NORD gratefully acknowledges Jennifer Pagano, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
X-linked myopathy with excessive autophagy (XMEA) is a very rare genetic condition. Autophagy is the process of breaking down damaged or unnecessary cell parts such as proteins and organelles. The most common feature of XMEA is muscle disease (myopathy) and slowly worsening muscle weakness, especially in the legs. This disorder is caused by a harmful change (mutation) in the VMA21 gene located on the X chromosome. The inheritance pattern of XMEA is X-linked, meaning that typically only males are affected and females are unaffected carriers. Signs and symptoms usually start between 5-10 years of age, but some patients do not become symptomatic until later in life. There are currently no specific treatments for XMEA. Management focuses on symptoms and may include physical therapy and exercise. XMEA was first reported in medical literature in 1988 and the VMA21 gene was discovered to be the cause of XMEA in 2013.
Symptoms of XMEA often appear in the first 10 years of life. First signs include an unusual walking pattern (gait) and problems running or climbing stairs. The muscles most affected include the shoulders, hips, thighs and occasionally ankles. The slowly progressive weakness tends to start with muscles that are closer to the center of the body (proximal muscles) such as the upper legs. During the second decade of life the upper limbs and shoulders may be affected. In some patients, muscles far away from the center of the body (distal muscles) such as the hands and feet may become involved. Patients may also experience joints that are tightened or flexed in fixed positions (joint contractures). Symptoms tend to stay consistent, but it is possible that they may worsen with age. Older patients often need help walking and may experience muscle wasting (atrophy). It is common for patients in their 50s and 60s to use a wheelchair. The heart, brain, spinal cord and lungs are not usually affected by XMEA. This condition does not typically lead to a shortened life span.
XMEA is most often diagnosed in children under 10 years of age. Additional research has identified patients with a mild form of the condition who do not develop symptoms until late adulthood. There are also children who experience onset of symptoms shortly after birth.
XMEA is caused by a harmful change (mutation) in the VMA21 gene. The VMA21 gene is responsible for creating a protein that aids in an important cellular process known as autophagy. Autophagy comes from the Greek words auto (self) and phagein (to eat). It is a normal and important process in which cells get rid of toxins and waste and recycle damaged cell parts. A non-working VMA21 gene leads to an incorrect and increased process of autophagy. This process occurs in the lysosomes which are specialized compartments inside our cells. They aid in autophagy, help the cell dispose of waste and break down particles. The mutation in the VMA21 gene causes increased acidity in the lysosomes, and they are no longer able to fully break down cell waste. This leads to build-up of lysosomes and other cell parts responsible for autophagy. This is what causes the symptoms commonly seen in XMEA.
Because the VMA21 gene is located on the X chromosome, the inheritance pattern of this condition is called X-linked and affects mostly males. Females that have a non-working gene on one of their X chromosomes are carriers for that condition. Carrier females usually do not have symptoms because they have two X chromosomes (one from each parent) and only one has the non-working gene. Males have one X chromosome that is inherited from their mother and one Y chromosome inherited from their father. If a male inherits an X chromosome that contains a non-working gene he will develop the condition.
Female carriers of an X-linked condition have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
XMEA is very rare. Less than 1 in 1,000,000 people are affected with this condition. Because this disorder is often unrecognized, it may not be diagnosed in all affected individuals. This can make it difficult to determine the true number of people who have XMEA.
Muscle biopsy can diagnose XMEA and findings are consistent across all patients with XMEA. A diagnosis can also be made by genetic testing if a mutation is found in the VMA21 gene that results in a reduced amount of protein product.
Many individuals with XMEA show high CPK (creatine phosphokinase) levels. However there have been people who have XMEA with normal CPK levels. CPK is an enzyme found in muscle and various tissues in the body. Elevated CPK indicates muscle damage. Neurological findings can sometimes be used in making a diagnosis. Nerve conduction studies are typically normal, but EMG (electromyography) findings are often abnormal. EMG is a procedure to assess the health of muscle and nerves. Findings from special staining of muscle biopsy tissue can distinguish XMEA from Danon disease.
Currently there are no therapies specific to XMEA. Management of the condition is based on specific symptoms. Physical therapy can be helpful to improve mobility and reduce joint contractures. It is also important to exercise and keep a healthy diet.
Genetic counseling is recommended for affected individuals and their families
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