The APOE ε2 allele increases the risk of Earlier Age at onset in Machado-Joseph disease

Background. Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by a (CAG)n expansion at the ATXN3 gene (14q32.1). Variation in age-at-onset is partially explained by the size of the (CAG)n tract in expanded alleles. The remaining variation should be the product of other factors, namely modifier genes. The genotype at the APOE locus has been described as a possible modifier in different neurological disorders, namely Parkinson (PD) and Huntington disease (HD). In the CNS, apolipoprotein E constitutes an important mediator of cholesterol transport/metabolism, which is essential for synaptic integrity and neuronal function. Objective. To investigate a modulating effect of the APOE polymorphism on age-at-onset of MJD. Design and Subjects. The APOE polymorphism was typed in a series of 192 MJD patients. Results. Cases with the ε2/ε3 genotype presented an earlier onset, when compared with those with ε3/ε3 or ε3/ε4. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age-at-onset. When combining, in a general linear model, several other predictors, namely the presence/absence of the APOE ε2 allele, with the size of the (CAG)n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset below 39 years (OR=5.00; 95% CI: 1.18-21.14). Conclusions. These findings indicate that the polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype.Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/63121/2009, SFRH/BPD/38659/2007, M3.1.3/F/004/2009, “Secretaria Regional da Ciência, Tecnologia e Equipamentos”.Fundação para a Ciência e a Tecnologia (FCT) - “Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado-Joseph disease (MJD)” (PIC/IC/83074/2007)Institute of Biotechnology and Biomedicine (IBBA) - “High prevalence diseases in the Azores Islands” (M2.1.2/I/026/2008

Alterações psiquiátricas e qualidade de vida em pacientes com homocistinúria clássica

Caracterizar o quadro psiquiátrico e a qualidade de vida (QoL) em uma coorte de pacientes com Homocistinúria Clássica (HCU). Métodos: estudo transversal, através da aplicação das escalas BPRS, Escala de Ansiedade de Beck, Escala de Depressão de Hamilton e Escala de Depressão de Beck (BDI) em 8 pacientes não responsivos à piridoxina e estudo retrospectivo avaliando qualidade de vida por meio da aplicação do questionário WHOQOL-Brief em 11 pacientes com HCU. Resultados: 5 pacientes avaliados apresentaram sintomas de depressão mínimos, 2 pacientes apresentaram sintomas leves, e 1 paciente sintomas moderados a graves. Para ansiedade, 5 pacientes apresentaram sintomas mínimos, 1 paciente apresentou sintomas leves e 2 pacientes apresentaram sintomas moderados. Cinco pacientes apresentaram algum sintoma relacionado à esquizofrenia. Em relação a QoL, todos pacientes apresentaram diagnóstico tardio e apenas 2 tinham QI>70 (Teste WASI). Os pacientes responsivos à piridoxina foram comparados com os não responsivos à piridoxina mostrando melhor pontuação nos aspectos psicológicos e sociais no primeiro grupo. Os 2 pacientes com tratamento foram comparados com os 9 sem tratamento mostrando um melhor escore no aspecto psicológico no primeiro grupo. Conclusão: este é o primeiro estudo que descreve QoL em pacientes HCU, mostrando uma diferença no aspecto psicológico e social, conforme o tipo de tratamentoFil: Donis, Karina C. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Kalil, Marco A.B. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Perrone, Solanger G. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Teruya, Kátia. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Vanz, Ana P. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Vairo, Filippo P. Universidade Federal do Rio Grande do Sul (Brasil).Fil: Schwartz, Ida V.D. Universidade Federal do Rio Grande do Sul (Brasil)

Sequence analysis of 5' regulatory regions of the Machado-Joseph Disease gene (ATXN3)

Machado–Joseph disease (MJD) is a late-onset autosomal dominant neurodegenerative disorder, which is caused by a coding (CAG)n expansion in the ATXN3 gene (14q32.1). The number of CAG repeats in the expanded alleles accounts only for 50 to 75 % of onset variance, the remaining variation being dependent on other factors. Differential allelic expression of ATXN3 could contribute to the explanation of different ages at onset in patients displaying similar CAG repeat sizes. Variation in 5′ regulatory regions of the ATXN3 gene may have the potential to influence expression levels and, ultimately, modulate the MJD phenotype. The main goal of this work was to analyze the extent of sequence variation upstream of the ATXN3 start codon. A fragment containing the core promoter and the 5′ untranslated region (UTR) was sequenced and analyzed in 186 patients and 59 controls (490 chromosomes). In the core promoter, no polymorphisms were observed. In the 5′ UTR, only one SNP (rs3814834) was found, but no improvements on the explanation of onset variance were observed, when adding its allelic state in a linear model. Accordingly, in silico analysis predicted that this SNP lays in a nonconserved position for CMYB binding. Therefore, no functional effect could be predicted for this variant.Institute of Biotechnology and Biomedicine of the Azores - “High Prevalence Diseases in the Azores Islands” M2.1.2/I/026/2008,Fundação para a Ciência e a Tecnologia (FCT) - “Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado–Joseph disease (MJD)Secretaria Regional da Ciência, Tecnologia e Equipamentos - M3.1.3/F/004/2009CNP

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia

Objective: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). Methods: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. Results: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. Interpretation: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022