NORD gratefully acknowledges Dr. Janice Holton, MB, ChB, PhD, FRCPath, Senior Lecturer and Honorary Consultant Neuropathologist, Division of Neuropathology, Institute of Neurology, Queen Square, London, for assistance in the preparation of this report.
X-linked myopathy with excessive autophagy (XMEA) is an extremely rare genetic disorder characterized by muscle disease (myopathy). The disorder is fully expressed in males only and is characterized by slowly progressive muscle weakness, especially in the legs. Onset is usually during childhood often between 5-10 years of age. XMEA occurs due to mutations of an unidentified gene on the X chromosome. The disorder is inherited an X-linked recessive trait.
The symptoms of XMEA usually become apparent during childhood. The disorder is fully expressed in males only. Females who carry the defective gene do not develop any apparent symptoms (asymptomatic) or only very mild symptoms.
The key finding in XMEA is slowly progressive muscle weakness, especially of the proximal muscles of the legs. The proximal muscles are those closer to the center of the body (e.g., upper leg muscles). As the disease progresses, some individuals may experience difficulty performing certain activities such as climbing stairs and running. During the second decade of life, muscles of the upper limbs or shoulders may become involved. In some cases, the muscles farther from the center of the body (distal muscles) such as those of the hands and feet may become involved.
During adulthood, muscle degeneration (atrophy) may occur. By the sixth decade of life, some individuals may need a wheelchair. According to the medical literature, XMEA is not associated with involvement of other organ systems.
XMEA is inherited as an X-linked recessive disorder. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome.
Females have two X chromosomes but one of the X chromosmomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their 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. Female carriers of an X-linked disorder 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.
Investigators have determined that XMEA occurs due to disruption or changes (mutations) to an unidentified gene located on the long arm (q) of the X chromosome (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the hundreds of genes that are present on each chromosome.
Unlike similar muscle disorders, XMEA rarely shows death (necrosis) of muscle tissue when studied under a microscope. However, the muscle tissue of individuals with XMEA does show excessive autophagy. Autophagy is a normal process in which components of a cell are broken down by that cell and reused, often during times of stress or starvation. Autophagy also plays a role in defending the body against foreign or invading substances, serving a second line of defense after the immune system. Although individuals with XMEA show excessive autophagy in muscle tissue, the exact role or significance of this finding in relationship to the development and progression of the disease is unknown.
XMEA has only been reported in approximately 20 families. It is fully expressed in males only, although females may develop mild symptoms. Because this disorder is often unrecognized, it may go undiagnosed making it difficult to determine its true frequency in the general population.
XMEA was first described in the medical literature in 1988.
A diagnosis of XMEA is made based upon a thorough clinical evaluation, a detailed patient history and surgical removal and microscopic evaluation (biopsy) of affected muscle tissue.
No specific therapy exists for XMEA. The treatment of XMEA is directed toward the specific symptoms that are apparent in each individual. In some cases, individuals in their sixties or older may eventually become wheelchair dependent.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Holton JL, Beesley C, Jackson M, et al., Autophagic vacuolar myopathy in twin girls. Neuropathol Appl Neurobiol. 2006;32:253-9.
Munteanu I, Ackerley CA, Mnatzakanian GN, Kissel TJ, Minassian BA. Electrophysiology extends the phenotypic spectrum of X-linked myopathy excessive autophagy. Neurology. 2005;64:927-8.
Sugie K, Noguchi S, Kozuka Y, et al., Autophagic vacuoles with sarcolemmal features delineate Danon disease and related myopathies. J Neuropathol Exp Neurol. 2005;64:513-22.
Kaneda D, Sugie K, Yamamoto A, et al., A novel form of autophagic vacuolar myopathy with late-onset and multiorgan involvement. Neurology. 2003;61:128-31.
Minassian BA, Aiyar R, Alic S, et al., Narrowing in on the causative defect of an intriguing X-linked myopathy with excessive autophagy. Neurology. 2002;59:596-601.
Jaaskelainen SK, Juel VC, Udd B, et al., Electrophysiological findings in X-linked myopathy with excessive autophagy. Ann Neurol. 2002;51:648-52.
Chabrol B, Figarella-Branger D, Coquet M, et al., X-linked myopathy with excessive autophagy: a clinicopathological study of five new families. Neuromuscul Disord. 2001;11:376-88.
Villard L, des Portes V, Levy N, et al., Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. Eur J Hum Genet. 2000;8:125-9.
Kalimo H, Savontaus ML, Lang H, et al., X-linked myopathy with excessive autophagy: a new hereditary muscle disease. Ann Neurol. 1988;23:258-65.
FROM THE INTERNET
Myopathy, X-linked, with excessive autophagy. Orphanet encyclopedia, June 2006. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=25980 Accessed on: July 30, 2006.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:310440; Last Update:12/16/2005. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=310440 Accessed on: July 30, 2004.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100