How is spinal muscular atrophy (SMA) treated?

Updated: May 29, 2019
  • Author: Jeffrey Rosenfeld, MD, PhD, FAAN; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP  more...
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In December 2016, the FDA approved nusinersen (Spinraza), the first drug approved to treat children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Using in vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. [45]

Nusinersen approval was based on the ENDEAR trial. The ENDEAR trial (n=121) is a phase 3 randomized, double-blind, sham-controlled study in patients with infantile-onset (most likely to develop Type 1) SMA. At a planned interim analysis, a greater percentage of infants treated with nusinersen achieved a motor milestone response compared to those who did not receive treatment (40% vs 0%; p<0.0001) as measured by the Hammersmith Infant Neurological Examination (HINE). Additionally, a smaller percentage of patients in the nusinersen group died (23%) compared to untreated patients (43%). [46]

Interim data from another phase 3 trial, CHERISH, included 126 nonambulatory patients with later-onset SMA (consistent with Type 2), including patients with the onset of signs and symptoms at >6 months and an age of 2 to 12 years at screening. Prespecified interim analysis demonstrated a difference of 5.9 points (p= 0.0000002) at 15 months between the treatment (n=84) and sham-controlled (n=42) study arms, as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved a mean improvement of 4.0 points in the HFMSE, while patients who were not on treatment declined by a mean of 1.9 points. [47]

Medications such as valproic acid, phenylbutyrate, hydroxyurea, and albuterol have been shown to increase SMN transcription in laboratory studies, but clinical trials have not demonstrated significant improvement in disease progression. The SMA CARNIVAL trials (parts 1 and 2) [51, 52] found valproic acid and L-carnitine ineffective with regard to strength or functional improvement at 6 months and 12 months in both ambulatory and nonambulatory children. Adverse effects were reported in 85% of patients. [51] Gabapentin, riluzole, and olesoxime have been studied for their suspected neuroprotective properties, without significant clinical benefit noted. [38, 53, 54] Treatment with creatine, phenylbutyrate, gabapentin, thyrotropin-releasing hormone, and hydroxyurea have also proved ineffective. [53]

A randomized, double-blind, placebo-controlled trial in male subjects with genetically confirmed spinobulbar muscular atrophy (Kennedy disease) using oral dutasteride (a 5-alpha-reductase inhibitor that reduces dihydrotestosterone) did not show a significant effect on the progression of muscle weakness. [55] Failure of this treatment trial in spinobulbar muscular atrophy may in part be attributed to the underpowered study and the relatively short period in which treatment effect can be accurately measured because of the slowly progressive nature of this disease. These results also suggest that the role of androgens in spinobulbar muscular atrophy is complex.

Supportive treatment should be aimed at improving the patients' quality of life and minimizing disability, particularly in patients with slow progression.

The goals are to maximize the patient's independence and quality of life at each stage of the disease.

The treatment of patients with adult-onset spinal muscular atrophy is similar to that for amyotrophic lateral sclerosis (ALS), except that the course and life span in spinal muscular atrophies is considerably longer.

A multidisciplinary approach is essential. Once diagnosis is reached, overnight oximetry, respiratory muscle function tests, cough effectiveness, forced vital capacity (for patients >5 years), swallow study with video, physical and occupational therapy assessments, assistive equipment evaluation, and hip/spine radiography are appropriate. Recognition of mandibular dysfunction manifested as limited mouth opening is an important factor in prevention of aspiration. [38, 56]

Interventions such as chest physiotherapy, assisted cough, nocturnal (+/- daytime) noninvasive ventilation, and Nissen fundoplication for nonsitting patients may be considered. Gastrostomy placement is often pursued at the time of diagnosis for SMA1. [38]

The use of splints, bracing, and spinal orthoses can be customized to each patient. [57] Wheelchair use should be determined by patient’s level of fatigue with activity as well as their rate of falling. [38]

Women with SMA who become pregnant have no increased risk of miscarriage or hypertensive diseases. Higher rates of caesarian delivery (42.5%) and preterm deliveries (29.4%) have been observed. Approximately one third of patients noted deterioration of symptoms during pregnancy. [13]

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