Hereditary amyloidosis

Definition

Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent, acute attacks of intense pain, lasting two to three days, usually in the abdomen, chest, or joints. FMF is often accompanied by fever and sometimes a rash. It is most prevalent in people of Armenian, Sephardic Jewish, Levantine Arabic, and Turkish ancestry.

Description

Estimates of the frequency of FMF within the affected populations range from 0.02-0.2%.

Episodes of FMF are associated with inflammation of sheets of tissue covering the organs (serosal membranes) inside the abdominal cavity (peritonitis), the chest cavity (pericarditis), and the membranes around joints (arthritis). During an episode, massive numbers of a certain type of white blood cell (neutrophils) move into the affected area or areas and cause inflammation.

In addition to episodes of painful inflammation, some FMF sufferers acquire chronic arthritis. Moreover, about 25% of the people afflicted by FMF develop amyloidosis, a serious condition where proteins called amyloids are mistakenly synthesized and deposited in organs and tissues in the body. Amyloidosis often leads to kidney failure.

FMF is inherited as a recessive trait. This means the disease is only active in persons who have two defective copies of a gene, one from each parent. How the gene involved acts, its relationship with FMF episodes, and its relationship to amyloidosis and chronic arthritis are all unknown.

However, FMF research is moving fast. In 1997 researchers cloned and determined the sequence of the gene responsible for FMF, and this breakthrough should pave the way for progress. Knowledge of the sequence of FMF DNA will allow the development of a much-needed diagnostic test. Such tests would allow the identification of prospective parents who each carry one masked copy of the FMF gene that could be passed to the next generation; and this would facilitate pre-natal genetic counseling. By comparing DNA sequences from different individuals with FMF, scientists could determine whether amyloidosis associated with FMF is genetically determined. If it is, a diagnostic test could be designed to distinguish between individuals who will get amyloidosis and those who will not, enabling more appropriate choices of drug regimens.

Knowledge of the sequence of FMF DNA has already provided information about the protein encoded by the FMF gene. The sequence of the protein has been deduced from the sequence of the DNA, and this protein, called pyrin, bears strong resemblance to other proteins known to be regulatory proteins. Knowledge to be gained about the function of this protein in normal cells and the role it plays in FMF episodes can lead to new drugs that will specifically act to correct the process that malfunctions during FMF episodes without the side effects and risks of the drugs in current use.

FMF is also known by many other names. They include: recurrent hereditary polyserositis, benign paroxysmal peritonitis, familial paroxysmal polyserositis, paroxysmal polyserositis, familial recurrent polyserositis, periodic fever, periodic amyloid syndrome, periodic peritonitis syndrome, Reimann periodic disease, Reimann's syndrome, Siegel-Cattan-Mamou syndrome, and Armenian syndrome.

Causes & symptoms

Causes

The underlying cause of the disorder is the defective FMF gene, but the series of reactions that bring about FMF and the role of the gene in those reactions are unknown. Furthermore, it is not known what factors trigger the episodes.

Symptoms

The recurrent acute attacks of FMF typically begin in childhood. The pain, usually in the abdomen, chest, or joints, or less commonly in the area surrounding the testes, and sometimes in two or more of these areas at the same time, lasts for 24-72 hours. FMF is often, but not always, accompanied by fever and sometimes with a rash (in less than 5% of the cases). Between episodes, most victims of FMF are completely without symptoms.

However, for some people the recurrent joint pain becomes chronic arthritis. Moreover, about 25% of the people afflicted by FMF develop amyloidosis, a condition that often leads to kidney failure and is potentially lethal. The percentage of people with FMF who get amyloidosis varies among the different populations affected by FMF and ranges between 0-60%. It is not known whether this variation is due to genetic differences or to external factors like diet.

Diagnosis

As of early 1998, there is no diagnostic test for FMF, so diagnoses must be based solely on the clinical symptoms. The symptoms of FMF (severe abdominal pain, for example), are difficult to distinguish from similar symptoms arising from completely different causes. For example, FMF is easily mistaken for appendicitis. In fact, according to one estimate, up to two-thirds of FMF sufferers have been subjected to appendectomies. In addition, FMF sufferers may undergo needless, sometimes repeated, exploratory surgery as a consequence of inadequate diagnoses. Internists and rheumatologists are best able to diagnose FMF, but many doctors in the United States are unfamiliar with this disorder and frequently do not recognize it.

FMF should be suspected for any patient who:

• Has had at least four episodes of abdominal pain or chest pain or both, lasting from 24-72 hours
• Is without symptoms between attacks
• Does not have any other condition that would explain the symptoms.

If the drug colchicine, eliminates or decreases the number of attacks, the diagnosis of FMF is confirmed because colchicine does not help any other ailments with similar symptoms. If colchicine is not effective, FMF cannot be ruled out. Fortunately, definitive diagnostic tests are on the horizon.

Treatment

For reasons nobody yet understands, the drug colchicine is effective at preventing or reducing the number of acute FMF episodes for a large percentage of FMF sufferers. Colchicine is also an effective treatment for FMF-associated amyloidosis. Some people think it acts against FMF attacks by inhibiting the movement of neutrophils (a type of white blood cell) to the areas that would otherwise become inflamed. Colchicine, however, has unpleasant side effects, including nausea, diarrhea, and stomach cramps. The drug can also cause chromosomal damage and infertility.

Prognosis

Currently, except for those who get amyloidosis and chronic arthritis, people with FMF have a good quality of life between episodes and an excellent prognosis. However, people with repeated episodes of amyloidosis will likely need kidney transplants. In addition, people who take colchicine to combat FMF risk chromosomal damage and infertility and often suffer from the drug's side effects, nausea, diarrhea, and stomach cramps.

However, this situation is likely to change soon. Knowledge of the newly-cloned gene and its gene product holds promise for better lives for FMF victims through a better understanding of the processes governed by this gene.

Prevention

Since FMF is a genetic disease, it can only be prevented if carriers of the defective gene can be identified. This is not currently possible, because at the moment there is no diagnostic test to identify the carriers of the defective gene, except in the cases of people who have the FMF disorder and, therefore, two copies of the defective FMF gene.

Now that the gene for FMF has been cloned, it may soon be possible to develop tests that will allow people in high risk groups to find out if they carry the gene. This would allow couples, where both partners carry the gene, to take measures to ensure their children will not have FMF.

Some researchers are interested in trying to determine whether there may be some advantage to carrying the FMF gene. Other defective genes that cause certain diseases have been found to provide carriers useful protections against specific infectious diseases. Perhaps FMF provides similar advantages. This gene has been in the human gene pool for over 2,000 years, and it is present in some populations at a high level, as many as 20% of the people in some groups may carry the gene. The fact that it has not disappeared suggests that it provides some evolutionary advantage to people who carry it. Also, after the pathways of reactions that lead to the various symptoms are understood, treatment may become simpler and more risk-free.

Key Terms

Amyloid

A glycoprotein (a type of protein with sugar groups attached) not synthesized under normal conditions.

Amyloidosis

A condition where amyloid is synthesized and deposited in organs and tissues in the body; it can lead to kidney failure.

Colchicine

A compound that blocks the assembly of microtubules, protein fibers necessary for cell division and some kinds of cell movements, including neutrophil migration. Its side effects are diarrhea, abdominal cramping, and nausea, and it can cause chromosomal damage and infertility.

Neutrophil (also called polymorphonuclear leukocyte)

A kind of white blood cell that is the primary cell in areas of acute inflammation.

Paroxysmal

Sudden and recurrent.

Polyserositis

Inflammation of serosal membranes, i.e., fluid-secreting membranes, consisting of cells and connective tissue, that cover the insides of body cavities and organs within them.

Recessive trait

An inherited trait that is outwardly obvious only when two copies of the gene for that trait are present, as opposed to a dominant trait where only one of the two gene copies needs to be that of the dominant trait for that trait to be outwardly obvious. The recessive condition is said to be masked by the presence of the dominant gene when both are present; the recessive condition is visible only in the absence of the dominant gene.

Further Reading

For Your Information

Books

• Kastner, Daniel L. "Intermittent and Periodic Arthritic Syndromes." In Arthritis and Allied Conditions: A Textbook of Rheumatology, 13th ed. Edited by William J. Koopman. Baltimore: Williams & Wilkins, 1996.
• Sha'ar, Khuzama H., and Haroutone K. Armenian. "Familial Paroxysmal Polyserositis (Familial Mediterranean Fever)." In Genetic Disorders Among Arab Populations, edited by Ahmad S. Teebi, and Talaat I. Faraq. New York: Oxford University Press, 1997.

  Periodicals

• "Ancient Missense Mutations in a New Member of the RoRet Gene Family Are Likely to Cause Familial Mediterranean Fever." Cell 90 (August 22, 1997): 797-807.
• Babior, Bernard M., and Yaacov Matzner. "The Familial Mediterranean Fever Gene--Cloned at Last." The New England Journal of Medicine 337 (November 20, 1997): 1548-1549.

  Organizations

• The National Organization for Rare Disorders, Inc. P.O. Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518, Fax: (203) 746-6481, Toll-Free: (800) 999-6673. http://www.pcnet.com/~orphan/.

Gale Encyclopedia of Medicine. Gale Research, 1999.