Single-institution Series of Hirayama Disease in North America.

STUDY DESIGN: A retrospective chart review. OBJECTIVE: The aims of this study were to review pathophysiology, workup, and treatment for Hirayama disease (HD); and to assess outcomes from a single institution. SUMMARY OF BACKGROUND DATA: HD is a rare, painless, cervical myelopathy with distal upper extremity weakness, muscle wasting, and spinal cord atrophy. Disease progression-a consequence of repeat flexion injury-occurs up to 5 years from the initial diagnosis. METHODS: Single-institution review of pediatric HD patients from 2010 to 2020. RESULTS: Patients (n=10 male, n=2 female) presented in the second decade (14-20 y) with painless progressive distal upper extremity weakness and atrophy without sensory loss. Electromyography (n=12) demonstrated denervation in C7-T1 myotomes and flexion/extension magnetic resonance imaging showed focal cord atrophy and anterior displacement of the posterior dura with epidural enhancement in flexion. Treatment included observation and external orthoses (n=9) and anterior cervical discectomy with fusion (n=3). One of the 9 patients managed conservatively experienced further deterioration; no patient who underwent anterior cervical discectomy with fusion progressed. CONCLUSIONS: Patients with HD require a multidisciplinary approach to diagnosis and treatment to preserve function. Treatment is preventive and aims to minimize flexion injury by inhibiting motion across involved joints. First-line management is avoidance of neck flexion and use of rigid orthosis; in cases of failed conservative management and/or rapid clinical deterioration, surgical fixation can be offered.

Variants in DTNA cause a mild, dominantly inherited muscular dystrophy.

DTNA encodes α-dystrobrevin, a component of the macromolecular dystrophin-glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in DTNA have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic DTNA variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G > A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del DTNA variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, ß, δ and γ-sarcoglycans, and α and ß-dystroglycans. The DTNA deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of DTNA cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic DTNA variants as a novel cause of skeletal muscle disease in humans.

Upper motor neuron signs and early onset gait abnormalities in young children with bi-allelic VWA1 variants.

Bi-allelic loss-of-function variants in Von Willebrand factor type A (VWA1) were recently discovered to lead to an early onset motor neuropathy or neuromyopathy. What makes this discovery particularly notable is the high frequency of one of the VWA1 (NM_022834.5) founder variants, c.62_71dup (p.Gly25ArgfsTer74), which nears 0.01% in European populations, and suggests that there may be a wide spectrum of disease features and severity. Here, we report two cases from nonconsanguineous families in North America that presented in early childhood with lower extremity weakness and prominent foot deformities, and were found to carry bi-allelic variants in VWA1. We draw focus to upper motor neuron signs and abnormal gait phenotypes as presenting symptoms in VWA1-related disorder and expand the clinical and molecular spectrum.

Diagnostic capabilities of nanopore long-read sequencing in muscular dystrophy.

Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long-read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy.

Electromyography in infants: experience from a pediatric neuromuscular center.

Electromyography plays a pivotal role in diagnosing neuromuscular disorders. The purpose of this study was to investigate the role of electromyography in infants. We performed a retrospective study of the infants who underwent electromyography from 2003 to 2017 and recorded demographic profile, indication, electrodiagnostic findings, and final diagnosis from the follow-up data. 179 studies were completed; electromyography was abnormal in 109 (60.9%) patients. The most common referral indication was hypotonia followed by birth trauma related injuries and rule out neuromuscular disorders. The most common electrodiagnostic diagnosis was localized to muscles followed by plexus and motor neurons. Among the patients with normal electromyography, the most common diagnosis was due to myopathies. Electromyography plays an important role in the workup of neuromuscular disorders in infants though with increased utilization of genetic testing we observed a declining trend in the number of electromyography performed in the latter half the study.

BET1 variants establish impaired vesicular transport as a cause for muscular dystrophy with epilepsy.

BET1 is required, together with its SNARE complex partners GOSR2, SEC22b, and Syntaxin-5 for fusion of endoplasmic reticulum-derived vesicles with the ER-Golgi intermediate compartment (ERGIC) and the cis-Golgi. Here, we report three individuals, from two families, with severe congenital muscular dystrophy (CMD) and biallelic variants in BET1 (P1 p.(Asp68His)/p.(Ala45Valfs*2); P2 and P3 homozygous p.(Ile51Ser)). Due to aberrant splicing and frameshifting, the variants in P1 result in low BET1 protein levels and impaired ER-to-Golgi transport. Since in silico modeling suggested that p.(Ile51Ser) interferes with binding to interaction partners other than SNARE complex subunits, we set off and identified novel BET1 interaction partners with low affinity for p.(Ile51Ser) BET1 protein compared to wild-type, among them ERGIC-53. The BET1/ERGIC-53 interaction was validated by endogenous co-immunoprecipitation with both proteins colocalizing to the ERGIC compartment. Mislocalization of ERGIC-53 was observed in P1 and P2's derived fibroblasts; while in the p.(Ile51Ser) P2 fibroblasts specifically, mutant BET1 was also mislocalized along with ERGIC-53. Thus, we establish BET1 as a novel CMD/epilepsy gene and confirm the emerging role of ER/Golgi SNAREs in CMD.

Developing outcome measures of disease activity in pediatric myasthenia.

INTRODUCTION: Pediatric myasthenia encompasses juvenile myasthenia gravis (JMG) and congenital myasthenic syndrome (CMS), which are chronic disorders with fluctuating symptoms amenable to medical therapy. Disease activity and treatment response may be difficult to assess, but, unlike adults, outcome measures have not been developed in children. METHODS: The study was performed in children (0-18 years of age) at the neuromuscular center of a pediatric hospital over a 3-year period. Patients were recruited prospectively as part of their routine clinical care. Demographic data, diagnosis (JMG/CMS), and the following scales were recorded at each visit: Myasthenia Gravis Foundation of America (MGFA) class, Myasthenia Gravis Composite (MGC), and Pediatric Myasthenia-Quality of Life 15 (PM-QOL15). RESULTS: Thirty-three patients (24 JMG, 9 CMS) were included in the study, 22 had two or more visits. We established known-groups validity of the MGC and PM-QOL15 scores as compared with the MGFA class. To establish concurrent validity, we constructed a receiver-operating characteristic curve and calculated threshold values of MGC and PM-QOL15 with optimal sensitivity and specificity for identifying a patient with more severe (MGFA III or higher) disease. Finally, we demonstrated the concordance between the MGC and PM-QOL15 by their statistically significant positive Pearson and Spearman correlations. DISCUSSION: Our study suggests that MGC and PM-QOL15 are important disease outcome measures in pediatric myasthenia that are easy to administer and provide reliable assessment of disease activity in the clinic setting. Further studies are needed to validate their use for pediatric clinical research trials.

Congenital Myasthenic Syndrome From a Single Center: Phenotypic and Genotypic features.

BACKGROUND: Congenital myasthenic syndrome is a group of rare genetic disorders affecting transmission across the neuromuscular junction. Patients present with variable ocular, bulbar, respiratory, and extremity weakness that may respond to symptomatic therapies. METHODS: We identified 18 patients with congenital myasthenic syndrome from a pediatric neuromuscular center over a decade. Through a retrospective chart review, we characterize demographic profile, clinical features, genetic variants, treatment, and follow-up of these patients. RESULTS: Patients had the following genetic subtypes: CHRNE (6), CHAT (2), MUSK (2), DOK7 (2), COLQ (1), RAPSN (1), PREPL (1), GFPT1 (1), CHRBB1 (1), and CHRNA1 (1). The phenotype varied based on the genetic variants, though most patients have generalized fatigable weakness affecting ocular, bulbar, and extremity muscles. There was a significant delay in the diagnosis of this condition from the onset of symptoms. Although most patients improved with pyridostigmine, some subtypes showed worsening with pyridostigmine and others benefited from albuterol, ephedrine, or 3,4-diaminopyridine treatment. CONCLUSION: Increasing recognition of this rare syndrome will lead to early diagnosis and prompt treatment. Prompt utilization of genetic testing will identify novel variants and the expanding phenotype of this condition.

Update on Muscular Dystrophies with Focus on Novel Treatments and Biomarkers.

PURPOSE OF REVIEW: Muscular dystrophies are a heterogeneous group of inherited muscular disorders characterized by progressive muscle weakness and in many cases cardiac and respiratory muscle involvement. Historically, these disorders are considered incurable with grave prognoses. The genes responsible for most muscular dystrophies are known, and early diagnosis is achievable with proper clinical recognition and advanced genetic testing. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population. RECENT FINDINGS: The therapeutic landscape of muscular dystrophies has changed with the development of new approved treatments for Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy. This has paved the way for the development of novel therapeutic strategies for not only DMD but also other muscular dystrophies. This article reviews recent advances in the development of novel treatments and biomarkers in the realm of muscular dystrophies commonly encountered in pediatric population.

Acute Neuromuscular Disorders in the Pediatric Intensive Care Unit.

BACKGROUND: The neuromuscular disorders encountered in the pediatric intensive care unit (PICU) encompass a broad spectrum of pathologies. These include acute disorders (eg, Guillain-Barre syndrome), acute-on-chronic disorders (eg, myasthenia gravis), progressive disorders (eg, muscular dystrophy), and disorders that develop in the PICU (eg, critical illness myopathy/polyneuropathy). Familiarity with the presenting features of these disorders is of paramount importance in facilitating timely diagnosis. METHODS: We conducted a retrospective review of the medical records of patients admitted to the PICU or Intermediate Care Program (ICP) at a single tertiary children's hospital from 2006 to 2017 with an acute or acute-on-chronic neuromuscular disorder. We did not include patients with a known progressive neuromuscular disorder or critical illness myopathy/polyneuropathy. RESULTS: Twenty-four patients were admitted to the PICU/ICP with acute or acute-on-chronic neuromuscular disorders. Diagnosis and indication for ICU/ICP admission were Guillain-Barre syndrome (n = 6; respiratory failure: 3, respiratory monitoring: 2, autonomic instability: 1), myasthenia gravis (n = 5; airway clearance: 3, respiratory failure: 2), acute flaccid myelitis (n = 3; respiratory failure: 2, respiratory monitoring: 1), periodic paralysis (n = 3; intravenous potassium replacement), rhabdomyolysis (n = 3; monitoring for electrolyte derangements), infant botulism (n = 2; respiratory failure), chronic demyelinating polyneuropathy (n = 1; respiratory failure), and congenital myasthenic syndrome (n = 1; apnea). No patients were admitted to the PICU/ICP with a diagnosis of tick paralysis, acute intermittent porphyria, or inflammatory myopathy. CONCLUSIONS: Although acute and acute-on-chronic neuromuscular disorders are encountered relatively rarely in the PICU, familiarity with the presenting features of these disorders is important in facilitating timely diagnosis. This, in turn, enables the institution of effective management strategies, thereby avoiding complications associated with diagnostic delays.