Wendy Liew

Update on juvenile myasthenia gravis.

Purpose of reviewJuvenile myasthenia gravis is a relatively rare autoimmune neuromuscular disorder. The pathophysiology of juvenile myasthenia gravis is similar to that of adult myasthenia gravis, though there remain important differences regarding presentation and therapeutic options. We review the pathophysiology, clinical presentation, and treatment options for juvenile myasthenia gravis. Recent findingsRandomized clinical studies of myasthenia gravis have been carried out primarily in adult populations. As juvenile myasthenia gravis is rare, it has been difficult to collect prospective randomized controlled data to evaluate treatment outcomes and efficacy. A recent retrospective series suggests that, as in adult myasthenia gravis, thymectomy is a viable therapeutic option for selected cases of generalized juvenile myasthenia gravis. This is corroborated by the clinical experience of the authors in a referral center with a cohort of patients affected by juvenile myasthenia gravis over a number of years. SummaryRecent studies illustrate that some, but not all, adult research on myasthenia gravis is applicable to children and adolescents with juvenile myasthenia gravis. Adult research can inform pediatric studies, but should not be regarded as a substitute for dedicated research in those populations.

Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals.

Current advances in drug development in spinal muscular atrophy.

Purpose of reviewSpinal muscular atrophy (SMA) is a pediatric neuromuscular condition characterized by progressive proximal muscle weakness. It is one of the most common genetic causes of infant mortality across different races and is caused by mutation of the survival of motor neuron 1 (SMN1) gene on chromosome 5q13. Recent findingsTo date, there have been many therapeutics developments for SMA targeting various potential pathways such as increasing SMN gene expression, enhancing SMN2 exon 7 inclusion, neuroprotection, cell replacement, and gene therapy. SummaryAlthough SMA remains an incurable disease to date, recent advances in the field of basic and translational research have enhanced our understanding of the pathogenesis of the disease and opened new possibilities for therapeutic intervention. This article reviews and highlights past and current translational research on SMA therapeutics.

Clinical Application of Whole-Exome Sequencing: A Novel Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Sequence Variation in a Child With Ataxia

IMPORTANCE Ataxia in children is a diagnostic challenge. Besides the more common acquired causes of ataxia, there are more than 50 inherited disorders associated with ataxia. Our objective was to highlight whole-exome sequencing as a rapidly evolving clinical tool for diagnosis of mendelian disorders, and we illustrate this in the report of a single case of a novel sequence variation in the SACS gene. OBSERVATIONS A 4-year-old girl presented with delayed gross motor development, ataxia, and polyneuropathy. Results of initial testing for the common causes of inherited and acquired ataxia were unrevealing. Whole-exome sequencing showed a novel frameshift homozygous sequence variation in the SACS gene, consistent with the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. CONCLUSIONS Whole-exome sequencing is a powerful clinical tool that has been increasingly used to assist in the diagnosis of mendelian disorders. It provides a cost-effective, efficient, and expedited approach to making a clinical diagnosis and, in some cases, may be the only way to make a diagnosis.

Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?

Background In Western cohorts, the prevalence of incidental findings (IFs) or incidentalome, referring to variants in genes that are unrelated to the patients primary condition, is between 0.86% and 8.8%. However, data on prevalence and type of IFs in Asian population is lacking. Methods In 2 cohorts of individuals with genomic sequencing performed in Singapore (total n = 377), we extracted and annotated variants in the 56 ACMG-recommended genes and filtered these variants based on the level of pathogenicity. We then analyzed the precise distribution of IFs, class of genes, related medical conditions, and potential clinical impact. Results We found a total of 41,607 variants in the 56 genes in our cohort of 377 individuals. After filtering for rare and coding variants, we identified 14 potential variants. After reviewing primary literature, only 4 out of the 14 variants were classified to be pathogenic, while an additional two variants were classified as likely pathogenic. Overall, the cumulative prevalence of IFs (pathogenic and likely pathogenic variants) in our cohort was 1.6%. Conclusion The cumulative prevalence of IFs through genomic sequencing is low and the incidentalome may not be a significant barrier to implementation of genomics for personalized medicine.

Referral and diagnostic trends in pediatric electromyography in the molecular era

Introduction: Major advances in genetic analysis and neuroimaging have modified the traditional diagnostic approach for neuromuscular disorders. The purpose of this study was to investigate the role of electromyography (EMG) in the molecular era. Methods: We retrospectively surveyed reports of all EMG studies performed at Boston Childrens Hospital from 2001 through 2011. Data were collected on study numbers, patient ages, referring provider subspecialty, study indication, electrophysiological diagnosis, and study utility. Results: A total of 2100 studies were performed. The volume increased from ∽160 to ∽250 studies/year. There was a trend toward studying older children. Neurologists, including neuromuscular specialists, constituted the major referral pool, whereas referrals from orthopedics increased steadily. Polyneuropathies followed by mononeuropathies were the most common indications and diagnoses. Fifty‐seven percent of studies were normal. EMG provided meaningful information in 94% of cases. Conclusion: EMG continues to play a cardinal role in the diagnosis of pediatric neuromuscular disorders, although its practice paradigm is evolving. Muscle Nerve 50:244–249, 2014

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization.

BACKGROUND Anatomical localization of the rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome has proved elusive. Most patients had neuroimaging after cardiorespiratory collapse, revealing a range of ischemic lesions. PATIENT DESCRIPTION A 15-year-old obese boy with an acute febrile encephalopathy had hypoventilation, autonomic dysfunction, visual hallucinations, hyperekplexia, and disordered body temperature, and saltwater regulation. These features describe the ROHHAD syndrome. Cerebrospinal fluid analysis showed pleocytosis, elevated neopterins, and oligoclonal bands, and serology for systemic and antineuronal antibodies was negative. He improved after receiving intravenous steroids, immunoglobulins, and long-term mycophenolate. Screening for neural crest tumors was negative. CONCLUSION Magnetic resonance imaging of the brain early in his illness showed focal inflammation in the periaqueductal gray matter and hypothalamus. This unique localization explains almost all symptoms of this rare autoimmune encephalitis.

Electrophysiologic features of fibular neuropathy in childhood and adolescence

Introduction: We studied patterns of nerve injury in pediatric common fibular (peroneal) neuropathy (CFN). Methods: A retrospective analysis was performed on data from 53 children with CFN at a pediatric electromyography laboratory. Results: Conduction block at the fibular head was present in 35% of patients. Deep fibular axonal loss was identified in 77%, while superficial fibular axonal loss was identified in 45%. The pathophysiology was predominantly axonal in 72%, mostly demyelinating in 6%, and mixed in 22%. Predominantly demyelinating lesions at the fibular head demonstrated sparing of the superficial fibular sensory nerve (P = 0.01, Fischer exact test). Predominantly axonal lesions had a moderate correlation between superficial and deep fibular axonal loss (Spearman r = 0.52; P = 0.0001). Conclusions: There is frequent axonal and fascicular injury in pediatric CFN, similar to adults. Deep and superficial fibular nerve involvements correlate in axonal lesions, whereas superficial fibular sensory fibers are often spared in demyelinating lesions. Muscle Nerve, 2016 Muscle Nerve 55: 693–697, 2017

Longitudinal Patterns of Thalidomide Neuropathy in Children and Adolescents

OBJECTIVE To characterize the longitudinal clinical and electrophysiological patterns of thalidomide neuropathy in children and adolescents. STUDY DESIGN Retrospective analysis of clinical records at a tertiary care childrens hospital, including serial electrophysiological studies. RESULTS Sixteen patients aged 6-24 years received thalidomide to treat Crohns disease from 2002 to 2012. Nine subjects had electrophysiological evidence of sensorimotor axonal polyneuropathy, 8 of whom had sensory and/or motor symptoms. The patients with polyneuropathy received thalidomide for 5 weeks to 52 months, with cumulative doses ranging from 1.4 to 207.7 g. All subjects with cumulative doses greater than 60 g developed polyneuropathy, and 4 of the 5 subjects who received thalidomide for more than 20 months developed polyneuropathy. The 7 subjects who had normal neurophysiological studies received therapy for 1 week to 25 months, with cumulative doses ranging from 0.7 to 47 g. In contrast to some previous reports, several patients had sensorimotor polyneuropathies, rather than pure sensory neuropathies. In patients with neuropathy who received therapy for more than 24 months and had 3 or more electromyography studies, the severity of the neuropathy plateaued. CONCLUSIONS Factors in addition to the total dose may contribute to the risk profile for thalidomide neuropathy, including pharmacogenetic susceptibilities. The severity of the neuropathy does not worsen relentlessly. Children, adolescents, and young adults receiving thalidomide should undergo regular neurophysiological studies to monitor for neuropathy.

KCNK9 imprinting syndrome—further delineation of a possible treatable disorder

Patients with KCNK9 imprinting syndrome demonstrate congenital hypotonia, variable cleft palate, normal MRIs and EEGs, delayed development, and feeding problems. Associated facial dysmorphic features include dolichocephaly with bitemporal narrowing, short philtrum, tented upper lip, palatal abnormalities, and small mandible. This disorder maps to chromosomal region 8q24, and it is caused by a specific missense mutation 770G>A in exon 2, replacing glycine at position 236 by arginine (G236R) in the maternal copy of KCNK9 within this locus. KCNK9 (also called TASK3) encodes a member of the two pore‐ domain potassium channel (K2P) subfamily. This gene is normally imprinted with paternal silencing, thus a mutation in the maternal copy of the gene will result in disease, whereas a mutation in the paternal copy will have no effect. Exome sequencing in four new patients with developmental delay and central hypotonia revealed de novo G236R mutations. Older members of a previously reported Arab–Israeli family have intellectual disability of variable severity, persistent feeding difficulties in infancy with dysphagia of liquids and dysphonia with a muffled voice in early adulthood, generalized hypotonia, weakness of proximal muscles, elongated face with narrow bitemporal diameter, and reduced facial movements. We describe the clinical features in four recently recognized younger patients and compare them with those found in members of the originally reported Arab–Israeli family and suggest this may be a treatable disorder.