SNP Shot: Genomic Insights

X-linked myotubular myopathy (XLMTM) is a condition that mainly affects the muscles used for movement (skeletal muscles) and almost exclusively occurs in males. Individuals with XLMTM experience muscle weakness (myopathy) and reduced muscle tone (hypotonia), typically noticeable from birth. Microscopic examination of muscle tissue reveals that muscle fibers are usually small and underdeveloped.

The muscle problems associated with XLMTM hinder the development of motor skills like sitting, standing, and walking. Affected infants may also struggle with feeding due to muscle weakness. Often, individuals with XLMTM lack the muscle strength to breathe independently and require a machine (mechanical ventilation) to assist with oxygen intake. The need for breathing support can be intermittent, often during sleep, or continuous. Other symptoms of XLMTM can include weakness in eye muscles (ophthalmoplegia), facial muscle weakness, and absent reflexes (areflexia).

In XLMTM, muscle weakness frequently disrupts normal bone development, potentially leading to fragile bones, spinal curvature (scoliosis), and joint deformities (contractures) in the hips and knees. Individuals with XLMTM might also present with a large head, a narrow, elongated face, and a high-arched palate. Recurrent ear and respiratory infections, seizures, or liver disease can also occur. A serious liver condition called peliosis hepatitis, which can cause life-threatening bleeding (hemorrhage), may develop in some cases.

Due to severe breathing difficulties, individuals with XLMTM typically survive only into early childhood, although some have lived into adulthood.

XLMTM is the most severe form of a group of disorders known as centronuclear myopathy. In centronuclear myopathy, the nucleus is located in the center of many rod-shaped muscle cells, rather than at the ends where it is normally found.

Inheritance:

XLMTM follows an X-linked recessive inheritance pattern. The gene responsible for the condition is located on the X chromosome, one of the two sex chromosomes. In males (who have one X chromosome), a single altered copy of the gene in each cell is enough to cause XLMTM. In females (who have two X chromosomes), both copies of the gene must be mutated for the disorder to manifest. Because it's less likely for females to have two altered copies of the gene, males are much more commonly affected by X-linked recessive disorders. A key characteristic of X-linked inheritance is that fathers cannot transmit X-linked traits to their sons. In XLMTM, affected males inherit the altered gene from their mothers in 80-90% of cases. In the remaining 10-20% of cases, the disorder arises from a new gene mutation during the formation of a parent's reproductive cells (eggs or sperm) or in early embryonic development. Females carrying one altered copy of the MTM1 gene generally do not show signs or symptoms of XLMTM. However, some females with one altered copy may experience mild symptoms, such as changes in muscle fibers, muscle weakness, and breathing difficulties. Researchers are currently investigating why some females are affected while others are not.