The novel p.Ser263Phe mutation in the human high-affinity choline transporter 1 (CHT1/SLC5A7) causes a lethal form of fetal akinesia syndrome.

A subset of a larger and heterogeneous class of disorders, the congenital myasthenic syndromes (CMS) are caused by pathogenic variants in genes encoding proteins that support the integrity and function of the neuromuscular junction (NMJ). A central component of the NMJ is the sodium-dependent high-affinity choline transporter 1 (CHT1), a solute carrier protein (gene symbol SLC5A7), responsible for the reuptake of choline into nerve termini has recently been implicated as one of several autosomal recessive causes of CMS. We report the identification and functional characterization of a novel pathogenic variant in SLC5A7, c.788C>T (p.Ser263Phe) in an El Salvadorian family with a lethal form of a congenital myasthenic syndrome characterized by fetal akinesia. This study expands the clinical phenotype and insight into a form of fetal akinesia related to CHT1 defects and proposes a genotype-phenotype correlation for the lethal form of SLC5A7-related disorder with potential implications for genetic counseling.

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing-like attacks in a pediatric patient found to have a pontine capillary telangiectasia and developmental venous anomaly: A case report exploring the root of the problem.

Introduction Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)-like attacks are rarely reported in the pediatric population and may remain undiagnosed and under-investigated as a result. Case presentation We present a case of a 15-year-old male with intermittent, episodic, right-sided brief headaches most in keeping with SUNCT, initially diagnosed as paroxysmal hemicrania, but with no response to indomethacin. The pain was likewise not responsive to typical migraine treatments or steroids. Management and outcome Contrast-enhanced magnetic resonance imaging demonstrated a right pontine capillary telangiectasia with an associated developmental venous anomaly that was adjacent to the root of the right trigeminal nerve. Differential diagnosis included first division trigeminal neuralgia with autonomic features. The patient's pain was partially alleviated by oxygen administration and responded well to carbamazepine; he remained pain free on carbamazepine a year later. Conclusion This case highlights the diagnostic dilemma of differentiating SUNCT from trigeminal neuralgia with autonomic features, both of which are rare diagnoses in pediatric patients, and the importance of appropriate neuroimaging to rule out secondary causes in patients presenting with trigeminal autonomic cephalalgias, recognizing that abnormalities identified on neuroimaging, such as vessels adjacent to the trigeminal nerve, may not be causative findings.

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies.

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core-rod myopathy, congenital fiber-type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal-dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca(2+) sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non-hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin-actin association or tropomyosin head-to-tail binding.

Cooperative International Neuromuscular Research Group Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy.

INTRODUCTION: Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). METHODS: This investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. RESULTS: Two hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. CONCLUSIONS: We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort.

Respiratory characteristics in children with spinal muscular atrophy type 1 receiving nusinersen.

BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a neuromuscular disorder with a natural history of chronic respiratory failure and death during infancy without ventilation. Recently, disease-modifying therapies such as nusinersen have improved disease trajectory. However, objective data on the trajectory of polysomnography outcomes, the relationship between motor scores and respiratory parameters, respiratory technology dependence and healthcare utilization in children with SMA1 remain to be elucidated. METHODS: This was a retrospective observational study of children with SMA1 receiving nusinersen between October 2016 and February 2021 at two tertiary care hospitals in Canada. Baseline polysomnography data, motor scores, respiratory technology, and unanticipated healthcare utilization were examined. RESULTS: Eleven children (five females, two SMN2 copies each) were included. Median (interquartile range [IQR]) age at diagnosis was 3.6 (2.8-5.0) months and age at diagnostic polysomnogram following nusinersen initiation was 9.4 (5.3-14.0) months. Nusinersen was initiated at a median (IQR) age of 5.4 (3.4-7.6) months and 8/11 children had respiratory symptoms at that time. Diagnostic polysomnography data showed a median (IQR) central apnea-hypopnea index (AHI) of 4.1 (1.8-10.0) and obstructive AHI of 2.2 (0-8.0) events/h. We observed an inverse relationship between motor scores and central apnea-hypopnea indices. All children required ventilatory support at the end of the study period. CONCLUSION: This study showed abnormal polysomnography parameters and need for ventilation despite nusinersen suggesting ongoing need for regular monitoring with polysomnography. Understanding the respiratory disease trajectory of children undergoing treatment with nusinersen will inform decision-making regarding optimal timing of ventilatory support initiation.

Alberta Spinal Muscular Atrophy Newborn Screening-Results from Year 1 Pilot Project.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by biallelic pathogenic/likely pathogenic variants of the survival motor neuron 1 (SMN1) gene. Early diagnosis via newborn screening (NBS) and pre-symptomatic treatment are essential to optimize health outcomes for affected individuals. We developed a multiplex quantitative polymerase chain reaction (qPCR) assay using dried blood spot (DBS) samples for the detection of homozygous absence of exon 7 of the SMN1 gene. Newborns who screened positive were seen urgently for clinical evaluation. Confirmatory testing by multiplex ligation-dependent probe amplification (MLPA) revealed SMN1 and SMN2 gene copy numbers. Six newborns had abnormal screen results among 47,005 newborns screened during the first year and five were subsequently confirmed to have SMA. Four of the infants received SMN1 gene replacement therapy under 30 days of age. One infant received an SMN2 splicing modulator due to high maternally transferred AAV9 neutralizing antibodies (NAb), followed by gene therapy at 3 months of age when the NAb returned negative in the infant. Early data show that all five infants made excellent developmental progress. Based on one year of data, the incidence of SMA in Alberta was estimated to be 1 per 9401 live births.

A population-based study of dystrophin mutations in Canada.

INTRODUCTION: We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period. OBJECTIVES: We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009. METHODS: De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics. RESULTS: 773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12. CONCLUSION: This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade.

Mutations in TPM3 are a common cause of congenital fiber type disproportion.

OBJECTIVE: Congenital fiber type disproportion (CFTD) is a rare form of congenital myopathy in which the principal histological abnormality is hypotrophy of type 1 (slow-twitch) fibers compared with type 2 (fast-twitch) fibers. To date, mutation of ACTA1 and SEPN1 has been associated with CFTD, but the genetic basis in most patients is unclear. The gene encoding alpha-tropomyosin(slow) (TPM3) is a rare cause of nemaline myopathy, previously reported in only five families. We investigated whether mutation of TPM3 is a cause of CFTD. METHODS AND RESULTS: We sequenced TPM3 in 23 unrelated probands with CFTD or CFTD-like presentations of unknown cause and identified novel heterozygous missense mutations in five CFTD families (p. Leu100Met, p.Arg168Cys, p.Arg168Gly, p.Lys169Glu, p.Arg245Gly). All affected family members that underwent biopsy had typical histological features of CFTD, with type 1 fibers, on average, at least 50% smaller than type 2 fibers. We also report a sixth family in which a recurrent TPM3 mutation (p.Arg168His) was associated with histological features of CFTD and nemaline myopathy in different family members. We describe the clinical features of 11 affected patients. Typically, there was proximal limb girdle weakness, prominent weakness of neck flexion and ankle dorsiflexion, mild facial weakness, and mild ptosis. The age of onset and severity varied, even within the same family. Many patients required nocturnal noninvasive ventilation despite remaining ambulant. INTERPRETATION: Mutation of TPM3 is the most common cause of CFTD reported to date.

Parental stress and quality of life in children with neuromuscular disease.

This study examined health-related quality of life and parental stress among pediatric neuromuscular patients with or without home mechanical ventilation. Parents completed the Parenting Stress Index or Stress Index for Parents of Adolescents, depending on their child's age. The Pediatric Quality of Life Inventory measured quality of life in children with neuromuscular disease. One hundred and nine families participated; 19 (17%) families had a child with neuromuscular disease requiring home mechanical ventilation. Overall, children on home mechanical ventilation had significantly lower mean total Pediatric Quality of Life Inventory scores than nonventilated children (47.9 versus 61.5, respectively; P = 0.013). No significant difference in mean total stress scores was found between parents of pediatric neuromuscular patients with or without home mechanical ventilation. Despite their child's lower health-related quality of life, parents of pediatric neuromuscular patients requiring home mechanical ventilation did not report significantly higher parental stress than parents of nonventilated children or parents in the normative sample. We postulated that for parents living with the constant demands of caring for their child with neuromuscular disease requiring home mechanical ventilation, these caretaking demands, over time, had become part of "normal" life and were not identified as creating additional stress.

Vanishing white matter disease with periodic (paroxysmal) hemiparesis.

Vanishing white matter disease is a chronically progressive leukodystrophy with periods of acute deterioration after head trauma and febrile illness. This report describes a child with genetically and clinically confirmed vanishing white matter disease exhibiting frequent episodes of right-sided hemiplegia, aphasia, and headache resolving fully within hours to days. This report describes a case of this condition presenting with episodes of hemiparesis with full discovery to baseline. Some possible mechanisms explaining this unusual presentation are provided.

The Landau-Kleffner syndrome.

Landau-Kleffner Syndrome is a rare childhood disorder which involves seizures and acquired aphasia. Anticonvulsants, or the passage of time, may control the seizures, but speech recovery is variable, and the aphasia may persist.

Clinical characteristics of pediatric myasthenia: a surveillance study.

OBJECTIVE: To evaluate the incidence, clinical features, diagnostic, and treatment trends of pediatric myasthenia in Canada. METHODS: Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data. Inclusion criteria were any child <18 years old with ≥1 of the following: (1) fluctuating ptosis or extraocular weakness, (2) skeletal muscle weakness or fatigue, and (3) any of the following supportive tests: clinical response to acetylcholinesterase inhibitor, positive antibodies, abnormal slow repetitive nerve stimulation, or single-fiber electromyography. RESULTS: In 2 years of surveillance, 57 confirmed cases were reported. There were 34 generalized and 18 ocular reports of juvenile myasthenia gravis plus 5 congenital myasthenic syndrome cases. There were 14 incident cases in 2010 and 6 in 2011. Age of onset ranged from "birth" to 17 years for the generalized form compared with 18 months to 11 years for the ocular subtype. Positive acetylcholine receptor titers were found in 22 (67%) of 33 generalized cases and 8 (44%) of 18 ocular patients. Of patients started on pyridostigmine, improvement was noted in 33 (100%) of 33 generalized cases and 15 (88%) of 17 ocular cases. CONCLUSIONS: This study represents the largest descriptive series of pediatric myasthenia in North America and provides valuable information about clinical characteristics. A high index of suspicion is important for this treatable disease. Children generally respond promptly to readily available therapies.

Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients?

INTRODUCTION: Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, is caused by mutations of the dystrophin gene. Removal of an exon or of multiple exons using antisense molecules has been demonstrated to allow synthesis of truncated 'Becker muscular dystrophy-like' dystrophin. AREAS COVERED: Approximately 15% of DMD cases are caused by a nonsense mutation. Although patient databases have previously been surveyed for applicability to each deletion mutation pattern, this is not so for nonsense mutations. Here, we examine the world-wide database containing notations for more than 1200 patients with nonsense mutations. Approximately 47% of nonsense mutations can be potentially treated with single exon skipping, rising to 90% with double exon skipping, but to reach this proportion requires the development of exon skipping molecules targeting some 68 of dystrophin's 79 exons, with patient numbers spread thinly across those exons. In this review, we discuss progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough. EXPERT OPINION: Antisense-mediated exon skipping therapy is targeted highly at the individual patient and is a clear example of personalized medicine. An efficient regulatory path for drug approval will be a key to success.

Symptomatic dystrophinopathies in female children.

Although manifesting female carriers of dystrophinopathies have been documented in adults, there are few reports of females presenting with symptomatic dystrophinopathies during childhood. The Canadian Pediatric Neuromuscular Group identified and characterized nine cases of female children 16 years or younger with genetically and/or histologically confirmed symptomatic dystrophinopathy, with an age range of 2-10 years at presentation. Presenting symptoms included proximal muscle weakness (6/9), calf pseudohypertrophy (5/9), abnormal gait (5/9) and myalgias (5/9). Five patients were noted to have significant behavioural and learning issues. The patients had a delay in diagnosis of 4 years from symptom onset. Skewed X inactivation was noted in 5/9 patients, while one patient had X inactivation levels in the normal range. Two of the patients were found to have X/autosome translocation, one of whom also had skewed X-inactivation. Increased awareness of manifesting females with dystrophinopathies will allow for earlier diagnosis and appropriate management for this rare group of patients.

A 10-month-old infant with reversible findings of brain death.

Death has occurred when there is irreversible loss of integration of the organism as a whole, and brain death is said to be a criterion for death. In the present case, a 10-month-old boy was found submerged in a bathtub and was given cardiopulmonary resuscitation for 37 minutes. He had received therapeutic dosing of phenobarbital and midazolam up to 5 hours prior to a brain death examination. He fulfilled all criteria for brain death according to Canadian Neurological Determination of Death Forum recommendations on an examination 42 hours after the drowning event, but started breathing another 15 hours later. Eleven previously published cases of purported reversal of findings of brain death are discussed here, including two infants who fulfilled all criteria for brain death for more than 24 hours. Recommendations for brain death determination may require revision for infants, to more clearly define a time interval between examinations and to incorporate consideration of confounding sedative drug effects. Together with previous reports, the present case calls into question the assumption that brain death as currently diagnosed is irreversible, and therefore equivalent to death of the patient.

Atypical facet of Möbius syndrome: association with facioscapulohumeral muscular dystrophy.

We describe a patient with facioscapulohumeral muscular dystrophy (FSHD) associated with Möbius syndrome and congenital ophthalmoplegia. This 7-year-old girl had profound limitation of extraocular movements since birth, congenital facial diplegia, neonatal hypotonia, and progressive limb-girdle weakness. FSHD genetic testing revealed a pathogenic haplotype with a D4Z4 repeat of 30 kb. The father carries the same allele, although is minimally affected. This unusual case expands the genotypic-phenotypic spectrum of FSHD.

Diagnosis of limb-girdle muscular dystrophy 2A by immunohistochemical techniques.

The Western blot technique is currently the standard detection method for suspected limb girdle muscular dystrophy (LGMD) 2A (calpainopathy). This is the first report in the English literature of the successful application of immunohistochemical techniques to support a diagnosis of LGMD 2A. This approach is straightforward and appears to be reasonably specific. We propose that immunohistochemical methods should be re-evaluated for the screening of undiagnosed patients with suspected LGMD 2A.

A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?

OBJECTIVE: The purpose of this study was to review the experience with herpes simplex encephalitis at the Hospital for Sick Children over the past 12 years. METHODS: All patients who were admitted to our institution with acute encephalitis between January 1994 and December 2005 were enrolled prospectively in an encephalitis registry. Children from the registry with herpes simplex encephalitis were included in this study; we detailed the clinical presentations, laboratory findings, electroencephalographic findings, diagnostic imaging findings, treatments, and outcomes for all cases. RESULTS: Of 322 cases of acute encephalitis, 5% were caused by herpes simplex virus. Initially negative herpes simplex virus cerebrospinal fluid polymerase chain reaction results were found in 2 cases (13%), but results became positive in repeat cerebrospinal fluid analyses. Classic clinical presentations were seen in 75% of cases, cerebrospinal fluid pleocytosis was found in 94%, elevated cerebrospinal fluid protein levels were found in 50%, electroencephalographic changes were observed in 94%, and diagnostic imaging abnormalities were noted in 88%. All patients were treated with intravenous acyclovir. Neurologic sequelae occurred in 63% of cases, including seizures in 44% and developmental delays in 25%. There were no deaths in this study group. CONCLUSIONS: Herpes simplex encephalitis continues to be associated with poor long-term neurologic outcomes despite appropriate therapy. Cerebrospinal fluid polymerase chain reaction results may be negative early in the course of herpes simplex encephalitis; therefore, repeat cerebrospinal fluid analysis should be considered if herpes simplex encephalitis is suspected. Atypical forms of herpes simplex virus central nervous system disease may occur in children.