Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare, genetically heterogeneous, autosomal recessive disorder caused by defects in the genes involved in repairing DNA damaged by ultraviolet radiation. These defects lead to a propensity to develop skin cancer at early ages as a hallmark, and progressive neurological degeneration can be observed in around 25% of patients. Eight clinically heterogeneous groups have been identified so far (XPA to XPG and XPV). Xeroderma pigmentosum variant type (XPV) is associated with pathogenic variants in POLH on chromosome 6, and no neurological dysfunction has been seen in these cases. However, on the same chromosome, it has been shown that TREM2 is associated with some types of dementia, particularly in patients with a behavioral variant frontotemporal phenotype. METHODS: Gene mutational analysis was performed by whole-exome sequencing. RESULTS: We report a case of a Caucasian woman with XP that developed behavioral and cognitive impairment at age 37. Whole-exome sequencing identified novel homozygous variants in POLH c.638C>G (p.Ser213*) and TREM2 c.154C>T (p.Arg52Cys), classifying the patient as XPV and suggesting that her frontotemporal dementia phenotype could be related to the variant in TREM2. CONCLUSION: This paper describes a rare case of a patient with two novel variants in the same chromosome associated with XPV and early-onset dementia.

Increased CSF levels of total Tau in patients with subcortical cerebrovascular pathology and cognitive impairment / Aumento dos níveis de CSF de Tau total em pacientes com patologia subcutânea cerebrovascular e comprometimento cognitivo

ABSTRACT. Cognitive impairment includes mild cognitive decline and dementia, such as Alzheimer's disease (AD) and cerebrovascular-related pathologies. Objective: To investigate the profile of AD-related CSF biomarkers in a sample of cognitively impaired and unimpaired older adults with concomitant subcortical cerebrovascular burden. Methods: Seventy-eight older adults attending an outpatient psychogeriatric clinic were enrolled. Diagnoses were based on clinical, neuropsychological, laboratory, and neuroimaging data. Participants were classified into: cognitively normal (controls, n = 30), mild cognitive impairment (MCI, n = 34), and dementia (AD, n = 14). All subjects were submitted to CSF analyses for determination of amyloid-beta (Aß1-42), total tau (t-tau), phosphorylated tau (p-tau) and Aß1-42/p-tau ratio according to the Luminex method. MRI was performed in all individuals, and was scored independently by two experts according to Fazekas scale. Statistical analyses were conducted with the aid of general linear model procedures, and the Chi-squared test. Results: T-tau levels were significantly associated with subcortical lesion pattern when Fazekas was considered as a group factor. CSF biomarkers were not associated with MCI, AD, or controls when considered separately. There was a tendency for reduction in CSF Aß1-42 together with increasing Fazekas scores, but without statistical significance. Comparisons of Aß1-42 and t-tau with each clinical group or with each neuroimaging pattern did not reach statistical differences. Likewise, Fazekas scores had no impact on CAMCOG scores. Conclusion: We found a significant association between t-tau levels and subcortical lesions when all Fazekas classifications were considered as a single group; comparisons of Fazekas subgroups and CSF biomarkers did not reach significance.

RESUMO. O comprometimento cognitivo inclui alterações leves da cognição e demência, como doença de Alzheimer (DA) e patologias vasculares associadas. Objetivo: Investigar o perfil de biomarcadores da DA no líquor e doença cerebrovascular concomitante em idosos com e sem alterações cognitivas. Métodos: Foram incluídos 78 sujeitos de um ambulatório de psicogeriatria. Efetuaram-se os diagnósticos com base em dados clínicos, neuropsicológicos, laboratoriais e neuroimagem. Os participantes foram classificados em: cognitivamente normais (controles, n = 30), comprometimento cognitivo leve (CCL, n = 34) e demência (DA, n = 14). Todos foram submetidos ao exame liquórico para determinação de ß-amiloide (Aß1-42), tau total (t-tau), tau fosforilada (p-tau) e razão Aß1-42/p-tau, segundo o método de Luminex. RM foi efetuada em todos os indivíduos. Dois especialistas independentes avaliaram as imagens segundo a escala de Fazekas. As análises estatísticas basearam-se em modelo linear geral e teste qui-quadrado. Resultados: T-tau foi significantemente associada ao padrão de lesão subcortical quando o grau de Fazekas foi considerado como fator grupal. Não houve associação entre biomarcadores e diagnóstico clínico de CCL, DA e grupo controle, considerados individualmente. Observou-se uma tendência de redução de Aß1-42 concomitante com elevação dos escores de Fazekas, sem correlação significante. Comparações entre Aß1-42 e tau e diagnóstico clínico ou neuroimagem não foram significantes. Os resultados de Fazekas não influenciaram os escores do CAMCOG. Conclusão: Como principal resultado, observou-se associação significante entre os níveis de t-tau e lesões subcorticais quando as classificações de Fazekas foram incluídas em um único grupo. As comparações dos subgrupos de Fazekas e biomarcadores liquóricos não foram significantes.

Increased CSF levels of total Tau in patients with subcortical cerebrovascular pathology and cognitive impairment.

Cognitive impairment includes mild cognitive decline and dementia, such as Alzheimer's disease (AD) and cerebrovascular-related pathologies. OBJECTIVE: To investigate the profile of AD-related CSF biomarkers in a sample of cognitively impaired and unimpaired older adults with concomitant subcortical cerebrovascular burden. METHODS: Seventy-eight older adults attending an outpatient psychogeriatric clinic were enrolled. Diagnoses were based on clinical, neuropsychological, laboratory, and neuroimaging data. Participants were classified into: cognitively normal (controls, n = 30), mild cognitive impairment (MCI, n = 34), and dementia (AD, n = 14). All subjects were submitted to CSF analyses for determination of amyloid-beta (Aß1-42), total tau (t-tau), phosphorylated tau (p-tau) and Aß1-42/p-tau ratio according to the Luminex method. MRI was performed in all individuals, and was scored independently by two experts according to Fazekas scale. Statistical analyses were conducted with the aid of general linear model procedures, and the Chi-squared test. RESULTS: T-tau levels were significantly associated with subcortical lesion pattern when Fazekas was considered as a group factor. CSF biomarkers were not associated with MCI, AD, or controls when considered separately. There was a tendency for reduction in CSF Aß1-42 together with increasing Fazekas scores, but without statistical significance. Comparisons of Aß1-42 and t-tau with each clinical group or with each neuroimaging pattern did not reach statistical differences. Likewise, Fazekas scores had no impact on CAMCOG scores. CONCLUSION: We found a significant association between t-tau levels and subcortical lesions when all Fazekas classifications were considered as a single group; comparisons of Fazekas subgroups and CSF biomarkers did not reach significance.

O comprometimento cognitivo inclui alterações leves da cognição e demência, como doença de Alzheimer (DA) e patologias vasculares associadas. OBJETIVO: Investigar o perfil de biomarcadores da DA no líquor e doença cerebrovascular concomitante em idosos com e sem alterações cognitivas. MÉTODOS: Foram incluídos 78 sujeitos de um ambulatório de psicogeriatria. Efetuaram-se os diagnósticos com base em dados clínicos, neuropsicológicos, laboratoriais e neuroimagem. Os participantes foram classificados em: cognitivamente normais (controles, n = 30), comprometimento cognitivo leve (CCL, n = 34) e demência (DA, n = 14). Todos foram submetidos ao exame liquórico para determinação de ß-amiloide (Aß1-42), tau total (t-tau), tau fosforilada (p-tau) e razão Aß1-42/p-tau, segundo o método de Luminex. RM foi efetuada em todos os indivíduos. Dois especialistas independentes avaliaram as imagens segundo a escala de Fazekas. As análises estatísticas basearam-se em modelo linear geral e teste qui-quadrado. RESULTADOS: T-tau foi significantemente associada ao padrão de lesão subcortical quando o grau de Fazekas foi considerado como fator grupal. Não houve associação entre biomarcadores e diagnóstico clínico de CCL, DA e grupo controle, considerados individualmente. Observou-se uma tendência de redução de Aß1-42 concomitante com elevação dos escores de Fazekas, sem correlação significante. Comparações entre Aß1-42 e tau e diagnóstico clínico ou neuroimagem não foram significantes. Os resultados de Fazekas não influenciaram os escores do CAMCOG. CONCLUSÃO: Como principal resultado, observou-se associação significante entre os níveis de t-tau e lesões subcorticais quando as classificações de Fazekas foram incluídas em um único grupo. As comparações dos subgrupos de Fazekas e biomarcadores liquóricos não foram significantes.

[Partial cross-cultural adaptation of the Aberrant Behavior Checklist (ABC) scale for analysis of patients with mental retardation]. / Adaptação transcultural parcial da escala Aberrant Behavior Checklist (ABC), para avaliar eficácia de tratamento em pacientes com retardo mental.

The aim of the ABC (Aberrant Behavior Checklist) is to evaluate the treatment response for aberrant behavior in patients with mental retardation. The aim of this study was to describe the partial cross-cultural adaptation of the ABC scale to Brazilian Portuguese. The process included conceptual and item equivalence, two translations (T1, T2) and their back-translations (R1, R2), evaluation of referential and general equivalence, expert evaluations, a pre-test, and elaboration of the final version. Conceptual and item equivalences of the ABC were considered pertinent to Brazilian culture. Semantic equivalence showed good correspondence between R1 items and ABC. Reasonable correspondence was obtained between ABC items and R2. All of the professors understood 94.8% of the items in the scale, while relatives understood 87.9%. The Brazilian Portuguese version of the ABC scale thus is available for use, with the appropriate conceptual, item, and semantic equivalence.

Adaptação transcultural parcial da escala Aberrant Behavior Checklist (ABC), para avaliar eficácia de tratamento em pacientes com retardo mental / Partial cross-cultural adaptation of the Aberrant Behavior Checklist (ABC) scale for analysis of patients with mental retardation

The aim of the ABC (Aberrant Behavior Checklist) is to evaluate the treatment response for aberrant behavior in patients with mental retardation. The aim of this study was to describe the partial cross-cultural adaptation of the ABC scale to Brazilian Portuguese. The process included conceptual and item equivalence, two translations (T1, T2) and their back-translations (R1, R2), evaluation of referential and general equivalence, expert evaluations, a pre-test, and elaboration of the final version. Conceptual and item equivalences of the ABC were considered pertinent to Brazilian culture. Semantic equivalence showed good correspondence between R1 items and ABC. Reasonable correspondence was obtained between ABC items and R2. All of the professors understood 94.8 percent of the items in the scale, while relatives understood 87.9 percent. The Brazilian Portuguese version of the ABC scale thus is available for use, with the appropriate conceptual, item, and semantic equivalence.

A ABC (Aberrant Behavior Checklist) visa avaliar a resposta ao tratamento de transtornos comportamentais em portadores de retardo mental. O objetivo deste estudo é descrever a adaptação transcultural parcial da escala ABC para o português do Brasil. Foi realizada avaliação da equivalência conceitual e de itens, foram feitas duas traduções (T1 e T2), suas respectivas retraduções (R1 e R2), avaliação das equivalências referencial e geral, avaliação de especialistas, pré-teste e elaboração da versão final. Em relação à equivalência conceitual e de itens a ABC foi considerada pertinente à nossa cultura. Quanto à equivalência semântica, houve uma boa correspondência entre os itens de R1 e a ABC original, e razoável entre estes e R2. Portanto optou-se por utilizar os itens de T1. Todos os professores compreenderam 94,8 por cento da escala, enquanto todos os parentes entenderam 87,9 por cento. Fica disponível a versão em português do Brasil da escala ABC, respeitando a equivalência conceitual e de itens e semântica.