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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 children's hospital, including serial electrophysiological studies. Results Sixteen patients aged 6-24 years received thalidomide to treat Crohn's 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.

Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown.We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual.Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = -0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = -0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = -0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = -0.40; P = 0.054 and rho = -0.32; P = 0.13, respectively).Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted.

Background The recurrent ∼600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. Objective To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. Methods We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. Results When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. Conclusions The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

Objective High reliability is a prerequisite for any test to be useful as a biomarker in a clinical trial. Here we assessed the reproducibility of electrical impedance myography (EIM) in children by comparing data obtained by different evaluators on separate days. Methods Healthy boys and boys with Duchenne muscular dystrophy (DMD) aged 2–14 years underwent EIM of multiple muscles performed by two evaluators on two visits separated by 3–7 days. Single and multifrequency data were analyzed. Reliability was assessed via calculation of the percent relative standard deviation (% RSD), Bland–Altman analysis, and the intraclass correlation coefficient (ICC). Results For both individual muscle data and data averaged across muscles, intra-evaluator measurements showed high repeatability for both 50 kHz phase and 50/200 kHz phase ratio values, with ICCs generally above 0.90 and % RSD below 10%. Inter-evaluator results showed very similar ICC and % RSD values as those obtained by the same evaluator. Conclusions Both the 50 kHz phase and 50/200 kHz phase ratio are reliable measures both across time and evaluators and in both health and disease. Significance These results support the concept that EIM can serve as a reliable measure in clinical therapeutic trials in a pediatric population.

This open-label, multiple ascending-dose study was conducted to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of ISIS-SMNRx (ISIS 396443) in children with Types 2 and 3 SMA. ISIS-SMNRx is an antisense oligonucleotide designed to alter splicing of SMN2 mRNA to increase the amount of functional SMN protein. Results from SMA mouse models indicate ISIS-SMNRx had a significant effect on functional and histological measures of neuromuscular health when delivered to the CNS. A Phase 1 single ascending-dose study in children with SMA had previously been completed, showing acceptable safety/tolerability. Multiple doses of ISIS-SMNRx (3 dose levels) were delivered by intrathecal injection to medically stable SMA patients 2–15 years of age (n = 25). Subjects were dosed 2–3 times over 3 months and then followed for 6 months post-dosing and monitored for drug safety and tolerability, CSF and plasma pharmacokinetics, CSF SMN protein levels, and clinical outcome measures. Overall, no safety or tolerability concerns related to ISIS-SMNRx were identified; the majority of adverse events were mild or moderate in severity and none were related to dose level of ISIS-SMNRx. No drug-related changes in neurological exams, laboratory assessments (including CSF safety), or systemic evaluations were reported. Repeated intrathecal injections were well tolerated in SMA children. CSF and plasma drug levels were dose-dependent predictable, and consistent with expected levels. HFMSE scores indicated an improvement in motor function at all doses levels, with a time and dose dependency. 6MWT and ULM functional tests also indicated improvement, although with limited data. Measurement of SMN protein levels in CSF indicated a significant increase at the highest dose (p = 0.004), indicating biological activity of ISIS-SMNRx in SMA patients. Results from this study support continued development and further examination of ISIS-SMNRx in a Phase 2/3 controlled study.