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Isaura Ribeiro1,2, Elisabete Silva1, Eugénia Pinto1, Fernanda Pinto1, Sónia Rocha1, Célia Ferreira1, Helena Ribeiro1, Sandra Jacinto3, Diana Antunes4, Ana Cristina Ferreira5, Dulce Quelhas1,2, Francisco Laranjeira1, Carla Caseiro1, Lúcia Lacerda1,2

1 Unidade de Bioquímica Genética, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, EPE, Porto, Portugal;
2 Unidade Multidisciplinar de Investigação Biomédica, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto - UMIB/ICBAS/UP;
3 Serviço de Neurologia Pediátrica, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, EPE, Lisboa, Portugal;
4 Serviço de Genética Médica, Hospital Dona Estefânia, Centro Hospitalar Lisboa Central, EPE, Lisboa, Portugal;
5 Unidade de Doenças Metabólicas, Hospital Dona Estefânia, Centro Hospitalar de Lisboa Central, EPE, Lisboa, Portugal.

- Comunicação oral no UMIB Summit 2015, Porto, 24-25 de Setembro de 2015

Fabry disease (FD, MIM # 301500) is a treatable X-linked inherited lysosomal storage disorder of glycosphingolipid catabolism, due to deficient or absent activity of the lysosomal enzyme α-galactosidase A. The enzymatic defect leads to progressive lysosomal accumulation of neutral sphingolipids, mainly globotriaosylceramide and globotriaosylshingosine, in most organs. FD is a chronic progressive condition with symptoms such as pain in the extremities, heat and cold intolerance, corneal changes and angiokeratoma, often beginning in childhood. Progressive renal insufficiency and cardiovascular involvement are the main causes of premature death. Reported male patients have partial reduction or absence of α-galactosidase A activity. In female carriers α-galactosidase A activity may range from zero to control values, due to X-linked inheritance phenomena so molecular genetic tests are mandatory for FD diagnosis in females. Over 770 pathogenic mutations found in GLA gene have been associated with FD. This work highlights the need for a multidisciplinary approach in the diagnosis of FD providing clinical, biochemical and molecular tests results. FD diagnosis underlay in three approaches: α-galactosidase A activity measured in capillary dried blood spots, peripheral blood plasma and total leukocytes; GB3 urinary excretion measured in 24 hour urine and genotype analysis by GLA gene exons and exon-intron boundaries sequencing. This work reports clinical, biochemical and molecular data of an atypical Fabry family, in which males affected by Fabry disease, hemizygous for a pathogenic mutation on GLA gene, c.827G>A (p.S276N), have reduced levels of α-galactosidase A activity in leukocytes, however they present normal α-galactosidase A activity in plasma. FD diagnosis is not straight forward through α-galactosidase A enzymatic activity, and frequently requires a combination of different technical approaches, even in male patients. Caution must be taken regarding screening methods such as those conducted on plasma α-galactosidase A activity, even in patients with early onset of the disease, because of their pitfalls. Preliminary results indicate that p. S276N is associated with the classic phenotype of FD. Identification of a α-galactosidase A mutation associated with a clinically relevant phenotype would be extremely useful for disease progression evaluation, as well as for enzyme replacement therapeutic decisions.

Palavras Chave: Fabry Disease, α-galactosidase A