Spinal Muscular Atrophy Update in Best Practices: Recommendations for Diagnosis Considerations.

Background and Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive progressive neurodegenerative primary motor neuron disorder caused by biallelic variants of the survival motor neuron 1 (SMN1) gene. The most recent SMA best practice recommendations were published in 2018 shortly after the approval of the first SMN-enhancing treatment. The availability of disease-modifying therapies for 5q SMA and implementation of SMA newborn screening (NBS) has led to urgency to update the SMA best practice recommendations for diagnosis and to reevaluate the current classification of SMA. In addition, the availability of disease-modifying therapies has opened the door to explore improved diagnosis of adult-onset SMA. Methods: A systematic literature review was conducted on SMA NBS. An SMA working group of American and European health care providers developed recommendations through a modified Delphi technique with serial surveys and virtual meeting feedback on SMA diagnosis to fill information gaps for topics with limited evidence. A community working group of an individual with SMA and caregivers provided insight and perspective on SMA diagnosis and support through a virtual meeting to guide recommendations. Results: The health care provider working group achieved consensus that SMA NBS is essential to include in the updated best practice for SMA diagnosis (100%). Recommendations for the following are described: characterizing NBS-identified infants before treatment; minimum recommendations for starting or offering SMA NBS in a state or country; recommendations for activities and services to be provided by an SMA specialty care center accepting SMA NBS referrals; and recommendations for partnership with individuals with SMA and caregivers to support NBS-identified infants and their caregivers. Limited data are available to advance efficient diagnosis of adult-onset SMA. Discussion: Updating best practice recommendations for SMA diagnosis to include SMA NBS implementation is essential to advancing care for individuals with SMA. In addition to testing, processes for the efficient management of positive newborn screen with access to knowledgeable and skilled health care providers and access to treatment options is critical to successful early diagnosis. Additional evidence is required to improve adult-onset SMA diagnosis.

Prevalence of morbidities across the lifespan for adults with spinal muscular atrophy: a retrospective cohort study.

BACKGROUND: Recently approved treatments for spinal muscular atrophy (SMA) may shift clinical care priorities to secondary complications associated with SMA-related aging. To date, there is little knowledge about the natural history of morbidities across the adult lifespan for SMA. The objective of this study was to identify the prevalence and odds ratio (OR) of various morbidities among adults with vs. without SMA prior to SMA-related treatment. METHODS: This was a retrospective cohort study that accessed Medicare fee-for-service and commercial claims data from 01/01/2008-12/22/2016. Data from adults ≥ 18 years old with SMA and without SMA matched (1:200 case:control) on demographics, region, and study entry year were included. The prevalence of 30 morbidities across physiologic systems (e.g., cardiovascular, metabolic, musculoskeletal, urinary) and mental health disorders was examined. Age- and sex-adjusted OR was estimated using logistic regression for each morbidity and effect modification by age and sex was tested. RESULTS: There were 2,427 adults with SMA (mean [SD] age, 59.7 [17.4] years; 49.0% female) and 484,528 matched adults without SMA. Adults with vs. without SMA had a higher prevalence and adjusted OR of all 30 morbidities, ranging from OR = 1.61 (95% CI = 1.45-1.80) for hypothyroidism to OR = 7.80 (95% CI = 7.10-8.57) for fluid/electrolyte disorders. There was effect modification by age for 24 morbidities. The OR was highest for the youngest age group (18-40 years; OR range, 2.38 to 117.7; all P < 0.05) and declined with older age groups, but still remained significantly elevated in the oldest age group (≥ 75 years; OR range, 1.30 to 5.96; all P < 0.05). CONCLUSIONS: The limitations of this study are that evidence of morbidities were limited to diagnostic claims and information on SMA type and symptoms or onset were not available. In conclusion, adults with SMA had a higher and earlier prevalence of a variety of morbidities across physiological systems and mental health disorders.

Necrotizing Enterocolitis following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series.

Onasemnogene abeparvovec treats spinal muscular atrophy by delivering a functional SMN1 gene. Necrotizing enterocolitis typically occurs in preterm infants. We report 2 term infants diagnosed with spinal muscular atrophy who presented with necrotizing enterocolitis after onasemnogene abeparvovec infusion. We discuss potential etiologies and propose monitoring for necrotizing enterocolitis after onasemnogene abeparvovec therapy.

Neonatal baclofen withdrawal following intrauterine exposure.

BACKGROUND: Pregnant women with spinal cord injuries are often advised to continue oral baclofen during pregnancy to manage spasticity, though the potential for adverse events in neonates is not well understood. OBJECTIVE: Here, a case is described in which a male neonate with intrauterine baclofen exposure, born at 34 3/7 weeks via Cesarean section, demonstrated a two-minute episode of extensor posturing at fifteen minutes of life possibly concerning for baclofen withdrawal. His mother had taken baclofen 30 milligrams orally four times per day throughout pregnancy for management of spasticity associated with a remote cervical spinal cord injury. Due to concern for possible withdrawal, the neonate was started on a baclofen taper beginning within hours of birth while evaluation for alterative etiologies was underway. Symptoms were monitored using the Finnegan Neonatal Abstinence Scale. The neonate tolerated the baclofen taper well and was successfully tapered off by the fourteenth day of life with full resolution of symptoms and no apparent neurologic deficits. CONCLUSION: Further research is needed to assess the incidence of neonatal baclofen withdrawal with regard to maternal dosage and route of administration, and to determine the most appropriate monitoring and management protocols for the neonate.

A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial.

BACKGROUND: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). OBJECTIVE: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 - < 8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks. METHODS: Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI). RESULTS: One hundred thirty one patients received edasalonexent (n = 88) and placebo (n = 43). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea). CONCLUSIONS: Edasalonexent was generally well-tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882).