"Rarissimo" is how neuroscientist Paul Browndescribes the inherited disorder, Fatal FamilialInsomnia (FFI).
He chose the Italian word to characterize this hyper-rare disease, because Italian research neurologistswere the first to report and name FFI, a decade ago.At the University of Bologna's Neurological Institute,Elio Lugaresi, an eminent authority on sleepdisorders, saw several patients in 1984 with whatlooked like a new kind of insomnia.
When one expired, he sent the brain for analysis toneuropathologist Luigi Gambetti at Case WesternReserve University in Cleveland, Ohio. Theyconcurred that it was indeed a novel disease, andreported it in the New England Journal of Medicinein 1986.
To this day, Gambetti told BioWorld Today, "thereare only a dozen or so FFI families known in theworld." Two of these strangely accursed kindreds,Brown said, are in the U.S., one in Maine, the other inTennessee. He estimates the total world-widenumber of afflicted individuals at "probably notmore than 50."
Brown does research on the spongiformencephalopathies in the Laboratory of CentralNervous System Studies at the National Institute ofNeurological Diseases and Stroke (NINDS). Thelaboratory's director is D. Carleton Gajdusek, whowon a 1976 Nobel prize in medicine fordemonstrating the transmissibility of kuru, the firsthuman spongiform encephalopathy. (See BioWorldToday, June 27, 1995, p. 1.)
Rarest Of The Rare Spongiform Diseases
Kuru is now virtually extinct, but several similarafflictions are still with us, namely, Creutzfeld-Jakobdisease (CJD), Gerstmann-Strassler-Scheinkersyndrome, and most recently, FFI. CJD afflicts one in1 million people; FFI infinitely fewer.
Despite its fatal name, it isn't relentless insomniaper se that kills FFI victims. "Pathologic lack of sleepmust contribute to the physical deterioration ofthese people," Brown opined, "but I find it hard toimagine that mere lack of sleep is the lethal aspect. Ithink what does them in, as with most patients withspongiform encephalopathy, is a helpless,bedridden state, which is liable to infection. Most ofthem die of that cause."
To be sure, the FFI-afflicted have short periods ofdaytime somnolence, "but the interesting thing,"Brown said, "is that even when they are outwardlyasleep, their electroencephalogram is abnormal."
All of the spongiform encephalopathies, includingscrapie in sheep and mad cow disease in bovines,are now known to be caused by prions(proteinaceous infectious particles), which are muchsmaller and more mysterious than other microbes.
These prion-disease patients all carry mutations ofthe same gene, PRNP, which in humans sits on theshort arm of chromosome 20. "Obviously," Brownobserved, "we also have the protein that normalPRNP encodes, which is unnamed, and its functionunknown.
Methionine Gives You FFI; Valine, CJD
In CJD, the PRNP gene has 15 or 20 mutations; inGerstmann-Strassler-Scheinker syndrome, three orfour; in kuru, none. "But FFI," Brown said, "has asingle pathogenic mutation, at the gene's codon 178.It's linked to a normal polymorphism on codon 129,which encodes either of two amino acids,methionine or valine.
"And that," Brown continued, "is the gangbusterstory of FFI: If 129, which is polymorphic and notpathogenic by itself _ that is, if nothing else isgoing on _ you and I are normal." However," heexplained, "if you have a mutation on 178, and themutant allele codes for valine, you have a diseasethat looks rather like CJD. If it codes for methionine,you've got FFI."
Basically, FFI is a disease of the thalamus, a large,vaguely egg-shaped mass of gray matter deepinside the brain.
"The thalamus is one of the primitive neurologicareas in the brain," Brown explained, "unlike theoverlying neocortex _ neo because it's newer. Soyou might call the much older thalamus the paleo-cortex."
He continued: "As such, it controls the morefundamental bodily functions. Here we're talkingabout wake-sleep patterns, blood pressure,temperature regulation, sweating, menstrual cyclesin females, autonomic functions in general."
"In FFI," he concluded, "the thalamus is shot. I don'tknow how many neurons are lost in this disease, butit probably approaches 90 percent. So these peopleare dying because they don't have a functioningthalamus _ with unexplained hypertension,unexplained fevers, unexplained menstrualirregularities."
FFI usually sets in between the ages of 35 and 65,Gambetti said, "with diminished sleep time and milddepression the first signs. Its course varies, fromseven to 33 months, before coma and deathintervene."
FFI is "exclusively familial," Brown emphasized. "Itdoesn't occur sporadically, the way some CJD does.And it's transmitted by autosomal dominantinheritance."
He went on, "The interesting thing to my mind isthat it has been so difficult to get it transmitted intoanimals, because so little prion protein can be foundin the FFI brain."
Transmitting The Untransmissible
Which leads to Brown's paper in last week's Nature,dated Aug. 3, titled, "First experimental transmissionof fatal familial insomnia."
To achieve this previously intractable transfer of thedisease to mice, Brown and his co-authors beganwith a piece of thalamic tissue containing prion-gene protein from the brain of a patient inTennessee who died of genetically verified FFI. Theyinoculated the homogenate into the brains of 19mice.
As controls, they injected cells from the frontalcortex of a patient with dementia, but no prionprotein, into the brains of 24 other mice.
Of the 19 test animals, 14 developed typical signs ofspongiform encephalopathy, and PRNP proteinshowed up in their thalami; they had died betweendays 397 and 506.
Five of the 24 controls were autopsied during the620-day observation period. None showedspongiform change or prion protein deposition.
Transmitting FFI to experimental animals is veryimportant," Gambetti observed, "because it furtherestablishes that it belongs among the priondiseases. Of course," he reflected, "expecting mice todevelop insomnia would be a bit far-fetched." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.