In a significant advance toward understanding a perplexing and painful neurological disorder, an international team of researchers has discovered gene mutations associated with an inherited chronic pain and weakness syndrome known as hereditary neuralgic amyotrophy (also called HNA). No treatment is known for this disabling condition, which short-circuits a peripheral nerve center called the brachial plexus, a network of more than 100,000 nerves, that branches from the spinal cord to supply muscular function and sensation to the shoulders, arms, and hands.
HNA may first appear in the childhood or teen years, and lead to recurring episodes of severe, sudden onset pain in the arms and shoulders as well as weakness, loss of sensation, and muscle wasting. Episodes are often triggered by an infection, an immunization, childbirth, or overworking the arms and shoulders. Nerve inflammation and changes in the blood suggest that problems with the person’s immune response are contributing to the episode. The on again/off again course of the condition, and the environmental triggers, are unusual among inherited nerve disorders.
An associated aspect of the disorder in some individuals is facial features — a long, slender face and narrow, close-set eyes slanting upward — reminiscent of portraits by the early 20th-century Italian painter Modigliani, according to Phillip F. Chance, MD, professor of pediatrics and neurology at the University of Washington in Seattle, whose laboratory first determined in 1996 that the gene for this disorder would be located on chromosome 17.
Twenty-seven medical scientists at universities in Germany, Belgium, the United States, Finland, and Spain conducted the research to find the specific gene responsible for HNA. The lead authors of the study, which appears in the Sept. 25 edition of Nature Genetics, include Dr. Gregor Kuhlenbaumer of the University of Munster, Dr. Vincent Timmerman of the University of Antwerp, and Dr. Mark C. Hannibal and Dr. Phillip Chance, both from the Division of Genetics and Developmental Medicine at the University of Washington.
By studying several multigenerational families who had several relatives with HNA, the researchers identified mutations in a gene named septin-9 ( known as SEPT9). Cells from a variety of life forms, ranging from yeast to fruit flies to humans, contain septins. Septins form protein filaments that provide the internal scaffolding of cells, and play key roles in the process by which cells divide. Out-of-control septins are implicated in certain abnormal cell divisions that lead to tumor formation, including breast cancer. Cells depleted of SEPT9 often fail to complete normal cell division. HNA is the first genetic disease found to be caused by a mutation in a gene of the septin family.
According to the authors of the SEPT9 gene mutations study, SEPT9 has particular structures that distinguish it from all other septins, but the significance and function of these structures is as yet unknown. Future research on the SEPT9 gene and its mutations may lead to a better understanding of the normal function of the gene and its protein products. Scientists also hope to learn how the mutated gene contributes to the development of specific facial features before birth and is later triggered to produce the nerve disorder, and why the disease goes through exacerbations and remissions.
The research on the genetic mutations of SEPT9 was supported by grants from the Deutsche Forschungsgemeinschaft, the Neuropathy Association, the National Institutes of Health, the Veterans Affairs Research Fund, the University of Antwerp, the Fund for Scientific Research, the Interuniversity Attraction Poles program of the Belgian Federal Science Policy Office, and the Medical Foundation Queen Elizabeth.