Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: From our experience of 4 cases including an autopsy case Hiroshi Kobayashi a,b,c, * , Yohta Shimada a , Masahiro Ikegami b , Toshinao Kawai b , Ken Sakurai b , Takashi Urashima b , Masatoshi Ijima b , Masako Fujiwara b , Eiko Kaneshiro b , Toya Ohashi a,b,c , Yoshikatsu Eto c , Keiko Ishigaki d , Makiko Osawa d , Sandra Obikawa Kyosen e , Hiroyuki Ida a,b,c a Department of Gene Therapy, Institute of DNA Medicine, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japan b Department of Pediatrics, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japan c Department of Genetic Disease and Genome Science, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japan d Department of Pediatrics, Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, Japan e Centro de Referência em Erros Inatos do Metabolismo, Universidade Federal de São Paulo, Brazil article info Article history: Received 27 January 2010 Accepted 27 January 2010 Available online 4 February 2010 Keywords: Pompe disease Late onset GAA ERT PVOD abstract We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM * 606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condi- tion at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family’s permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hyper- tension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of spe- cific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound car- diography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction. Ó 2010 Elsevier Inc. All rights reserved. Introduction Pompe disease, caused by the deficiency of acid alpha glucosi- dase (GAA) was reported by Pompe in 1932 [1], and proved by Hers in 1963 [2]. The incidence has been reported as 1/40,000 in the world. A-GAA cDNA is 3.6 kb coding 952 amino-acid. The gene in- cludes 20 exons, located in 17q25.2–25.3, and more than 200 mutations have been reported. The clinical course had been re- ported as progressive and lethal, especially juvenile type [3]. Re- cently, the recombinant GAA (rGAA) was developed using Chinese hamster ovary (CHO) cells and the ERT using this recombi- nant enzyme has been started in many countries. In some clinical trials, the ERT proved to be drastic effective especially in the severe juvenile type and some cases of late onset type [4]. Here we report the outcome of 4 patients with late onset Pompe disease who were under ERT, including the index case which resulted in autopsy, and try to estimate the causes of his poor prognosis. Methods Recombinant GAA (rGAA), Myozyme™, developed by Gen- zyme corporation using Chinese hamster ovary cell, was used in the ERT for these 4 Japanese patients. After initial study including genotyping, rGAA was injected by drip infusion of 20 mg/kg biweekly for the 4 patients diagnosed as late onset Pompe disease; their profiles are shown in Table 1. Patients are evaluated at some time points as 6, 12, 20 months after ERT started, including manual muscle test (MMT), arm and leg functional scores [5,6], and Walton and Gardner-Medwin scale (W&G scale) [7], echocardiography, and blood examination. MMT is assessment of muscle strength performed to determine the ability of a muscle or muscle group to function in movement 1096-7192/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2010.01.015 * Corresponding author. Address: Department of Gene therapy, Institute of DNA Medicine, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato- ku, Tokyo, Japan. Fax: +81 3 3433 1111x2345. E-mail address: hrkb@jikei.ac.jp (H. Kobayashi). Molecular Genetics and Metabolism 100 (2010) 14–19 Contents lists available at ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme