Natural history of Spinal Muscular Atrophy: Re(de)fining clinical phenotypes and exploring symptomatic treatment

Hereditary proximal spinal muscular atrophy (SMA) is a severe hereditary neuromuscular disorder, which usually presents in infancy or (early) childhood. SMA is caused by loss of SMN1 gene function, leading to a deficiency of SMN protein. The SMN2 gene in the human genome partially compensates for SMN1 loss, but insufficiently to prevent pathology. As a result of the SMN protein deficiency, patients suffer from progressive loss of bulbar and spinal cord alpha motor neurons. This causes progressive muscular weakness in patients.
Four main SMA types of varying disease severity are distinguished, primarily based upon highest achieved motor function during childhood. SMA type 1 is the most common and most severe form, with a symptom onset in infancy. Infants do not learn to sit without support and without treatment, survival is severely shortened. SMA types 2 and 3 are characterized by an onset in childhood. Patients with type 2 learn to sit without support but not walk, whereas patients with type 3 also learn to walk without support. SMA type 4 is a rare, adult-onset form of SMA.
The natural history of SMA is characterized by a progressive decline of muscle strength, motor abilities, and lung function. Until recently, no therapies were available for SMA. In the past couple of years, however, the prospect for patients with SMA has changed considerably following the introduction of several genetic therapies. These therapies improve life expectancy and motor function in infants and young children with SMA in the shorter term. Whether these therapies also work in the longer-term and whether they are effective for older children and adults remains to be elucidated.
To further study possible therapy efficacy, but also further improve care and counselling for patients and caregivers, it is important to further delineate the natural history of SMA, as it had not been fully studied prior to this thesis, specifically not for older children and adults with SMA. Most studies in the past decades had focused on infants and younger children, with more severe SMA types. In this thesis we therefore studied several characteristics of SMA’s natural history, with an emphasis on older children, adolescents and adult patients with SMA. This includes studies on survival, patterns of muscle strength and motor function decline, lung function, scoliosis development and associated need for scoliosis surgery. Additionally, we also studies possible involvement of tissues outside the nervous system, i.e. possible non-neuromuscular pathology in SMA. Finally, we studied fatigability, an important characteristic that impedes activities of daily life in many patients. We showed that pyridostigmine can improve patient’s fatigability and may be used as a safe, add-on therapy at low cost.

The insights gained in this thesis have improved our insights into the natural history of SMA, may further improve care and counselling for patients and their caregivers, and may aid in further evaluations of (future) therapy efficacy.