Researchers from the University of Helsinki and Folkhälsan Research Center have identified a new muscle disease in patients from five different European countries using deep phenotyping and high-throughput sequencing.
Distal myopathies are a group of inherited muscle diseases primarily affecting the distal muscles of arms and legs. In some cases, thigh and shoulder muscles may get involved with disease progression. More than 25 causative genes have so far been identified for different types of distal myopathies. In recent years, advancements in high-throughput sequencing techniques and data analysis have considerably increased the rate of molecular diagnosis for families with inherited rare neuromuscular disorders. However, over 40% of patients, in particular patients without any affected relative, remain without conclusive molecular diagnosis.
In a study recently published in Acta Neuropathologica, researchers from Folkhälsan Research Center and the University of Helsinki used high-throughput sequencing, deep phenotyping—i.e., the precise and comprehensive analysis of disease manifestations in the affected individuals—and functional studies to identify and describe a new adult-onset distal myopathy in nine different families from five European countries. The patients were available through a large international collaboration network.
“In absence of sufficient family data, molecular diagnosis of a genetic disease is very difficult. In Western countries, there are few large families left with rare neuromuscular diseases. Mostly small families or single patients with no family history of muscle weakness are waiting for their molecular diagnosis. In such cases, to consider previously unknown genes, data from multiple patients or small families are combined to develop a better understanding.” said Mridul Johari, PhD student in FHRC and the first author of this study.
In the study by Johari and colleagues, all patients had similar clinical features: adult-onset muscle weakness starting from hand or lower limb muscles and slowly progressing over decades, with preserved walking.
Disease-causing mutations were identified in a novel myopathy gene SMPX (Small muscle protein X-linked). The male patients inherited these mutations from their biological mothers (X-linked inheritance). No affected females were identified, and further studies will be needed to confirm whether female carriers of the mutations also develop symptoms of the disease at a very late age.
The mutations identified in myopathy patients are so-called missense variants, which alter single amino acid residues in the SMPX protein. Mutations that result in loss of SMPX protein are known to cause early onset hearing loss, but remarkably the myopathy patients even in their 50s and 60s had no documented hearing impairment. This suggests that the myopathy mutations cause disease by conferring harmful properties for the protein rather than preventing its normal function. In line with this, abnormal accumulation of the SMPX protein was seen in muscle biopsies of the patients, and studies in cell cultures confirmed that the mutant form of SMPX tend to aggregate. Functional studies also suggested that accumulated SMPX protein might delay the clearance of cellular stress granules, a mechanism implicated in other myopathies and neurodegenerative diseases.
Identification of several mutations in SMPX in different European countries suggests that this disease could be prevalent in other populations as well. Furthermore, haplotype analysis revealed that the disease could be more prevalent in Southern European populations.
Johari, M., Sarparanta, J., Vihola, A. et al. Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions. Acta Neuropathol (2021). https://doi.org/10.1007/s00401-021-02319-x
Simon Granroth, Science Communicator