Fatal familial insomnia

Fatal familial insomnia (FFI) is a very rare autosomal dominant inherited prion disease of the brain. The gene mutation responsible has been found in just 50 families worldwide; if only one parent has the gene, the offspring have a 50% chance of inheriting it and developing the disease. The disease's genesis and the patient's progression into complete sleeplessness is untreatable, and ultimately fatal.

History

Fatal familial insomnia (FFI) was first detected by Italian doctor Ignazio Roiter in 1974, who discovered two women from one family who apparently died of insomnia.^[1] Family records showed a history of seemingly related deaths. Another member of the family fell ill in 1984; the patient's deterioration was studied and after his death his brain was flown to the U.S. for further investigation.

In the late 1990s, researchers discovered that the disease is caused by a mutation in a protein called a prion protein (the PRNP gene): asparagine-178 replaces aspartic acid. This mutation will cause FFI if there is a methionine at codon 129 of the same PRNP gene allele. Thus, FFI is a variant form of familial Creutzfeldt-Jakob disease (Codon 129 is polymorphic in humans with about 60% of alleles in European populations carrying a methione and the remainder being valine. The D178N mutation on a V129 bearing allele causes disease similar to sporadic Creutzfeldt-Jakob disease.)^[2]

Pathophysiology

In FFI, as in other prion diseases, the normal conformation of PrP is altered, and the protein accumulates in the brain in an aggregated form. In FFI much of this accumulation occurs in the thalamus, whereas in other prion diseases the accumulation is more widespread, or focused on other parts of the brain.PrP^sc has autocatalytic properties that cause normally soluble PrP to be converted into the PrP^sc form upon interaction.

This conversion into insoluble protein causes plaques containing aggregates of PrP^sc to develop in the thalamus, a region of the brain responsible for regulation of sleep. This first results in insomnia, and then progresses to more serious problems over time.

Presentation

The age of onset is variable, ranging from 30 to 60, with an average of 50. However the disease tends to prominently occur in later years, primarily following childbirth. Death usually occurs between 7 and 36 months from onset. The presentation of the disease varies considerably from person to person, even among patients from within the same family.

The disease has four stages, taking 7 to 18 months to run its course:

1. The patient suffers increasing insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about four months.
2. Hallucinations and panic attacks become noticeable, continuing for about five months.
3. Complete inability to sleep is followed by rapid loss of weight. This lasts for about three months.
4. Dementia, during which the patient becomes unresponsive or mute over the course of six months. This is the final progression of the disease, and the patient will subsequently die.

Treatment

There is no cure or treatment for FFI; hope rests on the so far unsuccessful gene therapy. Sleeping pills have no helpful effect, but, in fact, make the situation much worse.^{[citation needed]}

While it is not currently possible to reverse the underlying illness, there is some evidence that treatments that focus upon the symptoms can improve quality of life.^[3]

Recently, a mouse model was made for FFI. These mice express a humanized version of the PrP protein that also contains the D177N FFI mutation discussed above. ^[4] These mice appear to have progressively fewer and shorter periods of uninterrupted sleep, damage in the thalamus, and early deaths, similar to people with FFI.

Related conditions

There are other diseases involving the mammalian prion. Some are transmissible (TSEs) such as kuru, bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cows, and chronic wasting disease in American deer and American elk in some areas of the United States and Canada, as well as Creutzfeldt-Jakob disease (CJD). These are generally not considered to be transmissible except by direct contact with infected tissue, such as from eating infected tissue, transfusion or transplantation.

References

Notes

Bibliography

• Case study at University of Michigan
• Online 'Mendelian Inheritance in Man' (OMIM) 600072
• Montagna P, Gambetti P, Cortelli P, Lugaresi E (2003). "Familial and sporadic fatal insomnia". Lancet Neurol 2 (3): 167–76. doi:10.1016/S1474-4422(03)00323-5. PMID 12849238. 
• Almer G, Hainfellner JA, Brücke T, et al. (1999). "Fatal familial insomnia: a new Austrian family". Brain 122 ( Pt 1): 5–16. doi:10.1093/brain/122.1.5. PMID 10050890. http://brain.oxfordjournals.org/cgi/content/full/122/1/5. 

External links

• "The Family that Couldn't Sleep" book by D.T. Max, NPR Interview
• "Medical Mystery: When Sleep Doesn't Come, Death Does" by Jay Schadler and Laura Viddy, ABC News.
• "Fatal Familial Insomnia by: Ann M. Akroush"
• Fatal Familial Insomnia Families Association website