INNOVATIVE THERAPIES IN GENETIC DISEASES: SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy is a congenital neuromuscular disease characterized by the deterioration of the motor neurons located mainly in the anterior horns of the spinal cord, leading to progressive muscle weakness and atrophy. Globally, SMA is, after cystic fibrosis, the second cause of death due to a a genetic disease in the pediatric population. Over 95% of the total cases of SMA are represented by 5q SMA, caused by biallelic mutations in the SMN1 gene (5q13.2), the rest of the SMA types being called, generically, non-5q SMA. Currently, a few genetic targeted therapies are available for 5q SMA, while other innovative therapies are still in clinical trials. Early diagnosis and treatment of 5q SMA have an essential role in preventing the onset and evolution of symptoms and can save the life of the patient and prevent debilitating sequelae. This article aims to briefly describe the cause and symptomatology of 5q SMA as well as to make a short review of the genetic therapies available for this disease.

Evaluation of the Core Formation Process in Congenital Neuromuscular Disease With Uniform Type 1 Fiber and Central Core Disease

Typical central core disease (CCD) is characterized pathologically by the presence of a core and is accompanied by type 1 fiber uniformity. Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is characterized pathologically by the presence of type 1 fiber uniformity but without the abnormal structural changes in muscle fibers. Interestingly, typical CCD and 40% of CNMDU1 cases are caused by the same mutations in RYR1, and thus CNMDU1 has been considered an early precursor to CCD. To better understand the nature of CNMDU1, we re-evaluated muscle biopsies from 16 patients with CNMDU1 using immunohistochemistry to RYR1, triadin and TOM20, and compared this to muscle biopsies from 36 typical CCD patients. In CCD, RYR1, and triadin were present in the core regions, while TOM20 was absent in the core regions. Interestingly, in 5 CNMDU1 cases with the RYR1 mutation, RYR1, and triadin were similarly present in core-like areas, while TOM20 was absent in the subsarcolemmal region. Furthermore, there was a correlation between the core position and the disease duration or progression—the older patients in more advanced stages had more centralized cores. Our results indicate that CNMDU1 due to RYR1 mutation is a de facto core myopathy.

CONGENITAL NEUROMUSCULAR DISEASE WITH UNIFORM TYPE-1 FIBERS SIMULTANEOUSLY PRESENTING GLUTEAL MUSCLES CONTRACTURE AND BRAIN ATROPHY: A CASE REPORT

We report the clinical presentation and pathological findings of congenital neuromuscular disease with uniform type-1 fibers presenting on an 11-year-old girl with the clinical diagnosis of unilateral (right-side) gluteal contracture and brain atrophy. CT image showed that right gluteus maximus muscle was atrophic. Brain MRI showed mild bilateral ventricular dilation and widening of the lateral fissure. A biopsy of quadriceps muscle revealed only uniformity of type-1 fibers with the absence of cores, and mild decrease of activity on oxidative enzyme staining. Although the exact cause of congenital gluteal muscle contracture is still not clear, we presume that the congenital gluteal muscle contracture may be caused by the neuromuscular disease with uniform type-1 fibers and this is the first case report of neuromuscular disease with uniform type-1 fibers complicated with brain atrophy in China.