Clinical trials in spinal muscular atrophy (SMA) have shown that early treatment improves outcomes, prompting inclusion in newborn screening (NBS) programs worldwide. The province of Quebec launched its SMA NBS program in October 2023, with a rapidly progressive implementation. We describe the program’s first-year experience, focusing on screening yield, birth prevalence, clinical outcomes, and challenges. In the first year, 6 of 67,933 newborns screened positive for SMA, all subsequently confirmed by diagnostic testing. Of these, 4 newborns (67%) had two SMN2 copies and 2 newborns (33%) had four copies. Additionally, one symptomatic compound heterozygote infant presented during this period, indicating a provincial birth prevalence of 1 in 9705 live births (95% CI: 1:20,032–1:4701). Two newborns with two SMN2 copies were symptomatic at initial consultation; one transitioned to palliative care and died at 43 days of life. Surviving newborns initiated treatment at a median age of 30 days (range: 9–103 days), with four receiving onasemnogene abeparvovec and one nusinersen. Motor outcomes at three or six months were stable or improved among treated infants. Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program’s impact, which is expected with full automation.

Oculogastrointestinal neurodevelopmental syndrome (OGIN; OMIN #619318) is a rare autosomal recessive disorder resulting from pathogenic variants in the CAPN15 gene. OGIN syndrome has been previously seen to affect many different body systems and has been described to cause coloboma, imperforate anus, structural cardiac defects, and horseshoe kidneys. There is still little information about the phenotypic spectrum of this disease. This case series aims to describe the phenotypic spectrum and development of affected individuals. Our study includes eight patients-five patients previously described, and three newly identified patients from centers in Ontario and Quebec ranging from three to 15 years of age. All the French-Canadian patients in our cohort were homozygous for the c. 1838C>T (p. Ser613Leu) variant. We also describe a non-French-Canadian patient who is compound heterozygous for the variants c.1957G>A (p. Gly653Ser) (paternally inherited) and c.2520delC p. Val841Trpfs133 (maternally inherited). Through this cohort, we describe some rare manifestations of OGIN syndrome; all four female patients had vaginal fistulae, and four of the patients had sensorineural hearing loss. All eight patients had pancreatic insufficiency requiring pancreatic enzyme replacement. More research is needed to investigate the genotype-phenotype correlation, as well as assess long-term complications and natural history of the disease.

To assess the feasibility of smartphone-based digital biomarkers (dBMKs) to objectively measure lower and upper limb motor functions in patients with Duchenne muscular dystrophy (DMD).

PepGen's enhanced delivery oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and nuclear uptake of therapeutic oligonucleotides. PGN-EDO51 is PepGen's investigational clinical candidate for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. In nonclinical studies and a Phase 1 trial in healthy volunteers, PepGen's technology demonstrated significant improvement in the delivery of oligonucleotides resulting in higher levels of tissue concentrations and exon 51 skipping. Nuclear delivery of the EDO was confirmed in human tissue from the Phase 1 trial. Collective nonclinical and clinical data strongly suggest that repeat administration of PGN-EDO51 in people with DMD may lead to higher production of functional dystrophin, potentially resulting in improved clinical outcomes. PepGen's Phase 2 clinical program includes 2 studies: CONNECT1-EDO51, an open-label multiple-ascending dose (MAD) study being conducted in Canada (NCT06079736), and CONNECT2-EDO51, a multinational randomized placebo-controlled MAD study. Participants who complete the MAD period in either study will have the opportunity to continue dosing in a long-term extension. The CONNECT1-EDO51 study objective is to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (dystrophin, exon skipping) of PGN-EDO51 following repeat dosing in male participants with DMD amenable to exon 51 skipping. Muscle biopsies are taken at Baseline and Week 13. Main inclusion criteria are age ≥8 years with a confirmed genetic diagnosis of DMD amenable to exon 51 skipping, and weight ≥25 kg. Participants will receive PGN-EDO51 in ascending doses across 3 cohorts. All participants (N=10) will receive 4 doses of PGN-EDO51 at approximately 4-week intervals over 12 weeks. Participants in the first cohort have received repeat doses of 5 mg/kg PGN-EDO51. Safety and initial dystrophin results from this cohort will be presented.

PLPHP (pyridoxal-phosphate homeostasis protein) deficiency is caused by biallelic pathogenic variants in PLPBP and is a rare cause of pyridoxine-responsive disorders. We describe three French-Canadian individuals with PLPHP deficiency, including one with unusual paroxysmal episodes lacking EEG correlation with a suspicious movement disorder, rarely reported in B6RDs. In addition, we review the clinical features and treatment responses of all 51 previously published individuals with PLPHP deficiency. Our case series underlines the importance of considering PLPBP mutations in individuals with partially B6-responsive seizures and highlights the presence of a founder effect in the French-Canadian population.

Background: Hormonal therapy is a standard treatment for infantile spasms. The high doses given and long treatment duration expose patients to the risk of adrenal insufficiency (AI). This study aims to quantify the incidence of AI among children with infantile spasms treated with corticosteroids and/or adrenocorticotropic hormone (ACTH). Methods: A retrospective chart review of patients treated for infantile spasms was performed between January 2009 to March 2020 in one pediatric specialized hospital. Variables collected included patient and treatment characteristics, risk factors of AI and adrenal function testing. Analysis included descriptive statistics. Results: Thirty-one patients met the inclusion criteria and received a total of 33 separated courses of treatment. Adrenal function following each course of treatment was evaluated in all patients. AI occurred in 25/33 (76% [95CI 58-89]) children. There was no predictive factor of AI. No drug regimen was deemed safe. The two patients (6%) with an acute adrenal crisis were the youngest of the cohort. Conclusions: Adrenal suppression is frequent and can lead to adrenal crisis after standard hormonal therapy for infantile spasms. A routine laboratory assessment of adrenal function should be done for all patients. Hydrocortisone replacement therapy should be given until testing results are obtained, particularly for younger infants.

X linked myotubular myopathy (XLMTM) is a rare, typically severe, congenital myopathy that often results in significant weakness from birth, with a need for mechanical ventilation and wheelchair assistance. It is caused by a mutation in the myotubularin (MTM1) gene, whose gene product plays an important role in muscle cell differentiation. In addition to the important role of MTM1 in skeletal muscle, there is emerging evidence that patients with XLMTM can have multisystem abnormalities, including liver concerns and cognitive impairment. An organ system of particular interest for us is the Central Nervous System (CNS). Brain involvement has been described in different neuromuscular disorders, though not typically in congenital myopathies. In contrast to other congenital myopathies, there are a handful of case reports and informal observations of structural brain abnormalities in XLMTM. However, there has not yet been a comprehensive review of neuroimaging features in XLMTM. We have developed a multi-site study, aiming to retrospectively gather brain MRI and relevant clinical information for patients with XLMTM around the world. Our goals are to define the relative prevalence of CNS structural anomalies in XLMTM and to describe the common features of brain MRIs from XLMTM patients. In particular, we hope to elucidate unifying or common changes amongst many patients, and whether they correlate with birth-related injury, genotype, clinical phenotype, long-term outcome, or survival. We hypothesize that there is unrecognized brain involvement XLMTM, as will be reflected by brain MRI findings, and that these changes will correlate with both clinical outcomes and the degree of illness/adversity. In addition to study design, we will present our findings from the first cases collected for the study. X linked myotubular myopathy (XLMTM) is a rare, typically severe, congenital myopathy that often results in significant weakness from birth, with a need for mechanical ventilation and wheelchair assistance. It is caused by a mutation in the myotubularin (MTM1) gene, whose gene product plays an important role in muscle cell differentiation. In addition to the important role of MTM1 in skeletal muscle, there is emerging evidence that patients with XLMTM can have multisystem abnormalities, including liver concerns and cognitive impairment. An organ system of particular interest for us is the Central Nervous System (CNS). Brain involvement has been described in different neuromuscular disorders, though not typically in congenital myopathies. In contrast to other congenital myopathies, there are a handful of case reports and informal observations of structural brain abnormalities in XLMTM. However, there has not yet been a comprehensive review of neuroimaging features in XLMTM. We have developed a multi-site study, aiming to retrospectively gather brain MRI and relevant clinical information for patients with XLMTM around the world. Our goals are to define the relative prevalence of CNS structural anomalies in XLMTM and to describe the common features of brain MRIs from XLMTM patients. In particular, we hope to elucidate unifying or common changes amongst many patients, and whether they correlate with birth-related injury, genotype, clinical phenotype, long-term outcome, or survival. We hypothesize that there is unrecognized brain involvement XLMTM, as will be reflected by brain MRI findings, and that these changes will correlate with both clinical outcomes and the degree of illness/adversity. In addition to study design, we will present our findings from the first cases collected for the study.

There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia. Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.

Our knowledge of congenital myopathies is expanding. Recent genes have been identified in troponin variants, among them only 2 families with TNNC2 mutations have been described. We report an 18 yo man with a severe neonatal congenital myopathy that slowly improved over time. He was born with significant hypotonia and feeding difficulties. He was fed through a gastrostomy until 5 years of age. He walked independently at 4 yo. He is now able to ride a mountain bike on a regular basis. His physical examination showed a distal more than proximal weakness in upper limb and a more pelvic girdle weakness in lower limbs. Striking features include mild oculoparesia and hypomimic face with high arch palate. CK levels were normal. Two EMGs showed nonspecific myopathic features. Muscle biopsy demonstrated nonspecific moderate myopathic features. Interestingly, muscle MRI showed very discrete fatty infiltration in the thigh. Next generation sequencing panels for dystrophic and non-dystrophic myopathies were negative. Whole exome sequencing identified a novel heterozygous mutation c.204 C>A in TNNC2. This case expands the clinical phenotype of patients with congenital myopathy related to TNNC2.

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.

ABHD16A (abhydrolase domain-containing protein 16A, phospholipase) encodes the major phosphatidylserine (PS) lipase in the brain. PS lipase synthesizes lysophosphatidylserine, an important signaling lipid that functions in the mammalian central nervous system. ABHD16A has not yet been associated with a human disease. In this report, we present a cohort of 11 affected individuals from six unrelated families with a complicated form of hereditary spastic paraplegia (HSP) who carry bi-allelic deleterious variants in ABHD16A. Affected individuals present with a similar phenotype consisting of global developmental delay/intellectual disability, progressive spasticity affecting the upper and lower limbs, and corpus callosum and white matter anomalies. Immunoblot analysis on extracts from fibroblasts from four affected individuals demonstrated little to no ABHD16A protein levels compared to controls. Our findings add ABHD16A to the growing list of lipid genes in which dysregulation can cause complicated forms of HSP and begin to describe the molecular etiology of this condition.

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

Background: Mutations in the slow skeletal muscle troponin T ( TNNT1 ) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1 . They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1 -related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

Background: Nusinersen is approved for spinal muscular amyotrophy type I,II,III and is available for adult and pediatric populations since January 2019 at the CHU de Québec-UL. Methods: Patients who received at least one dose of nusinersen between January 2019 and March 2021 were included. Required information was gathered from patients’ charts. Results: Ten adults (70 injections) and 23 infants and children (202 injections) were included. No child but two adults stopped the therapy for personal reasons. Tests were performed at 0, 6, 18, 24 months when possible to assess efficacy, tolerability and quality of life perception (Table 1). Preliminary data shows stabilization or improvement for many tests. Conclusions: Nusinersen is well tolerated. Favorable effects were observed in both populations. A monitoring is still imperative for an objective assessment and for evaluation of the most relevant tests. Long term benefits remain to be demonstrated but results are encouraging.

Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene ( NEB ) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB . The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.