements. At birth, three patients had contractures and hypotonia, and one had respiratory involvement. Motor developmental delay and muscle weakness were evident in all patients during their first year of life. Independent ambulation was achieved between 1.5-4 years (P1-P3) while P4 has not attained independent ambulation yet (3.8 years). P1 was diagnosed with respiratory insufficiency (forced vital capacity: 57% of predicted, age 9 years). None of the patients showed cardiac involvement at their last evaluation. Muscle imaging (P2 and P3) revealed features consistent with titinopathy, including dense, deep layers of echogenicity in the triceps and paraspinal muscles (on ultrasound), and mild fibroadipose transformation of the thigh muscles, with striking selective involvement of the semitendinosus muscle (on ultrasound and MRI). P1 had two muscle biopsies, both with myopathic changes, marked by significant variation in fiber size, increased centrally placed nuclei, and predominance of type-1 fibers. The first biopsy (age 7 months) suggested rod-like structures on GT, not confirmed on electron microscopy, and the subsequent biopsy (age 13 years) was consistent with central core myopathy. This work highlights early clinical manifestations of SRPK3-TTN -related myopathy and highlights muscle imaging patterns that resemble those observed in monogenic titinopathy cases. These features should help with the potentially challenging variant interpretation in digenic TTN/SRPK3 disease and allow for a confident diagnosis of this novel condition. [ABSTRACT FROM AUTHOR]

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ASPIRO (NCT03199469) is a first-in-human clinical study of resamirigene bilparvovec (AT132), an AAV-mediated, muscle-directed gene replacement therapy in boys with ventilator-dependent XLMTM, a devastating congenital myopathy. We previously reported study outcomes through 48 weeks following dosing, including 4 participants with treatment-related, fatal, hepatobiliary toxicity. Here we report long-term outcomes among the 20 surviving dosed participants (new data cut of 01MAR2022): n=6 at 1.3 x 1014 vg/kg AT132, (dosing age, median 0.9 [range, 0.8–4.1] years; post-dose follow-up period age, 4.1 [3.9–4.4] years); n=14 at 3.5 x 1014 vg/kg AT132 (dosing age, 1.9 [0.6–6.0] years; post-dose follow-up period, 2.5 [1.9–5.6] years). All participants were ventilator dependent at baseline (mean: 22.8 hours/day). Currently, 6/6 lower- and 10/14 higher-dosed participants are ventilator independent, and 4/6 lower-, and 5/14 higher-dosed patients have been decannulated. At baseline, 1/6 lower-dose and none of higher-dose participants were able to sit independently; none had achieved more advanced milestones. At data cut, all participants have achieved major motor milestones: 5/6 lower-and 4/14 higher-dose participants achieved and maintained independent walking (achieved mean 38.8 [SD, 14.1] months); 4/6 lower-and 2/14 higher-dose participants have achieved the ability to ascend stairs. Among the surviving participants, 2/6 lower- and 7/14 higher-dose experienced treatment-related serious adverse events (SAEs); 5/20 had hepatobiliary related SAEs. Overall, significant improvements and maintenance of ventilator independence, respiratory muscle strength and skeletal muscle function were observed compared to untreated controls. These substantial long-term durable improvements must be weighed against the occurrences of fatal serious adverse events, for which the ASPIRO program is on clinical hold while relevant clinical information is being gathered and reviewed. [ABSTRACT FROM AUTHOR]