X-linked type SMA (Kennedy’s disease) is a rare and progressive genetic neuromuscular disease that was first described by Dr. William Kennedy in 1964. An adult-onset disease, it usually develops between the ages of 30 and 50 and is associated with mutations in a gene called UBA1 (also known as UBE1 gene), located on the X chromosome.
Symptoms of this rare form of SMA vary greatly, but can include weakness and atrophy in the muscles of the face, jaws, and tongue, leading to difficulties in swallowing, chewing, and changes in speech. Early symptoms may include pain and fatigue, weakness in the arm and leg muscles, and muscle atrophy and fasciculations (twitching). Some individuals develop enlarged breasts (gynecomastia), a low sperm count, and infertility. Others may develop non-insulin-dependent diabetes mellitus.
It is estimated that X-linked type SMA affects 1 in 40,000 people worldwide, with most of them undiagnosed or misdiagnosed for years. Patients’ life expectancy is similar to that of unaffected individuals.
The genetic cause of X-linked type of SMA
Kennedy’s disease is an X-linked disease, meaning that if a mother carries a defective UBA1 gene in one of her X-chromosomes and passes it onto her children, she has a 50% risk of having a son affected by the disease and a 50% chance of having a daughter who is also a carrier of the disease.
Females have two X chromosomes, and males have one X and one Y chromosome. Therefore the disease primarily affects males, as they have no second X chromosome to compensate for the detrimental effects of a mutated gene on an X chromosome.
The UBA1 gene is responsible for making the ubiquitin-activating enzyme E1, involved in the degradation of proteins within cells. Protein degradation is essential to remove damaged or unnecessary proteins, and to maintain the normal function of cells. At least three mutations in the UBA1 gene have been identified. Two are thought to lead to the production of an impaired E1 enzyme. The third results in too little of the enzyme being produced, which ultimately disrupts the process of protein degradation and causes protein buildup. Motor neurons are especially vulnerable to damage/cell death from protein buildup.
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