What is fatal familial insomnia?

Definition

Fatal familial insomnia (FFI) is a rare, genetic prion disease transmitted as an autosomal dominant
trait. The responsible mutation causes prions (proteins found extensively in
the body) to assume abnormal shapes and thereby become pathogenic. A nongenetic
form of the disease, sporadic fatal insomnia, also exists.

Causes

The cause of FFI has been identified as a mutation at codon 178 of the prion-protein gene (PRNP) on chromosome 20. Disease characteristics, such as duration, are determined by a polymorphism at codon 129 of the PRNP gene.

Risk Factors

Each offspring of an affected parent has a 50 percent risk of inheriting the mutant gene, which is highly penetrant; as far as is known, those persons who inherit the gene will express the disease. Sporadic cases have no known risk factors.

Symptoms

Insomnia is the hallmark of this disease, although it is not
invariably present in the earliest stages. Symptoms are best understood in the
context of the histopathology of FFI, primarily involving degeneration and loss of
neurons in the thalamus. The thalamus has a crucial integrative function in the
brain, relaying all manner of sensory information to the cerebral cortex. A role
for the thalamus in regulating autonomic functions and key circadian
rhythms is consistent with prominent FFI symptoms.
Twenty-four-hour circadian patterns comprise not only the sleep-wake cycle but
also the normal ebb and flow of hormone secretions.

Other symptoms include severely impaired motor functions, uncoordinated and jerky muscle movements, and difficulty in speaking and swallowing. The autonomic dysregulation also manifests as fever and sweating. Affected persons are often described as inattentive, restless, and unable to concentrate. Cognition may also be affected.

Secretion of adrenocortical hormones is increased. These hormones are involved in the body’s stress reaction, and those affected experience chronic stress. The insomnia that characterizes this disease is progressive and untreatable, leading to the ultimate absence of any sleep patterns or responses.

The first reported case, in 1986, was that of a fifty-three-year-old man. The onset of FFI is most often in middle to late adulthood, although it has been reported in some patients in their early twenties. The duration of the disease, from less than one year to several years, largely depends on genetic factors.

Screening and Diagnosis

Neither careful clinical examination nor standard tests of sleep responses can
identify carriers of the FFI mutation before symptoms become
apparent. Findings of routine laboratory tests are generally normal.
Positron
emission tomography, however, which can measure the brain’s
consumption of glucose, has shown thalamic changes in an asymptomatic gene
carrier. Postmortem examination confirms the diagnosis.

Treatment and Therapy

Palliative
treatment has been the only reported treatment. Attempts to
alter the disease course with medications have been unsuccessful. Fatal familial
insomnia is considered untreatable.

Prevention and Outcomes

There is no known way to prevent the disease in a carrier. Prenatal diagnosis is theoretically possible.

Bibliography

Bosque, Patrick J., and Kenneth L. Tyler. “Prions and Prion Diseases of the Central Nervous System (Transmissible Neurodegenerative Diseases).” In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Gerald L. Mandell, John F. Bennett, and Raphael Dolin. 7th ed. New York: Churchill Livingstone/Elsevier, 2010.

Brown, David R., ed. Neurodegeneration and Prion Disease. New York: Springer, 2005.

Max, Daniel T. The Family That Couldn’t Sleep: A Medical Mystery. New York: Random House, 2007.

_______. “The Secrets of Sleep.” National Geographic, May, 2010, pp. 74-93.

Prusiner, Stanley B. “The Prion Diseases.” Scientific American 272, no. 1 (January, 1995): 48-57.

_______, ed. Prion Biology and Diseases. 2d ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press, 2004.

Rowland, Lewis P., and Timothy A. Pedley, eds. Merritt’s Textbook of Neurology. 12th ed. Philadelphia: Lippincott Williams & Wilkins, 2010.