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

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.

Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations.

Pompe disease is an autosomal recessive disorder caused by a deficiency in 1,4-alpha-glucosidase (EC.3.2.1.3), the enzyme required to hydrolyze lysosomal glycogen to glucose. While previous studies have focused on Pompe patients from Europe, the United States, and Taiwan, we have analyzed a group of South American Pompe patients to better understand the molecular basis of their disease. From 14 Argentinean patients diagnosed with either infantile or late-onset disease, we identified 14 distinct mutations in the acid alpha-glucosidase (GAA) gene including nine novel variants (c.236_246del, c.377G>A, c.1099T>C, c.1397T>G, c.1755-1G>A, c.1802C>G, c.1978C>T, c.2281delGinsAT, and c.2608C>T). Three different families displayed the c.377G>A allelic variant, suggesting a higher frequency among a subset of Argentineans. Comparison of patients with similar or identical variations in the GAA gene highlights the phenotypic diversity of late-onset disease and supports a role for other genetic and environmental factors in disease presentation.