Phenotype-genotype studies in kuru: Implications for new variant Creutzfeldt–Jakob disease

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.     

ELISA antibodies to cysticerci of Taenia solium in human populations in New Guinea, Oceania, and Southeast Asia

The presence of ELISA antibodies to cysticerci of Taenia solium was surveyed in populations of New Guinea, Micronesia, and several areas of Southeast Asia. It is confirmed that cysticercosis in New Guinea remains limited to the primary Wissel Lakes focus in Irian Jaya, where the disease was introduced by the importation of infected pigs, and that it has not spread to populations east or south of the Wissel Lakes, or to Papua New Guinea. On the island of Bali, Indonesia, 21% of sera were positive from one village where pigs are especially numerous, whereas in Sumatra, Indonesia, only 3%-4% of sera were positive. In Singapore, there was a higher proportion of positive sera among the Chinese (13%) than among the Indian (5%) or Malay (3%) Moslems. From 3 to 13% of sera from populations in Micronesia, Burma, Vietnam, and the Philippines were also found to react with cysticercus antigen. However, the problem of incomplete ELISA specificity raises the possibility that in areas not known to be endemic for T. solium, seropositive results could represent either subclinical infection with cysticerci or crossreactivity to other parasitic infections.     

Amyloid of neurofibrillary tangles of Guamanian parkinsonism-dementia and Alzheimer disease share identical amino acid sequence.

The presence of abundant intraneuronal amyloid in the form of neurofibrillary tangles (NFT) in the brains of Guamanian parkinsonism-dementia patients and the absence of extraneuronal amyloid in the form of vascular amyloid deposits or senile plaques permit the purification of NFT without contamination with extraneuronal amyloid. Thus, we have isolated and determined the amino acid sequence of the polypeptide subunit of the amyloid fibrils of these NFT and describe their ultrastructure. The NFT, which consist of single and paired helical filaments, similar to those of Alzheimer disease, and occasionally triple helical filaments, are composed of multimeric aggregates of a polypeptide of 42 amino acids (A4 protein). The relative molecular mass of the subunit protein, 4.0-4.5 kDa, is the same as the molecular mass of the amyloid of NFT, of the amyloid plaque cores, and of vascular amyloid deposits in Alzheimer disease and Down syndrome; the sequence of 15 amino acid residues at the N-terminus of the amyloid fibrils in the NFT of Guamanian parkinsonism-dementia is identical to that of the amyloid of NFT, amyloid plaque cores, and cerebrovascular deposits in Alzheimer disease and Down syndrome. Furthermore, the heterogeneity, or variation in polypeptide length, of the N-terminus of the amyloid of Guamanian parkinsonism-dementia is the same as in Alzheimer disease and Down syndrome. Our observations indicate that the brain amyloids of these diseases have a common subunit protein, which would also indicate a common pathogenesis.     

Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS)

Twelve cases of adult-onset progressive muscular atrophy variant of amyotrophic lateral sclerosis (PMA/ALS) were studied in a small rural population of 1500 in the Republic of Belarus (former Soviet Union). The patients were members of three apparently related kindreds, each showing autosomal dominant pattern of disease inheritance. The average age at clinical onset ranged from 26 to 57 years (mean, 40 years). Each patient suffered from skeletal muscle weakness and wasting, starting in the limbs and spreading to the trunk and neck, with very limited bulbar and no upper motor neuron involvement. Death from respiratory failure occurred from 13 to 48 months (mean, 28 months) after first symptoms. Dramatically decreased number of spinal motor neurons was the most characteristic neuropathologic feature in two autopsied cases. Most of the remaining degenerating neurons contained intracytoplasmic hyaline inclusion bodies. A D101N mutation in exon 4 of the SOD1 gene was identified in a PMA/ALS patient and in one of her three unaffected children. Our data support the view that some subtypes of familial ALS associated with SOD1 mutations may present as PMA. Diagnostic criteria of ALS should be accordingly modified to include the PMA variant of familial ALS.     

Longitudinal spinal cord sections as substratum for anti-neurofilament antibody detection

A rapid and technically simple method for demonstrating anti-neurofilament antibodies using longitudinal sections of rat spinal cord as substratum and indirect immunofluorescent technique is reported. The results compare well with those obtained by the technically more difficult and time-consuming methods using as substratum central neurons cultivated in vitro. A total of 195 serum specimens from different neurological disorders and healthy subjects were studied. Immunofluorescent autoantibodies to neurofilaments were found in specimens of serum from patients with Creutzfeldt-Jakob disease (CJD), kuru, amyotrophic lateral sclerosis, parkinsonism dementia (Guam), Alzheimer's disease, and multiple sclerosis but in higher frequency in CJD and kuru than in the other disease or in healthy control subjects.     

Humoral immunity in guamanians with amyotrophic lateral sclerosis and parkinsonism-dementia

Among Guamanian natives, serum IgA and IgG levels were found to be higher than normal in amyotrophic lateral sclerosis (ALS); serum IgA was higher and IgM lower than normal in parkinsonism-dementia (PD). IgA levels increased with age in ALS, PD, and normal subjects; IgG increased with age in ALS and IgM decreased with age in PD. Serum immunoglobulin (Ig) levels did not correlate with the duration of either disease. Immunodeficient ALS and PD patients had higher IgM and lower IgA levels than the other ALS and PD patients. Neither differences in viral antibody titers nor the presence of autoantibodies or circulating immune complexes could account for the variations in serum Ig levels between patients and controls. We conclude that differences in serum Ig levels in ALS and PD patients are probably due to repeated infections and abnormal immunoregulation accompanying immunodeficiency during the course of ALS and PD, rather than to a specific antiviral or autoimmune response.     

Creutzfeldt Jakob disease. Recommended precautions for patient management and diagnostic procedures (author's transl)]

The virus of Creutzfeldt Jakob disease differs from conventional viruses in its extraordinary resistance to commonly used physical and chemical methods of decontamination. Autoclaving the virus for 1 hour at 121 degrees C and 2 atmospheres pressure is the most certain means for achieving total inactivation. Exposure to 5 p. 100 hypochlorite for several hours can also totally inactivate the virus, and exposure to phenol or potassium permanganate is probably effective, but as yet insufficiently tested.     

Epidemiology of Creutzfeldt-Jakob disease in the Paris area]

The area studied includes the city of Paris and the neighboring departments of Val-d'Oise, Seine-Saint-Denis, Hauts-de-Seine, Yvelines, Essonne, Val-de-Marne, and Seine-et-Marne. Case finding methods and diagnostic criteria are defined. The temporal and spatial distribution of cases is described, and the absence of case clustering is noted. Incidence per million people (per year) was found to be 1,09 in the city, 0,55 in the adjacent departments, and 0,25 in the peripheral departments. These results are discussed.