BACKGROUNDSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODSWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTSIn the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P = 0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P = 0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONSAmong infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074.)

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease with severity ranging from progressive infantile paralysis and premature death (type I) to limited motor neuron loss and normal life expectancy (type IV). Without disease‐modifying therapies, the impact is profound for patients and their families. Improved understanding of the molecular basis of SMA, disease pathogenesis, natural history, and recognition of the impact of standardized care on outcomes has yielded progress toward the development of novel therapeutic strategies and are summarized. Therapeutic strategies in the pipeline are appraised, ranging from SMN1 gene replacement to modulation of SMN2 encoded transcripts, to neuroprotection, to an expanding repertoire of peripheral targets, including muscle. With the advent of preliminary trial data, it can be reasonably anticipated that the SMA treatment landscape will transform significantly. Advancement in presymptomatic diagnosis and screening programs will be critical, with pilot newborn screening studies underway to facilitate preclinical diagnosis. The development of disease‐modifying therapies will necessitate monitoring programs to determine the long‐term impact, careful evaluation of combined treatments, and further acceleration of improvements in supportive care. In advance of upcoming clinical trial results, we consider the challenges and controversies related to the implementation of novel therapies for all patients and set the scene as the field prepares to enter an era of novel therapies. Ann Neurol 2017;81:355–368

This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM.

LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations.

The natural history of SMA suggests considerable early loss of motor neurons, with severity related to differences in the number of remaining motor neurons. As the ensuing chronic course in milder phenotypes suggests relative stability of remaining motor neurons, the maximal therapeutic window presents early.

BackgroundEpileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost‐effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.MethodsWe conducted a retrospective cost‐effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well‐phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first‐tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.ResultsThe diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost‐effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost‐effective. The clinical utility of all diagnoses was reported.ConclusionOur study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.

IMPORTANCE Enterovirus 71 (EV71) causes a spectrum of neurological complications with significant morbidity and mortality. Further understanding of the characteristics of EV71-related neurological disease, factors related to outcome, and potential responsiveness to treatments is important in developing therapeutic guidelines. OBJECTIVE To further characterize EV71-related neurological disease and neurological outcome in children. DESIGN, SETTING, AND PARTICIPANTS Prospective 2-hospital (The Sydney Children's Hospitals Network) inpatient study of 61 children with enterovirus-related neurological disease during a 2013 outbreak of EV71 in Sydney, Australia. The dates of our analysis were January 1, to June 30, 2013. MAIN OUTCOMES AND MEASURES Clinical, neuroimaging, laboratory, and pathological characteristics, together with treatment administered and functional motor outcomes, were assessed. RESULTS Among 61 patients, there were 4 precipitous deaths (7%), despite resuscitation at presentation. Among 57 surviving patients, the age range was 0.3 to 5.2 years (median age, 1.5 years), and 36 (63%) were male. Fever (100% [57 of 57]), myoclonic jerks (86% [49 of 57]), ataxia (54% [29 of 54]), and vomiting (54% [29 of 54]) were common initial clinical manifestations. In 57 surviving patients, EV71 neurological disease included encephalomyelitis in 23 (40%), brainstem encephalitis in 20 (35%), encephalitis in 6 (11%), acute flaccid paralysis in 4 (7%), and autonomic dysregulation with pulmonary edema in 4 (7%). Enterovirus RNA was more commonly identified in feces (42 of 44 [95%]), rectal swabs (35 of 37 [95%]), and throat swabs (33 of 39 [85%]) rather than in cerebrospinal fluid (10 of 41 [24%]). Magnetic resonance imaging revealed characteristic increased T2-weighted signal in the dorsal pons and spinal cord. All 4 patients with pulmonary edema (severe disease) demonstrated dorsal brainstem restricted diffusion (odds ratio, 2; 95% CI, 1-4; P = .001). Brainstem or motor dysfunction had resolved in 44 of 57 (77%) at 2 months and in 51 of 57 (90%) at 12 months. Focal paresis was evident in 23 of 57 (40%) at presentation and was the most common persisting clinical and functional problem at 12 months (observed in 5 of 6 patients), with 1 patient also requiring invasive ventilation. Patients initially seen with acute flaccid paralysis or pulmonary edema had significantly greater frequencies of motor dysfunction at follow-up compared with patients initially seen with other syndromes (odds ratio, 15; 95% CI, 3-79; P < .001). CONCLUSIONS AND RELEVANCE Enterovirus 71 may cause serious neurological disease in young patients. The distinct clinicoradiological syndromes, predominantly within the spinal cord and brainstem, enable rapid recognition within evolving outbreaks. Long-term functional neurological morbidity is associated with paresis linked to involvement of gray matter in the brainstem or spinal cord.