Choosing the optimal mouse model for the study of late-onset spinal muscular atrophy: Why the 4-copy SMN2 model offers ideal translational relevance.

Myotonic Dystrophy type 1 (DM1) is a genetically inherited neuromuscular disorder that is caused by a CTG trinucleotide repeat expansion in the (DMPK) gene on chromosome 19. Whereas healthy individuals have 5 to 35 CTG repeats, repeats in DM1 affected individuals range from 50 to 5000. The length of the repeat expansion is moderately correlated with disease severity, as a larger repeat expansion is associated with a more severe phenotype and earlier onset of symptoms. DM1 is generally characterized by muscle weakness and myotonia (inability to relax muscles), although several organ systems can be affected. Cardiac and pulmonary complication are typically prioritized in clinical follow-up due to possible life-threatening complications. However, gastrointestinal (GI) symptoms, along with urinary and bowel control issues, have the greatest impact on the lives of patients with DM1. Described complaints may vary substantially within and between patients and include dyspepsia, diarrhea, abdominal pain or discomfort, constipation and fecal incontinence. Currently, the occurrence of GI symptoms in the DM1-population is mainly attributed to affected striated and smooth muscle cells. Striated and smooth muscle cells are found in the whole gastrointestinal tract, which explains the clinical symptoms pallet ranging throughout the whole tract. GI symptoms are generally attributed to the direct cause of the illness, but can also indirectly flair up due to involvement of the neuroendocrine system. Although GI-complaints play a large role in the burden of disease for DM1-patients, the course of GI impairment and interaction with muscular symptoms has not yet been fully understood. Studies that have considered the interaction between esophageal and gastric dysfunction, and the degree of skeletal muscle involvement have found little if any correlation. However, a relationship between the severity of esophageal and gastric dysfunction, and the duration of skeletal muscle disease have been reported. Alongside its debilitating impact on patients with DM1, GI impairments may be the first presenting complaints of the disease. In general, GI symptoms develop gradually, leading to adaptation of the patients with little awareness. Consequently, the negative impact of GI symptoms on quality of life, combined with the incomplete understanding of their development in DM1, underscores the need for a psychometrically sound outcome measure.