Assessing Long-Term Neurologic Outcomes in SAMD9L-Related Ataxia-Pancytopenia Syndrome.

BACKGROUND: Most published reports on SAMD9L-related ataxia-pancytopenia syndrome (ATXPC) have emphasized the hematologic findings. Fewer details are known about the progression of neurologic manifestations and methods for monitoring them. CASES: We present six individuals from two families transmitting a heterozygous variant in SAMD9L, exhibiting clinical variations in their hematologic and neurologic findings. Serial motor function testing was used to monitor motor proficiency over a 2 to 3 year period in the proband and his father from Family 1. CONCLUSIONS: Our case series focuses on the neurologic progression in patients with heterozygous variants in SAMD9L. Patients with ATXPC should be followed to evaluate a wide range of neurologic manifestations. Serial motor function testing using a standardized method is helpful to track changes in balance and coordination in children and adults with ATXPC and could aid in a future extended natural history study.

Polysomnography findings in children with spinal muscular atrophy after onasemnogene-abeparvovec.

BACKGROUND: Sleep disordered breathing (SDB) is common in patients with neuromuscular diseases, including spinal muscular atrophy (SMA). While polysomnography (PSG) findings have been described in natural history studies of patients with SMA, reports regarding PSG in treated children are limited to nusinersen. We aim to describe the sleep characteristics in a cohort of children treated with Onasemnogene-abeparvovec. METHODS: We conducted a cross-sectional cohort study of children with SMA followed at the University of Florida Center for neuromuscular and rare diseases and had a diagnostic or split night PSG after SMA treatment. RESULTS: Eight children were included in the cohort (four female), aged 5-250 days at diagnosis. Five children had two survival motor neuron 2 (SMN2) copies, two had three SMN2 copies and one subject had four SMN2 copies. Median age at the time of treatment was 46.5 days (range 20-257). All children received onasemnogene-abeparvovec (OA) before their PSG; in addition to OA, one received nusinersen and one received risdiplam. Apnea hypopnea index (AHI) ranged from 3.6 to 24.1/h. REM AHI was higher than NREM AHI. Median Children's Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP-Intend) score at the time of PSG was 55 (range 33-64). There was no correlation between age at treatment, CHOP-Intend score and AHI. CONCLUSION: SDB is common in treated children with SMA, regardless of age at diagnosis, treatment and neuromotor scores. While AHI may not be the only indicator of SDB in this population, indications, timing of PSG in this cohort remain unknown.

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.

Clinical, electrophysiological, and imaging findings in childhood brachial plexus injury.

AIM: To assess the prognostic capabilities of various diagnostic modalities for childhood brachial plexus injuries (BPIs) and brachial plexus birth injury (BPBI) and postneonatal BPI. METHOD: In this single-center retrospective cross-sectional study, we examined children with BPIs diagnosed or confirmed by electrodiagnostic studies between 2013 and 2020, and compared the prognostic value of various components of the electrophysiologic findings, magnetic resonance imaging (MRI) data, and the Active Movement Scale (AMS). We developed scoring systems for electrodiagnostic studies and MRI findings, including various components of nerve conduction studies and electromyography (EMG) for electrodiagnostic studies. RESULTS: We identified 21 children (10 females and 11 males) aged 8 days to 21 years (mean 8y 6.95mo) who had a total of 30 electrodiagnostic studies, 14 brachial plexus MRI studies, and 10 surgical procedures. Among the diagnostic modalities assessed, brachial plexus MRI scores, EMG denervation scores, and mean total EMG scores were the most valuable in predicting surgical versus non-surgical outcomes. Correspondingly, a combined MRI/mean total EMG score provided prognostic value. INTERPRETATION: Brachial plexus MRI scores and specific electrodiagnostic scores provide the most accurate prognostic information for children with BPI. Our grading scales can assist a multidisciplinary team in quantifying results of these studies and determining prognosis in this setting. WHAT THIS PAPER ADDS: A new scoring system to quantify results of electrodiagnostic and magnetic resonance imaging (MRI) studies is presented. Severity of denervation has good prognostic value for childhood brachial plexus injuries (BPIs). Composite electromyography scores have good prognostic value for childhood BPIs. Brachial plexus MRI has good prognostic value for childhood BPIs.

Inherited Ataxias in Children.

The purpose of this review is to describe the current diagnostic approach to inherited ataxias during childhood. With the expanding use and availability of gene testing technologies including large sequencing panels, the ability to arrive at a precise genetic diagnosis in this group of disorders has been improving. We have reviewed all the gene sequencing studies of ataxias available by a comprehensive literature search and summarize their results. We provide a logical algorithm for a diagnostic approach in the context of this evolving information. We stress the fact that both autosomal recessive and autosomal dominant mutations can occur in children with ataxias and the need for keeping in mind nucleotide repeat expansions, which cannot be detected by sequencing technologies, as a possible cause of progressive ataxias in children. We discuss the traditional phenotype-based diagnostic approach in the context of gene testing technologies. Finally, we summarize those disorders in which a specific therapy may be indicated.

Rituximab as Adjunct Maintenance Therapy for Refractory Juvenile Myasthenia Gravis.

BACKGROUND: Juvenile myasthenia gravis is a pediatric autoimmune disorder of the neuromuscular junction associated with substantial morbidity, for which standard therapies are not always efficacious. The objective of our study was to assess the tolerability and efficacy of rituximab use in children with refractory juvenile myasthenia gravis. METHODS: We conduced a retrospective cohort study at a single tertiary care referral center to evaluate children with juvenile myasthenia gravis who were treated with rituximab. The clinical status of these participants before and after initiation of rituximab therapy was measured, focusing on numbers of hospital admissions, numbers of immunomodulatory or immunosuppressive medications needed, and Myasthenia Gravis Foundation of America severity class. RESULTS: Five children with juvenile myasthenia gravis were ascertained who received rituximab as part of their regimen, four of whom had elevated acetylcholine receptor antibodies and one of whom had elevated muscle-specific kinase antibodies. After initiation of rituximab therapy, all participants experienced reduced numbers of immunomodulatory medications during the follow-up period (mean 11.6 months). Four of the five subjects experienced fewer juvenile myasthenia gravis-related hospital admissions and reduced (improved) Myasthenia Gravis Foundation of America classes, with no subjects having moderate or severe symptoms following treatment with rituximab. No significant adverse events were recorded for any of the participants. CONCLUSION: Rituximab was well-tolerated and efficacious in this juvenile myasthenia gravis cohort. The beneficial effect of rituximab was most pronounced in the one participant with muscle-specific kinase antibodies.

A multidisciplinary approach to dosing nusinersen for spinal muscular atrophy.

BACKGROUND: In December 2016, nusinersen gained FDA approval as the first pharmacologic treatment for spinal muscular atrophy (SMA), a disorder of motor neurons and the leading genetic cause of infant mortality. Nusinersen's intrathecal delivery requirement, strict dosage protocol, and accelerated FDA approval presented a challenge to health care centers hoping to implement treatment of patients with SMA. Scheduling logistics, combined with the specific ventilatory, anesthetic, and spinal access needs of this patient population, requires extensive coordination of care. This complexity, in addition to the high cost of treatment, may lead to overburdening of an institution's dosing resources, causing delays in treatment initiation and limiting patients' access to therapy and may result in barriers to coverage. METHODS: We initiated a comprehensive stepwise protocol to maximize patient inclusion, as well as safety and efficiency outcome measures. This retrospective cohort study reviews the dosing process. RESULTS: As a result of immense collaborative efforts involving care coordination of patients and families, in addition to health providers in the divisions of neurology, anesthesiology, pulmonology, orthopedics, interventional radiology, physical therapy, and neurosurgery, we have successfully dosed 62 SMA patients. Throughout this process, we have improved anesthetic techniques, as well as minimized procedural complications and missed scheduled doses. CONCLUSION: We present here recommendations for safe and effective implementation of nusinersen utilizing a multidisciplinary approach, based on our 1 and a half year experience at a tertiary care children's hospital.