Unsolved muscle diseases

A large number of patients with a distal myopathy, i.e. a muscular disease mainly affecting the hands and feet, still lack a proper diagnosis since the genetic defect is not located in previously known disease genes. In this study, we describe a new clinical form of distal myopathy, named actininopathy, due to defects of a protein, alpha actinin 2, which is crucial for muscle function. A larger analysis of myopathy patients will probably reveal an increasing number of patients with this disease in the coming years.

Distal myopathies are rare genetic diseases characterized by a predominant weakness in the feet and/or hands. Over 20 different genes have been identified which contribute to the genetic defects causing distal myopathy. However, 40–50% of patients with distal myopathy do not have any defects in the previously identified genes. This suggests the presence of novel disease-causing genes that have not yet been identified.

In this study, we focused on patients with distal myopathy through a sample of four families, three Spanish and one Swedish. All patients developed symptoms, mainly a weakness in the hands or legs, in adulthood (from the age of 40–50). This often resulted in a steppage gait, later leading to more widespread weakness and eventually walking inability.

Using state-of-the-art methodology, we identified the same mutation in the ACTN2 gene in all three Spanish families, who came from a small region in Northern Spain. The ACTN2 gene codes for the alpha actinin 2 protein, which is highly expressed in human muscles. A different mutation in the same gene was identified in the Swedish family. Alpha actinin 2 is a crucial protein for heart and skeletal muscles, and deficit function in the protein results in muscular histological and morphological alterations.

The identification of the genetic causes of this rare disorder is an important step for defining a prognosis, genetic counselling, correct treatment/management and, above all, for developing specific therapies. We expect a large number of myopathy patients around the world with novel ACTN2 defects to be identified.

Original article:

Savarese M, Palmio J, Poza J, Weinberg J, Olive M, Cobo AM, Vihola A, Jonson PH, Sarparanta J, García-Bragado F, Urtizberea A, Hackman P, Udd B. Actininopathy – a new muscular dystrophy caused by ACTN2 dominant mutations. Ann Neurol 85: 899-906, 2019 (doi: 10.1002/ana.25470).