Hometown Highlights: Clinical Experience Treating Adults With Spinal Muscular Atrophy

Treating adult patients with antisense oligonucleotide therapy proven effective in children presents unique challenges.

By Lauren Elman, MD

Types of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease, occurring in approximately 1 in 10,000 live births with a carrier frequency of 1 in 50. There are 4 forms, although SMA4 is later onset and is so rare that we usually discuss 3 forms. Approximately 60% of cases are SMA1, and SMA2 is the next most common. The third, SMA3, is rare, affecting approximately 10,000 adults in the US. Patients with SMA3 may have onset in childhood or later and are clinically defined as having had the ability to walk at some time in their lives.

Clinical Presentation

Weakness begins proximally and progresses distally. The diaphragm is involved late in the disease, and respiratory involvement is primarily due to weakening of the intercostal muscles, which leads to a typical barrel-chested appearance. The bulbar muscles are affected last, which accounts for the classic description of a bright-eyed, intelligent child with low muscle tone.

Pathophysiology and Genetic Etiology

All 4 types have the same pathophysiology, neurodegeneration of the lower motor neurons and subsequent muscle atrophy. In 1990, SMA was linked to chromosome 5 and in 1995, the responsible gene, which encodes the protein survival motor neuron (SMN), was identified in the telomeric region of chromosome 5.1,2 A very similar gene, SMN2, is located in the centromeric region of chromosome 5. In 1999, the difference between SMN1 and SMN2 transcripts was determined to be alternative splicing that, for SMN2, excludes exon 7 thereby preventing the RNA product from being translated to a stable protein.3 In a person without disease, SMN1 is transcribed with exon 7 present, and the RNA product is translated into functional SMN protein. With regard to SMN2, approximately 10% of the mRNA transcribed includes exon 7 and is thus translated into functional SMN protein.

In 95% of patients with SMA, both copies of SMN1 on chromosome 5 are completely deleted. In 5% of patients, there is a deletion of 1 copy of SMN1 and a mutation in the other. Both result in the absence of functional SMN protein, which leads to degeneration of lower motor neurons. The type of SMA a patient has correlates with the number of copies of SMN2 they possess (Table).4

Treatment in Adults

Antisense Oligonucleotide Therapy

Mechanism of Action. Understanding that alternative splicing was the difference between SMN1 and SMN2 protein production and that disease severity correlates with copy number of SMN2 led to the theoretical idea of exon 7 inclusion, which has come to fruition as the antisense oligonucleotide therapy nusinersen (Spinraza; Biogen, Cambridge, MA).

In the native state, a heterogeneous nuclear RNA (hn-RNA)-dependent silencer causes exon 7 to be excluded from most SMN2 transcripts. Nusinersen is an antisense oligonucleotide, delivered via intrathecal injection, that blocks the hn-RNA silencer, such that all SMN2 transcripts made in the presence of nusinersen include exon 7 and are translated into functional SMN protein.

Treatment Administration. In clinical trials in pediatric patients, nusinersen was so effective that some trials were stopped early because it became unethical not to give a potentially life-saving treatment to all patients involved in the trial. On December 23, 2016, the Food and Drug Administration approved nusinersen for the treatment of all patients with any type of SMA—a very happy day for patients. On January 2, 2017, when the drug became available, it became necessary to address how to deliver it, especially for adult patients with SMA. Challenges include the lack of data in adult patients, the high cost of the drug ($125,000/dose), and convincing insurance companies to pay for something in the absence of efficacy data for adults. The dosing schedule is complicated: 4 loading doses are given over a 10-week period, and then a maintenance dose is given every 4 months.

Intrathecal administration can be complicated in adults with SMA because many patients have scoliosis and may have had spinal stabilization surgery with metal hardware, making access to the intrathecal space difficult. This is compounded by the fact that the package insert calls for delivery at the lumbar level, making different injection locations technically off-label. Some institutions are using laminotomy or laminectomy, cutting a hole for dosing access. This procedure carries a risk of infection or cerebrospinal fluid (CSF) leak. It is possible to use CT-guided injection for a transforaminal approach in patients with complicated anatomy, although this requires a great deal of skill on the part of the injector.

Efficacy Measures. An interesting and unfortunate issue in the care of adults with SMA3 is that we don’t know a lot about the natural history of the disease. In the authors’ clinical experience, SMA3 is heterogenous and slowly progressive; there is a lack of natural history data and no biomarkers for the disease. This became apparent after a treatment became available, and a search for appropriate measures of efficacy was carried out.

There are very few studies of disease progression in patients with SMA. In a single observational study of respiratory involvement in people with SMA2 and SMA3 ages 20 months to 45 years; no change was seen after 1 year and the study was stopped.5 Children and young adults with SMA2 or SMA3 who were followed for 4 years showed declines in the Hammersmith rating scale, declines in leg strength, increases in elbow flexion strength, and no findings on imaging or EMG. The authors of that study suggested the contradictory findings were a result of their subjects continued growth.6 In a third study, 10 patients with SMA3 who were followed for 10 years had an average decline of 1 medical research council (MRC) scale per involved muscle over 5 years.7

The Revised Upper Limb Module (RULM) is a measure validated and used only for patients with SMA that evaluates shoulder, wrist, and hand functions. The patient may not wear a splint or support during the evaluation and contractures, if present, are simply noted and do not affect scoring. The RULM takes approximately 15 minutes to administer and requires a toolkit that is used to have the patient repeat specific tasks (eg, picking up a coin, bringing hand to mouth) with both arms.

Results. In our clinical practice, we measured RULM scores in adult patients, 5 with SMA2 and 13 with SMA3, before and after treatment with nusinersen in an observational, uncontrolled, and unblinded study. Most patients had statistically significant improvement in RULM scores in the right arm that were not seen in the left. Clinically, our patients tell us that they are having fewer bad days, believe their core strength is improved, and that activities of daily living are becoming easier. We have also seen a few instances of return of reflexes that has been quite unexpected and quite remarkable.

Gene Therapy

Gene therapy for SMA is possible both because the disease is caused by deletion or mutation of a single gene and because a good vector for delivering a replacement gene is available. The vector being used to study gene replacement therapy for patients with SMA is the adeno-associated virus (AAV), which is nonpathogenic and integrates into the host cell nuclei, but not into the host cell DNA. This is important because it removes the risk of oncogenesis. Gene therapy for other diseases using AAV is already in use.

In phase 1 clinical trials to assess the safety of gene replacement therapy with AAV for SMA, the only side effects seen were transitory elevations in liver enzymes that were well controlled with steroid treatment. All patients survived, which is notable because without treatment only 8% of these 15 patients would have been expected to survive. In exploratory analysis of data from this study, functional improvements were seen on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score.8 There is an ongoing phase 3 clinical trial of systemic gene replacement therapy for patients with SMA1 with results expected in 2020. A phase 1 trial of intrathecal gene replacement therapy for patients age 2 to 5 years with SMA2 is currently recruiting subjects.

Implications for Clinicians

Diagnosis, and specifically genetic diagnosis, is more important now than ever. The relative increased ease of obtaining genetic tests is remarkable and has been life-changing for many patients. It is possible to find unexpected and treatable diagnoses, and early diagnosis can lead both to better understanding of the natural history of SMA and also earlier initiation of treatment.

Keeping up with what diseases have new treatments is essential as is knowing when to refer patients to a tertiary care center. This is especially true for patients who need complicated treatments like nusinersen. At our center, we have developed a cohesive team that knows how to manage the insurance issues, set up the treatment protocols, and deliver this complicated dosing schedule. We have built a large program to serve this population.

Future Directions

Clinical studies of gene therapy to replace SMN1 continue.

Further studies of the natural history of SMA are also underway and SMA is now part of the Recommended Uniform Screening Panel for Newborns but has yet to be implemented in every state due to cost issues.


The development of antisense oligonucleotide and gene therapy treatments for children and adults with SMA creates hope that, like polio, SMA may become a historical motor neuron disease. Genetic diagnosis, understanding the natural history of the disease, and including patients with all types of SMA in clinical trials will be important to achieve this goal.

1. Brzustowicz LM, Lehner T, Castilla LH, et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature. 1990;344(6266):540-541.

2. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995; 80(1):155-165.

3. Monani UR, Lorson CL, Parsons DW, et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999;8(7):1177-1183.

4. Prior TW, Nagan N. Spinal muscular atrophy: overview of molecular diagnostic approaches. Curr Protoc Hum Genet. 2016 Jan 1;88:Unit 9.27. doi: 10.1002/0471142905.hg0927s88.

5. Kaufmann P, McDermott MP, Darras BT. Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol. 2011;68(6):779-786.

6. Kaufmann P, McDermott MP, Darras BT et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012;79(18):1889-1897.

7. Werlauff U, Vissing J, Steffensen BF. Change in muscle strength over time in spinal muscular atrophy types II and III. A long-term follow-up study. Neuromuscul Disord. 2012;22(12):1069-1074.

8. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017;377(18):1713-1722.

Lauren Elman, MD

Associate Professor
Department of Neurology
Muscular Dystrophy Association Care Center
Associate Director
Penn Comprehensive ALS Center
University of Pennsylvania Medical Center
Philadelphia, PA


The author has served as a consultant for Biogen.

Column editor Stephen M. Gollomp, MD

President, Philadelphia Neurological Society
Clinical Professor of Neurology
Thomas Jefferson University
Louis & Elizabeth Pipi Endowed Chair in Neurology Lankenau Medical Center
Philadelphia, PA


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