Studies on spinal muscular atrophy: Exploring clinical variability, genetics, biomarkers and treatment

Abstract

In this thesis, I describe the natural history and clinical variability of spinal muscular atrophy (SMA) in the Dutch SMA population, have explored various (epi)genetic factors in search for predictors of disease severity and systematically investigated different treatment strategies in SMA. All of these studies were set up to improve patient care for patients with SMA. The recent discovery of the antisense-oligonucleotide 'Nusinersen' has changed the prospects of SMA completely. The results from the studies of this thesis can be used as a natural history cohort in future studies and provide insight into other treatment strategies besides SMN2 modification. SMA is a genetic disorder, caused by a homozygous deletion of the SMN1 gene, in which alpha motor neurons in the anterior horns degenerate resulting in progressive muscle weakness of the limbs and respiratory muscles. SMA is classified into 3 types (SMA types 1, 2 and 3) based on the highest achieved motor milestones 'sitting' and 'walking'. Based on retrospective analysis of 200 Dutch patients with SMA, the milestones 'rolling' and 'standing' have added value in determining prognosis. These milestones can distinguish patients with a milder or severe course within a SMA type. A refinement of the classification based on 4 milestones provides a better prediction of disease course in the individual patient. SMA is a progressive disease in all types and ages. Patients with type 3 have the highest perceived disease burden compared to more severe SMA types 1 and 2. In addition to muscle weakness, fatigability plays an important role in the physical limitations in SMA. Structurally altered neuromuscular junctions seem to be an additional characteristic in SMA. Electrophysiological studies confirm the presence of a neuromuscular junction transmission dysfunction in SMA, which (partially) explains the symptoms of fatigability. SMN2 copy number is the most important predictor of disease severity. Hybrid SMN1-SMN2 genes and point mutations in SMN2 have additional value, but still do not fully explain the clinical variability in SMA. The SMN2 status can’t predict clinical severity in presymptomatic children with SMA. Current clinical assessment scales are not sufficiently sensitive to identify subtle clinically relevant changes in motor function or muscle strength over relatively short periods of time (months to years). Levels of the SMN protein are strongly tissue-dependent. The SMN protein and RNA have as yet no role as biomarkers for disease severity or course. The SMN protein level in fibroblasts correlates with clinical severity and might have biomarker potential. The SMN protein level in blood declines with age, in patients as well as healthy controls, suggesting a crucial role for SMN in early development. Nusinersen is the first treatment to show efficacy in children with SMA improving both motor function and survival in the majority of patients. Other treatment strategies have shown no effect in clinical trials so far. Treatment strategies to reduce fatigability might improve motor abilities and quality of life.