Analysis of the prion protein gene in thalamic dementia.

Petersen RB; Tabaton M; Berg L; Schrank B; Torack RM; Leal S; Julien J; Vital C; Deleplanque B; Pendlebury WW; et al Division of Neuropathology, Case Western Reserve University, Cleveland, OH 44106.

Neurology 42: 1859-63 (1992) > Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation). We amplified the carboxyl terminal coding region of the PrP gene from subjects with selective thalamic dementia or thalamic dementia associated with multiple system atrophy. Three of the four kindreds with selective thalamic dementia and none of the three kindreds with thalamic dementia associated with multiple system atrophy had the PrP 178Asn mutation. Thus, analysis of the PrP gene may be useful in diagnosing the subtypes of thalamic dementia. Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.

Prion dementia without characteristic pathology.

Collinge J; Owen F; Poulter M; Leach M; Crow TJ; Rossor MN; Hardy J; Mullan MJ; Janota I; Lantos PL Division of Psychiatry, Clinical Research Centre, Harrow, UK. Lancet 336: 7-9 (1990)

Gerstmann-Straussler syndrome (GSS) was diagnosed in a family with presenile dementia by prion protein gene analysis. Extensive histological examination of the brain of an affected individual from this family showed no characteristic features of GSS or Creutzfeldt-Jakob disease (CJD). Thus "spongiform encephalopathy" (GSS or CJD) cannot always be excluded on neuropathological grounds in an individual dying of a dementing condition, and the true prevalence of these diseases is likely to be underestimated. Screening by prion protein gene analysis will help to determine the full clinical and neuropathological phenotype in familial cases. This observation may be relevant to the assessment of possible transmission of bovine spongiform encephalopathy to man.

British Study Says Brain Patients Had Psychiatric Symptoms

By LAWRENCE K. ALTMAN ... April 5, 1996

Many of the 10 British patients afflicted with a new variant of a fatal brain disease possibly linked to mad-cow disease had behavioral and emotional changes that initially fooled doctors into thinking they had psychiatric disorders, according to the first published scientific report about the cases.

In nine of the patients, early symptoms included personality changes, depression, difficulty sleeping, withdrawal, fearfulness, and paranoia, said the report, being published on Saturday in The Lancet, an international journal issued in London. Several patients were referred by their doctors to a psychiatrist.

The doctors were also fooled because brain wave tracings of the patients did not show the changes that are usually observed in traditional cases of the human brain disease, known as Creutzfeldt-Jakob Disease.

The findings were reported to alert doctors to the unusual new face of a rare disease. Creuzfeldt-Jakob Disease itself is so rare that physicians find it hard to diagnose.

The report was also intended to alert doctors to the distinctive pattern of waxy deposits known as amyloid plaques that were found in the brain along with the usual holes that give the brain an appearance of Swiss cheese.

Seven of the 10 British cases were not classified as probable Creutzfeldt-Jakob Disease when first reported to the special surveillance unit that the British government set up in 1990 to look for any human version of mad-cow disease. If such a unit had not been in place, it would have taken much longer for individual doctors to compare notes to detect the new variant.

In 1989, a British committee concluded that inclusion of animal protein from sheep afflicted with scrapie in commercial cattle feed was the source of the mad-cow disease. A ban on such feed was imposed at that time. If humans can acquire a variant of Creutzfeldt-Jakob disease from beef contaminated by mad-cow disease, the exposure is believed to have been greatest in the 1980s.

In the latest research, several factors led to the recognition that the patients suffered from a new variant of Creutzfeldt-Jakob Disease, the researchers, headed by Dr. Rob G. Will of Western General Hospital, in Edinburgh, reported.

One was that patients also developed motor abnormalities such as difficulty maintaining balance. A second was pain when a patient was touched on the face, arms, and legs. One patient had pain in the feet that persisted throughout the illness. Another factor was the rapid course to death, averaging about one year from onset of symptoms.

Still another factor was the chemical stains on brain tissue obtained at autopsies for examination under a microscope. The stains showed a distinctive pattern, being scattered throughout the brain but most evident in the areas known as the basal ganglia, thalamus, and cerebellum.

The plaques resembled those found in scrapie, the sheep disease, and kuru, a human disease. Kuru is believed to result from ritualistic cannibalism among the Fore group in the highlands of Papua-New Guinea. The diseases are now thought to be due to rogue proteins known as prions.

A striking feature of the six females and four males diagnosed with the new variant of Creutzfeldt-Jakob Disease was their young age, which ranged from 16 to 39 years at the time they fell ill from February 1994 to October 1995. Health records showed that from 1970 to 1989, only four cases of Creutzfeldt-Jakob Disease occurred in people younger than 34 years.

Examination of brain tissue collected at the autopsy of one of the earlier cases did not show similar amyloid changes.

The researchers also searched for cases outside Britain and found no similar pattern in countries that had a similar surveillance system.

The overall incidence of Creutzfeldt-Jakob Disease rose in Britain in the 1990s, but most cases were in people older than 75. The most likely explanation, the researchers said, was that publicity had led doctors to be more alert to diagnosing it.

The researchers said they found the cluster of variant cases over the last 10 months by studying possible cases reported by physicians and looking at death certificates and newspaper articles.

The researchers said that all 10 had eaten beef in the last 10 years but none was reported to have eaten brain. One had been a strict vegetarian since 1991. One patient worked as a butcher from 1985 to 1987; another had visited an abattoir for 2 days in 1987. None had ever worked on farms with livestock, although one patient had spent a one-week holiday on a dairy farm where there was no known mad-cow disease.

In an editorial, Dr. J. Gerald Collee, of the University of Edinburgh, said that experts suspect that a teaspoonful of highly infective cattle feed is enough to cause mad-cow disease. But he said that if the disease can be transmitted to humans, the amount needed for infection cannot be estimated.

The infectious agent causing Creutzfeldt-Jakob and similar diseases is believed to be resistant to chemicals in the digestive track and able to enter the body through lymph tissue in the tract. Factors such as coexistent infection or foods and alcohol could facilitate such entry.

Copyright 1996 The New York Times Company