Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations

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Oba-Shinjo, Sueli M. ^[1] ; da Silva, Roseli ^[1] ; Andrade, Fernanda G. ^[1] ; Palmer, Rachel E. ^[2] ; Pomponio, Robert J. ^[2] ; Ciociola, Kristina M. ^[2] ; Carvalho, Mary S. ^[1] ; Gutierrez, Paulo S. ^[3] ; Porta, Gilda ^[4] ; Marrone, Carlo D. ^[5] ; Munoz, Veronica ^[6] ; Grzesiuk, Anderson K. ^[7] ; Llerena, Jr., Juan C. ^[8] ; Berditchevsky, Celia R. ^[9] ; Sobreira, Claudia ^[10] ; Horovitz, Dafne ^[11] ; Hatem, Thamine P. ^[12] ; Frota, Elizabeth R. C. ^[13] ; Pecchini, Rogerio ^[14] ; Kouyoumdjian, Joao Aris ^[15] ; Werneck, Lineu ^[16] ; Amado, Veronica M. ^[17] ; Camelo, Jr., Jose S. ^[11] ; Mattaliano, Robert J. ; Marie, Suely K. N. ^[1]

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^[1] Univ Sao Paulo, Sch Med, Dept Neurol, Myopathies & Mol Biol Grp, BR-01246903 Sao Paulo - Brazil

^[2] Genzyme Corp, Mol Genet Anal Grp, Clin Sci Lab, Framingham, MA 01701 - USA

^[3] Univ Sao Paulo, Inst Heart, BR-01246903 Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Med, Dept Pediat, BR-01246903 Sao Paulo - Brazil

^[5] Clin Marrone, Div Anat Pathol, Porto Alegre, RS - Brazil

^[6] Hosp Clin Porto Alegre, Porto Alegre, RS - Brazil

^[7] Inst Neurol & Coluna Vertebral, Cuiaba, Mato Grosso - Brazil

^[8] Fundacao Oswaldo Cruz, Inst Fernandes Figueira, Rio De Janeiro - Brazil

^[9] Hosp Servidores Estado Rio de Janeiro, Rio De Janeiro - Brazil

^[10] Univ Sao Paulo, Dept Neurol Psychiat & Med Psychol, BR-14049 Ribeirao Preto, SP - Brazil

^[11] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Puericulture & Pediat, BR-14049 Ribeirao Preto, SP - Brazil

^[12] Unidade Cardiol & Med Fetal, Recife, PE - Brazil

^[13] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG - Brazil

^[14] Santa Casa de Misericordia Med Sch, Sao Paulo - Brazil

^[15] Sch Med Sao Jose do Rio Preto, Dept Neurol Sci, Sao Paulo - Brazil

^[16] Univ Parana, Hosp Clin Parana, Curitiba, Parana - Brazil

^[17] Univ Brasilia, Sch Med, Brasilia, DF - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF NEUROLOGY; v. 256, n. 11, p. 1881-1890, NOV 2009.
• Citações Web of Science: 36

Resumo

Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an inherited autosomal recessive deficiency of acid alpha-glucosidase (GAA), with predominant manifestations of skeletal muscle weakness. A broad range of studies have been published focusing on Pompe patients from different countries, but none from Brazil. We investigated 41 patients with either infantile-onset (21 cases) or late-onset (20 cases) disease by muscle pathology, enzyme activity and GAA gene mutation screening. Molecular analyses identified 71 mutant alleles from the probands, nine of which are novel (five missense mutations c.136T > G, c.650C > T, c.1456G > C, c.1834C > T, and c.1905C > A, a splice-site mutation c.1195-2A > G, two deletions c.18\_25del and c.2185delC, and one nonsense mutation c.643G > T). Interestingly, the c.1905C > A variant was detected in four unrelated patients and may represent a common Brazilian Pompe mutation. The c.2560C > T severe mutation was frequent in our population suggesting a high prevalence in Brazil. Also, eight out of the 21 infantile-onset patients have two truncating mutations predicted to abrogate protein expression. Of the ten late-onset patients who do not carry the common late-onset intronic mutation c.-32-13T > G, five (from three separate families) carry the recently described intronic mutation, c.-32-3C > A, and one sibpair carries the novel missense mutation c.1781G > C in combination with known severe mutation c.1941C > G. The association of these variants (c.1781G > C and c.-32-3C > A) with late-onset disease suggests that they allow for some residual activity in these patients. Our findings help to characterize Pompe disease in Brazil and support the need for additional studies to define the wide clinical and pathological spectrum observed in this disease. (AU)

• Processo FAPESP: 01/00422-5 - Estudo das mutações no gene alpha-glucosidade ácida (GAA) na glicogenose tipo II (GS II)
• Beneficiário: Suely Kazue Nagahashi Marie
• Modalidade de apoio: Auxílio à Pesquisa - Regular