Doctoral defence: Sanna Puusepp “Comparison of molecular genetics and morphological findings of childhood-onset neuromuscular disorders”

On 13 December at 14:00 Sanna Puusepp will defend her doctoral thesis “Comparison of molecular genetics and morphological findings of childhood-onset neuromuscular disorders” for obtaining the degree of Doctor of Philosophy (in Medicine).

Supervisors:
Professor Katrin Õunap, University of Tartu
Professor Werner Stenzel, Charité – Universitätsmedizin (Germany) 

Opponent:
Professor Edoardo Malfatti, Université Paris-Est Créteil Val de Marne – Université Paris (France)

Summary
Hereditary neuromuscular disorders (NMDs) include spinal motor neuron, nerve, neuromuscular junction, and muscle diseases caused by a single gene defect. In addition to the patient's disease history and examination, the diagnosis of NMDs can be reached using various instrumental investigations, including muscle biopsy. Several different stains and techniques are used to analyze muscle tissue, showing the structure and chemical and enzymatic properties of muscle fibers and the presence or absence of various proteins. Histological changes in muscle tissue have historically been the basis for identifying and diagnosing several hereditary NMDs and have provided guidance on which genes to study. However, nowadays, it is possible to study all genes at once with one analysis (whole exome sequencing), which has also shown good diagnostic efficiency. Thus, the role of muscle biopsy in NMD diagnostics is changing.

The present study included 70 patients with a suspected hereditary NMD or mitochondrial disease, of whom 44 received a genetic diagnosis. The study found that muscle biopsy played a vital role in the diagnostic process in many cases, with 15 patients having specific histological changes in the muscle tissue. In several cases, a muscle biopsy was necessary to detect changes in mitochondrial DNA. In addition, studies of muscle tissue provided valuable additional information in many cases with previously undescribed gene variants, changes in a candidate gene, or without genetic findings. For example, in one patient with muscular dystrophy, we discovered changes in the new JAG2 gene and confirmed its disease association owing to international cooperation. Of note, by studying the expression of genes and specific proteins in the muscle tissue of this patient, we got an indication that the development of the disease may be related to the dysfunction of muscle stem cells. However, muscle biopsy did not provide additional information in most patients with a disease affecting the central nervous system. Lastly, the dissertation described the association of SPATA5 gene defect with mitochondrial dysfunction and nerve growth impairment and one patient with a suspected congenital myopathy, eventually diagnosed with PRPS1 gene-related inborn error of purine metabolism.