Human prion diseases include Creutzfeldt-Jakob disease, Gerstmann-Stráussler-Scheinker disease, fatal familial insomnia, and kuru. Each of these diseases has a specific clinical presentation while spongiform encephalopathy, neuronal loss, and gliosis are their neuropathological hallmarks. We studied a Brazilian family with an autosomal dominant form of dementia. Nine members of the family were affected by a dementia with frontotemporal clinical features, with a mean age at onset of 44.8 +/- 3.8 years and a mean duration of symptoms of 4.2 +/- 2.4 years. Neuropathological examination of 3 patients showed severe spongiform change and neuronal loss in the deep cortical layers and in the putamen, but minimal gliosis in the most severely affected areas. The putamen and cerebellum, but not other areas of the affected brain, displayed prion protein immunoreactivity. A novel prion protein gene mutation causing a nonconservative substitution at codon 183 was identified in 2 neuropathologically confirmed affected individuals (mother and son). The mutation was transmitted in a mendelian fashion to 12 members of the family. Therefore, we identified a novel prion disease variant characterized by an early onset and long duration of the symptoms, severe spongiform change with minimal gliosis, associated with a prion protein gene mutation at codon 183.

Here we present the results of a study performed on 59 patients affected by Waardenburg syndrome (WS), 30 with the I variant, 21 having the type II, and 8 of them being isolated cases without telecanthus. These patients belong to 37 families; the main contributions and conclusions are based on the detailed study of 25 of these families, examined using standard procedures. All patients were examined as to the presence of eight cardinal signs important for the diagnosis of the condition; from each patient, from many of his/her normal relatives, and from a control sample of 300 normal individuals stratified by age and sex, 23 different craniofacial measurements were obtained. We also estimated, using our own data as well those collected from the literature, the frequencies of the cardinal signs, based on a total sample of 461 affected individuals with WSI and 121 with WSII. In order to originate discriminant functions to separate individuals affected by one of the two variants, both metric (from craniofacial measurements) as well as categoric data (based on the frequencies of the cardinal signs or symptoms) were used. Discriminant analysis based on the frequency of the eight cardinal signs can improve the separation of WSI patients without telecanthus from those presenting the variant II. We present also a Table with the conditional probabilities favoring the diagnosis of WSI for suspect subjects without telecanthus and any combination of the other seven signs/symptoms. The discriminant function based on the four ocular measurements (inner and outer intercanthal, interpupillary, and inferior lacrymal distances), on the other side, perfectly classifies patients affected by one of the variants of WS, the same taking place when the average values of the W index of all affected individuals per family are used. The discriminant function based solely in the individual W index values of patients correctly classifies 93% of WSII subjects, but only 60% of the patients with the I variant of WS.

13 Brazilian families with at least three affected patients. The findings from the present report confirm nonallelic heterogeneity for LGMD and suggest that in our population about 33% ofthe LGMD families are caused by mutations in the 15q gene, 33% in the 2p gene, 17% by mutations in the adhalin gene, and less than 10% may be by mutations at the 13q locus. They also suggest that there is at least one other gene responsible for this phenotype. In addition, the main clinical features of the different forms are discussed.

We report on a four-generation inbred family including 10 individuals affected with a form of craniotubular dysplasia (CTD). All affected patients were born to consanguineous healthy parents; this finding, together with the equal sex ratio among affected individuals and the occurrence of only normal individuals among their offspring, indicates that the disease in this family is an autosomal recessive (AR) trait. Taking into account the segregation pattern of the disease in the family and the radiological characteristics of two young CTD patients, the most likely diagnosis for the defect is AR craniometaphyseal dysplasia (CMD). CMD is a CTD, with both autosomal dominant (AD) and recessive forms. The description of the present genealogy confirms the AR pattern of inheritance of some cases of CMD and contributes to a better delineation of the clinical spectrum of AR CMD, suggesting a more pronounced diaphyseal involvement in the AR compared with the AD CMD. Through genomewide scanning, we mapped the AR CMD to a 7 cM interval, between D6S302 and D6S1639, at 6q21-22 region. We have also excluded the positional candidate COL10A1 gene as being the responsible for this disorder. Curiously, a form of AR spondylocostal dysplasia (SD) also segregates in the family, including one affected individual with both conditions. The gene DLL3, mapped to 19q13 region, was recently found to be responsible for one form of AR SD; however, we did not find evidence of linkage between this 19q region and the SD segregating in our family, thus implying in genetic heterogeneity for AR SD.

-Objective:To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 . Background: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD), the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. Method: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. Results: The mean age at onset was 44.0 ± 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. Conclusion: These clinical features bear a considerable resemblance to those described in FTDP-17.KEY WORDS: prion protein mutation, prion disease, Creutzfeldt-Jakob disease, frontotemporal dementia, parkinsonism. Doença priônica com características clínicas semelhantes à demência frontotemporal e parkinsonismo associada ao cromossoma 17.RESUMO -Objetivo: comparar as características clínicas de doença priônica com as da demência frontotemporal e parkinsonismo associada ao cromossoma 17 (FTDP-17). Fundamentos: doenças priônicas não são usualmente incluídas no diagnóstico diferencial da FTDP-17 porque a doença de Creutzfeldt-Jakob (DCJ), a mais comum entre as doenças priônicas hereditárias, frequentemente manifesta-se como demência rapidamente progressiva. Por outro lado, a FTDP-17 apresenta-se insidiosamente na quinta década, com alterações do comportamento e sinais parkinsonianos. Método: apresentamos as características clínicas de 12 membros de uma família com DCJ associada à mutação de ponto no codon 183 do gene da proteína priônica. Resultados: os sintomas iniciaram-se aos 44.0 ± 3.7 anos e a duração até o óbito foi de dois a cinco anos. Alterações do comportamento foram os sintomas iniciais mais frequentes. Nove pacientes foram atendidos inicialmente por psiquiatras. Oito pacientes manifestaram sinais parkinsonianos. Conclusão: as características clínicas apresentam considerável semelhança com as descritas na FTDP-17. PALAVRAS-CHAVE: mutação da proteína priônica, doença priônica, doença de Creutzfeldt-Jakob, demência frontotemporal, parkinsonismo.