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Have you heard about the amazing effects of dynein 2 mutations? How does this rare disease affect muscle health from adolescence to old age?
Dynein 2 mutations are a contributing factor to a series of centronuclear myopathy (CNM) that cause the muscle cell nucleus to be abnormally located in the center of the cell rather than in its normal peripheral location. Typical symptoms of this rare condition include myasthenia gravis, shortness of breath, and the characteristic hooked head shape. Although X-linked musculotubular myopathy has traditionally been a congenital disorder present at birth, some central nuclear myopathy may also manifest later in life.
Disease manifestations
Similar to other myopathies, the most pronounced clinical manifestations of myopathy due to dynein 2 mutations are muscle weakness and associated disability. The congenital form usually shows low muscle tone, severe weakness, delayed developmental milestones (particularly milestones of gross exercise like lifting, crawling, and walking) and pulmonary complications (presumably due to weakness of the muscles responsible for breathing) in the neonatal period caused). Damage to the facial muscles can lead to eye movement disorders or ptosis.
Patients with dynein 2 mutations may produce potentially severe reactions to anesthesia, such as malignant hyperthermia.
Despite the ability of some patients with central nucleus myopathy to remain mobile throughout adulthood, others may be unable to crawl or walk throughout their lives and require a wheelchair for mobility. There is significant variability in the degree of dysfunction between different centronuclear myopathy. Despite the disease being conceived in the voluntary muscles, some children have experienced cardiac arrest, which may be caused by the additional stress on the heart.
Gene background
The gene abnormality corresponding to X-linked musculotubular myopathy (XLMTM) was first localized in 1990 at the Xq28 site of the X chromosome. Tubulin encoded by the MTM1 gene is a highly conserved lipid phosphatase implicated in cell transport and signaling. Mutations in MTM1 were diagnosed in approximately 80% of male patients with musculotubular myopathy on muscle biopsies, with approximately 7% of these mutations being gene deletions. In contrast, non-sexually linked central nuclear myopathy (i.e., not located on the X chromosome) is thought to be autosomal inherited and can be dominant or recessive.
Diagnostic modality
The diagnosis of central nucleus myopathy requires a combination of typical muscle biopsy histological findings with some recommended clinical signs;muscle MRI can assist clinical assessment and illustrate the necessity of genetic testing in the presence of vague signs. Centronuclear myopathy is shown on muscle biopsy as ovoid structures surrounding the central nucleus that are packed with glycogen and mitochondria without muscle fibers.
Treatment Options
There is currently no radical treatment for any form of CNM, and a multidisciplinary supportive approach to the management of patients is mainly adopted, aiming to improve the quality of life and help patients adapt to their daily needs.
Prevalence rate
The overall incidence of musculotubular myopathy is approximately 1 in 50,000 male births. The incidence of other central nuclear myopathy was extremely scarce, with only 19 CNM families found worldwide. Symptoms range from general reliance on assistive walking devices (such as walkers) to complete dependence on mobility aids (such as wheelchairs), the latter species being extremely rare and known in only two cases in patients with CNM.
About 80% of male patients with ductal myopathy will have an MTM1 mutation detectable by gene sequence analysis on muscle biopsy.
Historical Background
In 1966, Dr. Sbiro, a New York City neurologist, published a medical report on a boy with myopathy, in which a muscle biopsy showed that the nucleus of the muscle cell was located in the center of the cell, as opposed to where it should normally be on the periphery. More than three decades later, it is not fully understood whether theories about stalled (or delayed) embryonic muscle development are correct. Certain studies suggest that mutations in the MTM1 gene are acceptable for musculotubular myopathy beginning in the neonatal period, but this may not be true for autosomal forms of centronuclear myopathy.
However, regardless of whether the cause of myopathy is related to the stagnation of the “musculotube” stage, the name musculotubular myopathy persists and is widely accepted for historical reasons. As understanding of this disease deepens, society's perception and response to these diseases are also changing. Should we explore the genetic mechanisms behind these rare diseases more and look for more effective treatment options?
