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Genetic diversity of Lysosomal Storage Disorders in Portugal

Publication . Amaral, Olga

Since the beginning of the analysis of mutations causal of Lysosomal Storage Diseases (LSDs) it became perceptible that the Portuguese presented distinct disease and mutational patterns from those of other populations. Some LSDs, such as Gangliosidosis GM2 (GM2), Metachromatic Leukodystrophy (MLD), Gaucher Disease (GD), Mucopolysaccharidosis type I (MPS I) and even Niemann Pick type C1 (NPC1) were noted for their relevance in terms of their representation in the Portuguese population. Concomitantly, other diseases seemed to be under represented (Pinto et al, 2004). In terms of causal mutations there were particular patterns of diversity which raised interest and led to the determination of the frequency of specific mutations in the Portuguese population. The patterns encountered were sometimes indicative of founder effects and of particular population demographic movements, which were later confirmed by the study of the haplotypes associated with the mutations. In this work we carried out three population screenings in order to establish the frequency of different mutations associated with variant B1 of GM2, MPS I and the infantile form of MLD. Such studies allowed the evaluation of the respective frequencies.

2015-07-03Lecture

Restricted access

Doenças lisossomais de sobrecarga em Portugal: 10 anos de experiência em estudos moleculares no INSA (2006-2016)

Publication . Coutinho, Maria Francisca; Duarte, Ana Joana; Matos, Liliana; Santos, Juliana Inês; Amaral, Olga; Alves, Sandra

As Doenças Lisososomais de Sobrecarga (DLS) são um grupo de mais de 50 doenças hereditárias do metabolismo, sendo a maioria causada por defeitos em enzimas lisossomais específicas. A característica distintiva das DLS é a acumulação lisossomal do(s) substrato(s) não degradado(s), bem como a acumulação de outro material secundariamente à disfunção lisossomal. A apresentação clínica destas patologias é bastante heterogénea, variando desde formas pré-natais, até apresentações infantis ou na idade adulta, sendo frequente a presença de atraso psicomotor e neurodegeneração progressiva. Neste artigo são apresentados os resultados de vários estudos de caracterização molecular efetuados ao longo da última década (2006-2016) em doentes portugueses com as seguintes DLS: Mucopolissacaridose II, Mucopolissacaridose IIIA, Mucopolissacaridose IIIB, Mucopolissacaridose IIIC, Sialidose, Galactosialidose, Gangliosidose GM1, Mucolipidose II alfa/beta, Mucolipidose III alfa/beta, Mucolipidose III gama e Doença de Unverricht-Lundborg. De um modo geral, estes trabalhos permitiram conhecer as variações genéticas associadas a estas DLS, analisar a sua distribuição na população portuguesa e compreender o seu papel na forma de apresentação clínica destas patologias.

2016-05-12Journal article

Open access

Study of cellular localization of Cystatin B in Unverricht-Lundborg disease

Publication . Duarte, Ana Joana; Ribeiro, Diogo; Chaves, Joao; Amaral, Olga

Epilepsy is a common finding in metabolic diseases and in lysosomal diseases in particular.Unverricht-Lundborg disease (ULD; MIM #601145) is a Progressive Myoclonic Epilepsy caused by mutations in the Cystatin B gene (CSTB) and leading to the impaired action of this intracellular proteinase inhibitor which reversibly binds cathepsins. A unique patient homozygous for mutation p.Q22Q, r.[66g>a,65_66ins66+364pb], which affects normal splicing and gives rise to two cDNA transcripts (normal and abnormal), was recently described. CSTB is ubiquitously expressed, the 98 aminoacid peptide can have nuclear, cytoplasmatic and lysosomal localization. The cellular location varies among different types of cells.

2013-03-21Conference object

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Rapid and cost-effective method for the detection of the c.533G>A mutation in the HEXA gene

Publication . Ribeiro, D.; Duarte, A.J.; Amaral, O.

Tay-Sachs disease is a rare autosomal recessive neurodegenerative disorder that results from mutations in the HEXA gene, leading to β-hexosaminidase A (HexA) α subunit deficiency. An unusual variant of Tay-Sachs disease is known as the B1 variant. Previous studies indicated that, in northern Portugal, this is not only the most common variant but also one of the most prevalent lysosomal storage diseases. Additionally, this variant might also show a higher prevalence in populations of Portuguese and Spanish ancestry. A single mutation is invariably present in at least one of the alleles of B1 variant patients, HEXA mutation c.533G >A. To implement a method for c.533G >A testing in individuals and populations, we have optimized two distinct mutation analysis techniques, one based on restriction fragment length polymorphism analysis and the other based on allelic discrimination. We present the comparison of both methods and their advantages. Mutation screening by allelic discrimination proved to be particularly useful for the studying of large samples of individuals. It is time saving and highly reproducible, and under the conditions used, its cost is lower than the cost of polymerase chain reaction-based restriction fragment length polymorphism analysis.

2011-03Journal article

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Unverricht–lundborg disease: report of a new mutation

Publication . Freitas, Joel; Pinto, Eugénia; Duarte, A.J.; Amaral, Olga; Chaves, Joao; Lopes-Lima, J.

P301: Unverricht-Lundborg disease is the most frequent cause of progressive myoclonic epilepsy. CSTB mutations, with cystatin B loss of function, have been described as the major cause of this disease.

2011-08Conference object

Open access