The Canadian Neuromuscular Disease Registry 2010-2019: A Decade of Facilitating Clinical Research Througha Nationwide, Pan-NeuromuscularDisease Registry.

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.

MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

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.

Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum.

Mutations in GLE1 cause two recessive subtypes of arthrogryposis multiplex congenita (AMC), a condition characterized by joint contractures at birth, and all previously reported patients died in the perinatal period. GLE1 related AMC has been almost exclusively reported in the Finnish population and is caused by a relatively common pathogenic splicing mutation in that population. Here, we report two non-Finnish brothers with novel compound heterozygous splicing mutations in GLE1, one of whom has survived to 12 years of age. We also demonstrate low levels of residual wild type transcript in fibroblasts from the surviving brother, suggesting that this residual wild-type transcript may contribute to the relatively longer-term survival in this family. We provide a detailed clinical report on the surviving patient, providing the first insight into the natural history of this rare neuromuscular disease. We also suggest that lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn disease (LAAHD), the two AMC subtypes related to GLE1, do not have sufficient clinical or molecular differentiation to be considered allelic disorders. Rather, GLE1 mutations cause a variable spectrum of AMC severity including a non-lethal variant described herein.

The prevalence of incidental findings in multiple sclerosis patients.

BACKGROUND: Incidental findings arising from imaging research have important implications for patient safety. Magnetic resonance imaging is widespread in multiple sclerosis (MS) studies and care, yet the prevalence rate of incidental findings in MS is poorly defined. The absence of such reports in the MS literature suggests that such findings may be deemed inappropriate for documentation in research publications, or possibly, not fully reported at all. OBJECTIVE: We sought to document incidental findings from a study designed to detect features of chronic cerebrospinal venous insufficiency (CCSVI) in MS patients and control subjects. METHODS: Magnetic resonance images were obtained as part of a prospective study conducted between October 2010 and September 2012. Patients with MS (relapsing-remitting, primary progressive, secondary progressive), clinically isolated syndromes, and neuromyelitis optica and age/sex-matched healthy controls were included. All images were reviewed by neuro-radiologists for quality-control purposes. RESULTS: Magnetic resonance imaging was successfully obtained in 166 participants (110 patients, 56 controls). Incidental abnormalities (n = 33) were detected in 15% of patients (n = 17) and 27% of controls (n = 15), comprising 19% overall (n = 32). CONCLUSIONS: The prevalence of incidental findings from the MS population was not significantly different from the control population. However, the overall prevalence was high and warrants a careful management strategy for future imaging studies.Prévalence des découvertes fortuites chez les patients atteints de sclérose en plaques.

Pentoxifylline as a rescue treatment for DMD: a randomized double-blind clinical trial.

OBJECTIVE: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). METHODS: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. RESULTS: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. CONCLUSION: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis.

Anti-myelin basic protein (MBP) antibodies in pediatric-onset MS and controls were characterized. Serum samples were obtained from 94 children with MS and 106 controls. Paired CSF and serum were obtained from 25 children with MS at time of their initial episode of acute demyelinating syndrome (ADS). Complementary assays were applied across samples to evaluate the presence, and the physical binding properties, of anti-MBP antibodies. While the prevalence and titers of serum anti-MBP antibodies against both immature and mature forms of MBP were similar in children with MS and in controls, binding characteristics and formal Surface Plasmon Resonance (SPR) studies indicated surprisingly high binding affinities of all pediatric anti-MBP antibodies. Serum levels of anti-MBP antibodies correlated significantly with their CSF levels, and their presence in children with MS was associated with significantly increased risk of an acute disseminated encephalomyelitis-like initial clinical presentation. While antibodies to both immature and mature forms of MBP can be present as part of the normal pediatric humoral repertoire, these anti-myelin antibodies are of surprisingly high affinity, can access the CNS during inflammation, and have the capacity to modulate disease expression. Our findings identify an immune mechanism that could contribute to the observed heterogeneity in spectrum of clinical presentations in early-onset MS.

Family-centred care and health-related quality of life of patients in paediatric neurosciences.

BACKGROUND: Little is known about the influence of contextual factors such as health services characteristics on health-related quality of life (HRQL) for children with a neurological condition. To address this gap, we conducted an exploratory study of the relationship between family-centred care (FCC) and HRQL outcomes in children from neurosciences clinics in a large acute care hospital. METHODS: A total of 187 family caregivers completed questionnaires regarding their socio-demographic status, the severity of their children's condition (FIM), perceptions of their children's HRQL (PedsQL 4.0) and their experiences of FCC (MPOC-20). Hierarchical regression analyses explored the hypothesis that FCC is a significant predictor of children's HRQL, independent of illness severity. RESULTS: Illness severity and FCC jointly explained one-third of the variance in children's total HRQL. When FCC was controlled for illness severity, it remained a significant predictor of physical, psychosocial and total HRQL scores. CONCLUSIONS: This study provides evidence that the level of FCC is positively related to paediatric HRQL independent of neurological illness severity. The implication is that the uptake of FCC practices by service providers can positively impact the quality of life of children with neurological disorders.

Incidence of acquired demyelination of the CNS in Canadian children.

BACKGROUND: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS). OBJECTIVE: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS. METHODS: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children. RESULTS: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66-18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3. CONCLUSION: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Pediatric status epilepticus: a perspective from Saudi Arabia.

The purpose of this study was to assess risk factors and management of status epilepticus and non-status epilepticus seizures at a community hospital in Saudi Arabia. The research design was a prevalence study of a convenience sample of pediatric seizure episodes admitted to a 350-bed hospital from 1992 to 1997. The mean age at presentation was 2 years, 10 months, 43% of patients had no history of seizures, and 17% were transferred from other hospitals. Fifty-nine (28%) of 212 seizure episodes were status epilepticus (SE). These SE episodes were significantly more likely than non-SE episodes to be associated with a history of seizures, prior antiepileptic drug (AED) therapy, the presence of an acute etiology, and prolonged duration of seizures before hospitalization. SE episodes were also significantly more likely than non-SE episodes to receive an inappropriate AED, to require intensive care unit admission, to suffer morbidity, and to have SE recurrence at follow-up; however, the difference in mortality was not significant. In conclusion, children with SE were more likely than those with non-SE seizures to have a history of seizures and acute brain insults, prolonged seizure duration before hospitalization, and less optimal management and outcomes. Management of SE in this referral population can be improved by more rapid access to appropriate medical care.

Brain MR imaging findings in two patients with Alpers' syndrome.

We describe the magnetic resonance (MR) imaging findings in two patients with the clinical diagnosis of progressive neuronal degeneration of childhood with liver disease (Alpers' syndrome). One patient showed atrophy of both occipital lobes, and one patient showed high signal intensity in deep gray matter nuclei and diffuse atrophy. Although the imaging findings were nonspecific, they correlated well with the patients' clinical findings.

Prevalence of sexually transmitted diseases in juvenile prostitutes and street youth.

Four groups of adolescents - 35 juvenile prostitutes, 36 street youth, 31 monogamous sexually active adolescents and 35 non-sexually active adolescents - were studied between January 1, 1988 and December 31, 1988 for the presence of sexually transmitted diseases and other genital pathogens. The high prevalence of sexually transmitted diseases found in the juvenile prostitutes (Neisseria gonorrhoeae, 49%; Chlamydia trachomatis, 83%) is in contrast to other studies, which document much lower rates of infection. This could be due to the fact that there are few studies done on juvenile prostitutes as a well defined group. Despite high risk sexual behaviour, the consistent use of contraception was low. No contraceptives were used by 57% of the juvenile prostitutes and 85% of the street youth. None of the adolescents sought medical attention although 48% of the juvenile prostitutes and 53% of the street youth had genital symptoms. It appears that the present public health education and health care delivery do not reach this high risk population.