Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.

Background and Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020. Methods: This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected. Results: Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH (p = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH (p = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, p = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up. Discussion: This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned. Classification of Evidence: This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.

Antineurofascin IgG2-associated paediatric autoimmune nodopathy.

In this case series of four paediatric patients, we present the first described cases of immunotherapy-responsive autoimmune nodopathy with IgG2 antineurofascin antibodies. In three cases, the antineurofascin antibodies were predominantly of the IgG2 subclass, a novel finding in comparison to previously described adult cases where IgG4 and/or IgG1/3 have typically been described. One patient had low signal for IgG2 with predominant IgG1 and IgG4 antibodies, a pattern commonly seen in adult patients. Two patients had antibodies targeting all three neurofascin isoforms (155, 186, and 140), whereas antibodies in the sera from the third targeted only the nodal isoforms 186 and 140, and the fourth patient only neurofascin 155. The three patients with IgG2 predominant antibodies appear to be responsive to intravenous immunoglobulin (IVIG) to varying degrees thus far, whereas the patient with IgG1/4 antibodies had poor response to IVIG but good response to steroids. Although the full clinical significance of IgG2 predominant antineurofascin antibodies in the context of childhood polyneuropathy remains unclear, emerging evidence of serological-phenotypic correlation may inform prognostication and therapeutic decision-making, warranting further study into this area. WHAT THIS PAPER ADDS: Paediatric immunotherapy-responsive nodopathies were associated with antineurofascin antibodies predominantly of the IgG2 subclass in 3 out of 4 patients. Identification of antibodies and understanding their phenotypic relevance could predict response to treatment and guide therapeutic decision-making in children.

Post-Anoxic Reticular Reflex Myoclonus in a Child and Proposed Classification of Post-Anoxic Myoclonus.

OBJECTIVE: We describe a child with post-anoxic myoclonus of the reticular reflex type and discuss the classification of post-anoxic myoclonus. PATIENT DESCRIPTION: A nine-year-old boy with severe hypoxic-ischemic encephalopathy due to submersion developed early epileptic spasms followed by stimulus sensitive multifocal generalized myoclonus and later dystonia. Video electromyography (EMG) polygraphy performed before treatment demonstrated that the discharges associated with the myoclonus lasted less than 50 milliseconds. Cortical myoclonus was excluded by jerk-locked averaging using arm muscles, which showed no cortical correlates. The recruitment order on EMG polygraphy was consistent with a brainstem generator for the myoclonus, characteristic of reticular reflex myoclonus. Both myoclonus and dystonia responded to clonazepam. He remains in a persistent vegetative state. CONCLUSIONS: Reticular reflex myoclonus can be demonstrated by detailed neurophysiological assessment in children as in adults, and it has a similar poor prognosis in children. Post-anoxic myoclonus can have several mechanisms and should not be considered synonymous with Lance-Adams myoclonus.

Dual diagnosis of dihydropyrimidine dehydrogenase deficiency and GM1 gangliosidosis.

An 8-month-old girl, born to consanguineous parents, presented with developmental delay, decreased muscle tone, disinterest in her surroundings, and sleepiness. Tests revealed a marked excretion of thymine with significantly increased uracil excretion in the urine, indicating a pyrimidine catabolic disorder, i.e., dihydropyrimidine dehydrogenase deficiency. Plasma endogenous purines confirmed elevated plasma thymine (21 µmol/L) and uracil (29 µmol/L), also consistent with dihydropyrimidine dehydrogenase deficiency. Purine mutation analysis confirmed complete dihydropyrimidine dehydrogenase deficiency with a 16 [ corrected] base pair homozygous deletion in exon 16, corresponding to DPYD c.2043-2058del. Cranial magnetic resonance imaging at 14 months indicated severe hypomyelination with gliosis. Her basal ganglia were also involved. At age 15 months, she was hospitalized for aspiration pneumonia and seizures, and also manifested hepatosplenomegaly. White cell enzymes revealed a marked deficiency of ß-galactosidase activity (4 µmol/g/hour) in white cells and an elevated chitotriosidase activity (443 µmol/L/hour) in plasma indicating GM(1) gangliosidosis. Mutation analysis confirmed c.841C>T (p.His281Tyr) homozygosity for GM(1) gangliosidosis. She died at age 19 months.