Introduction. Specific etiologies, namely, mutations in specific genes, have only been discovered for some few dementing illnesess, such as Alzheimer's diseases and frontotemporal dementia. Other dementias now require investigation to identify the cause. Aim. To report the clinical and molecular study of a large autosomal dominant southern Italian family, with a complex neurological syndrome comprising dementia, psychiatric symptoms, extrapyramidal and cerebellar features. Methods. The family has been genealogically reconstructed over six generations, back to 1850. Affected living patients were clinically studied. Direct mutation analysis was performed to exclude neurodegenerative disorders in which dementia may be present. PCR was used to analyze the CAG repeat of HD, SCA1, SCA2, SCA3, SCA6, and DRPLA. We used HD333-HD447, Rep1-Rep2, SCA2A-SCA2B, MJD52-MJD70, S-5-F1/S-5-R1 and CTG-B37 as oligoprimers to detect CAG repeats. The PRNP ORF was amplified by PCR and fractionated on a 1% agarose gel. Insertions and point mutations at codon 102, 117, 129, 178, 200, and 210 were screened. Linkage study was performed for familial Alzheimer's disease loci (APP, PSEN1, PSEN2); FTDP on chromosome 17 for frontotemporal dementia; BRI on chromosome 13 for British dementia ; FND on chromosome 3cen for familial nonspecific dementia; and HD-like on chromosome 20p for Huntington-like disease. Results. Among 14 affected subjects identified, ten have been personally observed. The illness is characterized by a wide range of age at onset (17-53 years, mean 34 + 10.03) with prominent behavioral and psychiatric symptoms (delusions, hallucinations, and mood depression) as first signs. Tremor, dystonia, and dysarthria follow, together with a subcortical dementia. The illness progresses slowly with the appearance of marked gait ataxia, rigidity, anarthria, myoclonus and generalized epileptic seizures. In the latest stage of the disease patients are bedridden, anarthric,dysphagic,incontinent and in a state of cachexia. Age at death was at 55.25 + 6.8 (range 52-69) in eight patients. Neurophysiological investigation shows impairment of the brainstem. CT and MRI show marked atrophy of the brain and of the cerebellum. All the direct mutation analyses were negative, excluding pathological CAG expansions and PRNP mutations. Linkage was completely negative for FAD loci, FTDP-17, British dementia, familial non-specific dementia and Huntington-like disease. Conclusion. The phenotype of this family, which includes early onset with psychiatric prodromes, followed by dementia, ataxia, rigidity, dystonia and epilepsy with a slowly progressive course, is clearly different from the other types of degenerative dementia. We suggest a new dementing disorder for which a genome -wide linkage screen should be conducted.
|Issue number||4 SUPPL.|
|Publication status||Published - 2000|
ASJC Scopus subject areas
- Clinical Neurology