Spinal muscular atrophy - rare disease with individual course

One in about 10,000 newborns has a gene defect, so that the impulse transmission of the motoneurons is disturbed. The muscles no longer receive signals and atrophy. Due to the individually very different manifestations, there are children who do not reach the second year of life, but also affected persons who are diagnosed with the disease only in adulthood.

Spinal muscular atrophy (SMA) is the most common inherited disease resulting in death in infancy and is often diagnosed at a very early age [1,2]. However, this does not have to be the case. This is because the disease, which belongs to the “spectrum diseases”, may only become apparent in adulthood in some affected individuals [3]. This heterogeneity does not make dealing with the SMA any easier.

The cause of SMA is a mutation of the SMN1 gene. This forms the “survival of motor neuron” (SMN) protein, which plays a central role in the transmission of impulses from the nerve cells to the muscles. If the SMN1 gene fails, the all-important protein can only be produced by the remaining SMN2 gene copies. However, only about 10% of a functional SMN protein can be produced per copy [1]. Far too little to maintain the muscles. Therefore, all muscles in the body may also be affected. However, it is often the proximal muscles that are most affected.

Every patient is different

The disease is divided into four different forms, which are distinguished by the distribution pattern, onset of disease, severity, and inheritance pattern [4].

Acute infantile SMA – it occurs in babies before 6 months of age and is manifested in a severe form by a marked inability to move. If left untreated, important motor milestones in child development are not reached and affected individuals often die before reaching the age of two.
Chronic infantile SMA – onset of disease is in the first year of life and motor development is severely delayed. Nevertheless, these children can sit without aids. Standing or walking, however, are milestones that are not achieved.
Juvenile SMA – here symptoms usually appear around the age of three. The children – mostly boys – can stand and walk at least some of the time. However, they can lose this ability again in the course of the disease. Life expectancy is not significantly reduced in this rather mild course.
Adult SMA – the symptoms do not become apparent until adulthood over the age of 30 and can have a very different individual course. Life expectancy is not reduced.

Basically, the transitions between the different types of SMA are fluid and the symptoms may differ from patient to patient. SMN protein deficiency affects the whole body. The variety of complications can include respiratory, cardiovascular, and digestive problems, dysphagia, and an increased risk of bone fractures [5,8].

Holistic treatment

Due to the complexity of the disease, comprehensive, interdisciplinary care is indicated. This includes acute care as well as measures regarding rehabilitation, orthopedics, respiratory support, physical therapy and drug interventions. Since 2017, nusinersen has been approved as the first agent that addresses the causes of the disease by correcting the underlying gene defect [9]. In clinical trials, significant improvement in reaching motor milestones has been recorded by using it as early as possible [10,11]. It is approved for the treatment of SMA of all types and stages [9]. The clinical trial program included more than 340 patients in whom stabilization or improvement of disease progression was achieved [10,12,13]. For example, infantile SMA showed significant improvement in the 6-minute walk test after only 180 days, and further long-term follow-up showed improvement in lung function [14]. In adults, treatment resulted in a significant increase in mean Hammersmith Functional Motor Scale Expanded (HFMSE) score and thus clinically meaningful improvement in motor function in a real-world cohort [15].

Literature:

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Borasio G, et al: Diagnostics of spinal muscular atrophies. Neurology 2001; 20: 113-118.
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www.muskelgesellschaft.ch/diagnosen/spinale-muskelatrophien-sma (last accessed 08/17/2020)
Lipnick SL, et al: Systemic nature of spinal muscular atrophy revealed by studying insurance claims. PLoS One 2019; 14: e0213680.
Simone C, et al: Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications? Cell Mol Life Sci 2016; 73: 1003-1020.
Finkel RS, et al: Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord 2018; 28: 197-207.
Nash LA, et al: Spinal Muscular Atrophy: More than a Disease of Motor Neurons? Curr Mol Med 2016; 16: 779-792.
^Spinraza® SmPC, as of Aug 2019; www.swissmedicinfo.ch
De Vivo DC et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the phase 2 NURTURE study. Neuromuscul Disord. 2019;29(11): 842-856.
Finkel, R. et al. Primary Efficacy and Safety Results From thePhase 3 ENDEAR Study of Nursinersen in Infants Diagnosed With Spinal Muscular Atrophy (SMA). Eur J Paed Neurol 2017; 21(1):E14-E15. DOI: https://doi.org/10.1016/j.ejpn.2017.04.1219
Mercuri E et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-35.
Darras BT et al. Nusinersen in later-onset spinal muscular atrophy. Long-term results from the phase 1/2 studies. Neurology 2019;92: e1-e15.
Darras BT, et al: Longerterm Assessment of Nusinersen Treatment in Children With Later-onset Spinal Muscular Atrophy Who Enrolled in CS2/CS12: An Interim Analysis of the SHINE Study.^13th Congress of the European Paediatric Neurology Society; 17-21 September 2019; Athens, Greece.
Hagenacker T, et al: Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multi-centre, observational cohort study. Lancet Neurol 2020; 19: 317-325.