Molecular Genetics and Metabolism 100 (2010) 14–19

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Molecular Genetics and Metabolism

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Prognostic factors for the late onset Pompe disease with enzyme replacementtherapy: 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, Japanb Department of Pediatrics, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japanc Department of Genetic Disease and Genome Science, The Jikei University School of Medicine, 3-5-28 Nishi-Shinbashi, Minato-ku, Tokyo, Japand Department of Pediatrics, Tokyo Women’s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, Japane Centro de Referência em Erros Inatos do Metabolismo, Universidade Federal de São Paulo, Brazil

a r t i c l e i n f o a b s t r a c t

Article history:Received 27 January 2010Accepted 27 January 2010Available online 4 February 2010

Keywords:Pompe diseaseLate onsetGAAERTPVOD

1096-7192/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.ymgme.2010.01.015

* Corresponding author. Address: Department of GMedicine, The Jikei University School of Medicine, 3-5ku, Tokyo, Japan. Fax: +81 3 3433 1111x2345.

E-mail address: hrkb@jikei.ac.jp (H. Kobayashi).

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 hisfamily’s permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragmor 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 casecomparing 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 insufficiencyreceiving 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 Pompedisease, an early diagnosis for the early start of ERT before the onset of respiratory failure should beimportant, and the deliberate management and care should be needed even after the ERT start, especiallyfor severe cases including pulmonary dysfunction.

� 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 Hersin 1963 [2]. The incidence has been reported as 1/40,000 in theworld. 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 200mutations 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 usingChinese hamster ovary (CHO) cells and the ERT using this recombi-nant enzyme has been started in many countries. In some clinicaltrials, the ERT proved to be drastic effective especially in the severejuvenile type and some cases of late onset type [4]. Here we report

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ene therapy, Institute of DNA-28 Nishi-Shinbashi, Minato-

the outcome of 4 patients with late onset Pompe disease who wereunder ERT, including the index case which resulted in autopsy, andtry to estimate the causes of his poor prognosis.

Methods

Recombinant GAA (rGAA), Myozyme™, developed by Gen-zyme corporation using Chinese hamster ovary cell, was usedin the ERT for these 4 Japanese patients. After initial studyincluding genotyping, rGAA was injected by drip infusion of20 mg/kg biweekly for the 4 patients diagnosed as late onsetPompe disease; their profiles are shown in Table 1. Patientsare evaluated at some time points as 6, 12, 20 months afterERT started, including manual muscle test (MMT), arm and legfunctional 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 determinethe ability of a muscle or muscle group to function in movement

Table 1Profiles of 4 patients and average data of expanded Access Program (EAP, by Genzyme Co., n = 5) of this study was shown. In EAP, NIV rate decreased (from 40% to 20%) in12 months with ERT.

Profile Case 1 Case 2 Case 3 Case 4 EAP

Sex Male Female Female Male Male 40%Age of onset 4 4 13 13 7.8Age of ERT starting 28 17 36 44 24.8Therapy-off period 24 13 23 29 17Familial history None None Father as Pompe disease Parents as consaguinous marriageGenotype R600C/M439K R608X/c.546G > T R600C/c.546G > T c.546G > T/c.546G > T

Condition on baseline BMI 9.7 18 19 21.3 11.5*

Respiration NIV n.d. n.d. n.d. NIV 40% IMV 60%

Compilation PT, SMAS None None None

Outcome at 12 month Respiration IMV Normal Normal Normal NIV 20% IMV 80%

Compilation PH, pneumonia None None None

General Deceased (29 years) Alive Alive Alive 20% (5.4%)**

BMI, body mass index; NIV, non-invasive ventilation; n.d., nocturnal dyspnea (mild); PT, pneumothorax; SMAS, superior mesenteric artery syndrome; IMV, intermittentmechanical ventilation (tracheotomy); PH, pulmonary hypertension.* BMI score of EAP group was significant lower than the score of the case 2–4, as the group without severe respiratory insufficiency (p = 0.0028, by t-test, each data of EAP notshown).** The mortality of EAP group was 20% (1/5, this patient is the index case of this study), comparing the data in the parenthesis, as the mortality of 5.4% in all late onset Pompedisease.

H. Kobayashi et al. / Molecular Genetics and Metabolism 100 (2010) 14–19 15

and to provide stability and support (Fig. 1A). It is recommendedthat MMT will be performed in the sitting, prone, side lying andsupine positions, in which larger grade means better score. Inthis study the data was represented by the score in the sittingposition. Arm and leg functional scores, and W&G scale are orig-inally used for evaluating the natural progression and efficacy oftreatment of Duchenne muscular dystrophy, in which smallergrade means better score, i.e. grade 0 means pre-clinical, allactivities available in W&G score (Fig. 1B). The evaluating ofthese scores or scales was done by the specialist ofrehabilitation.

Fig. 1. (a) MMT (manual muscle test) score as summarized of all part at variouspositions for rate to normal (1.0 as 100%). All four patients and EAP average scoreshowed improvement in time course. (b) W&G (Walton and Gardner-Medwin)scale, in which smaller grade means better score, i.e. grade 0 means pre-clinical [7].Only the case 2 showed improvement, another patients showed no change orgetting worse.

In this study, we focused on the case 1 (Table 1) as the index,because his general condition was the worst among these 4 pa-tients, and resulted in death. The autopsy revealed some importantprognostic factors for his poor outcome. We got the agreement forpublication of the clinical data from all these patients and theirfamilies before the beginning of this study under the approval ofthe ethical committee in the Jikei University School of Medicine.

Results

Case 1, the index case, was 29 years-old at the ERT starting point,Japanese man, with the onset of symptoms at 4 years of age as dif-ficult for climbing stairs, and had been suffering from dyspnea andmorning headache as reflection of hypoxia since 19 years-old. Hehad also past history of frequent episodes of pneumothorax andsuperior mesenteric artery syndrome, both should be from his se-vere emaciation. Despite the improvement of pneumothorax afterthe pleurodesis, he presented multiple blebs and fibrosis on CTscan and enlarged esophagus on X-ray (Fig. 2). His genotype wasR600C/M439K, the former has been reported as common in Japa-nese, and severe mutation. We started rGAA ERT for him biweekly,and he has shown some improvement in MMT score, but not inW&G scale (Fig. 1), and deterioration in respiratory function. Onbaseline, his nutrition markers themselves were not so bad, as totalprotein (TP) 7.6 g/dl, Albumin (Alb) 4 g/dl, Calcium (Ca) 9.0 mg/dl,suggesting that his emaciation was not from malnutrition butthought to be from autophagic mechanism. Creatine Kinase (CK)was higher than normal range, but got better after 18 months withERT. And his respiratory state had been poor or chronic hypercap-nia (pCO2 61.4 mmHg on baseline) and we could not improve fi-nally. Eighteen months after ERT starting, he has hospitalized foralmost one month due to an aspiration pneumonia, and recoveredafter one month hospitalization receiving antibiotics as Merope-nem. But 2 weeks later, he had severe pneumonia again, neededtracheal intubation in emergency. Escaping the narrow crisis withintensive care, he left the ICU one month after the admission. Hisgeneral symptom got better, but developed tachypnea which gotslowly progressive worse arising the clinical suspicion of pulmon-ary hypertension. It was supported by the study of ultrasound car-diography (UCG) as the right ventricular dilatation (RVH) and highscore (more than 40 mmHg) of DPG, pressure gradient between

a b

ERT 8M

Months after ERT starting

a

b

c

Δ

d

Fig. 2. Time–course, images, and lab data of case 1. (a) Time–clinical course of case 1. Number means months after ERT starting, empty box means follow up in the outpatientoffice, gray box means in hospital, black box means in ICU (intensive care unit). He died 21 months after ERT starting. Black arrow means time points of lab data andultrasound cardiography (UCG), white arrow means the time point of computer tomography (CT) or X-ray. NIV, no invasive ventilation; IMV, intermittent mechanicalventilation (tracheotomy). (b) The chest CT taken at 8 months after ERT starting; we detected multiple blebs and fibrosis in his lungs, almost same as baseline. (c) The chestX-ray taken at 8 months after ERT starting; we detected enlarged esophagus (arrow), almost same as baseline. (d) Lab data and ultrasound cardiography (UCG) data, taken onbaseline, 12 and 19 months after ERT starting, chosen from many data of time points. Both 12 and 19 months after ERT were stable periods under the NIV (frequency 5/min,Tidal volume 200 ml, pressure support 17 mmHg, O2 flow 3 l/min) and IMV (frequency 12/min, FiO2 0.6, PEEP [positive end-expiratory pressure] 4 cm H2O, PIP [maximuminspiratory pressure] 28 cm H2O), WBC, white blood cell (mm3); Hb, hemoglobin (mg/dl); PLT, platelet (�10e3/mm3); AST (GOT), aspartate aminotransferase (IU/l); ALT(GPT),alanine aminotransferase (IU/l); CK, creatinine kinase (IU/l); TP, total protein (g/dl); Alb, albumin (g/dl); Ca, calcium (mg/dl); EF, ejection fraction (%); DPG, pressure gradientbetween right atrium and right ventricle (mmHg); which reflects pulmonary hypertension when it is more than 40, calculated by the data of UCG.

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right atrium and right ventricle (Fig. 2a and d). Four months later,he got gastroenteritis, lead for severe progressive respiratory fail-ure. He had acute renal and cardiac failure again, and in spite ofthe intensive care including gamma-globulin, steroids, nitrogenoxide gas, and continuous hemodiafiltration, he died 21 monthsafter ERT starting.

Under the permission and agreement of his family, the autopsywas done about 12 h after his death. Most influenced organs werehis lungs and skeletal muscles. In his lung, we detected severefibrosis due to frequent organizing pneumonia (Fig. 2a) especiallyin the superior lobe, less severe occlusion in his small pulmonaryartery (Fig. 2b), and severe occlusive endothelial hypertrophy inthe small pulmonary vein, as ‘‘pulmonary veno-occlusive syn-drome” (PVOD) (Fig. 2c). And in his muscle of iliopsoas, intercostal,paravertebral, diaphlagma, upper esophagus, and limbs, we de-tected severe fibrosis and vacuolar degeneration resulted in severevolume loss with the Masson stain (Fig. 2d and h), and glycogenaccumulation in degenerated striated muscle with PAS stain(Fig. 2e and i). In his upper esophagus, we could detect only mu-cous membrane with no muscle resulted in severe dilatation ofesophagus (Fig. 2b and c), severe fibrosis (Fig. 3d), and glycogenaccumulation in striated muscle with PAS stain (Fig. 3e). But we

could detect no degeneration, nor atrophy in his cardiac muscle(Fig. 3f and g) and tongue. In his heart, we detected right ventric-ular hypertrophy (RVH) and moderate dilatation in both ventriclesdue to Cor pulmonale. We traced his data of pressure gradient be-tween right atrium and right ventricle (DPG) reflects pulmonaryhypertension when it is more than 40 mmHg by echo cardiogram,baseline score was 35.3 mmHg, but deteriorated gradually untilthe score of 81 mmHg, one week before his death (Fig. 2d). Wetried specific therapy for PH including milrinone or phosphodies-terase (PDE) III inhibitor, nitric oxide (NO), but resulted in no effect.His central nervous system, kidney, liver, spleen, and ileum werenormal in the structure with no accumulation of glycogen. Withthe electron microscope (20,000�), diffuse accumulation of glyco-gen and destroyed myofibril in the muscle cell of the iliopsoas wasseen (Fig. 4).

Case 2, as a 17-years-old girl at the ERT starting, onset of symp-toms was at 4 years-old, and has shown much improvement sincethe start of ERT (Fig. 3). Since around four years-old, she has per-formed liver damage and hyper Creatine Kinase (CK), and felt dif-ficulty in up and down the stairs. At 10 years-old, her proximalmuscle weakness progressed rapidly, resulted in much more diffi-cult in up and down the stairs, or showing the Gowers’ sign, and at

Fig. 3. The pathological study of the case 1. Superior lobe of lung (Masson stain; fibrosis, organizing pneumonia). (a) Small pulmonary artery, we could not detect severeocclusion. (b) Small pulmonary vein; PVOD (pulmonary veno-occlusive disease) was detected as the severe occlusive endothelial hypertrophy. (c) Upper esophagus (Massonstain; severe fibrosis). (d) Upper esophagus (PAS stain; allows means glycogen accumulation in striated muscle). (e) Cardiac muscle (Masson stain; no fibrosis and kept innormal structure). (f) Cardiac muscle (PAS stain; no glycogen accumulation). (g) Iliopsoas muscle (Masson stain; fibrosis and vacuolar degeneration of striated muscle). (h)Iliopsoas muscle (PAS stain; allows means glycogen accumulation in degenerated striated muscle, shown by broad arrow).

H. Kobayashi et al. / Molecular Genetics and Metabolism 100 (2010) 14–19 17

11 years-old, the physician in charge diagnosed her illness asPompe disease by the muscle biopsy. At 14 years-old, she hasstarted to use wheel-chair and felt nocturnal dyspnea, but hasnot used any kinds of ventilator yet. Before ERT, she could notmove by herself without wheel-chair, but after the ERT of 2-years,

Fig. 4. Electron microscope study of iliopsoas muscle (20,000�) of the case 1 showsdiffuse accumulation of glycogen (broad white arrow) and destroyed myofibril(narrow white arrows) in the muscle cell.

she has been able to come to our clinic by herself, with the trainand plane. As her onset of disease was at 4 years-old, and rGAAERT start was at 17 years-old, the length of off-therapy was13 years, and regarding the age of ERT starting, she is the youngestin the 4 cases. At the baseline, her respiratory state was almostnormal (she felt slight dyspnea at night) and with no other compli-cation. She has shown much improvement reflected in the MMTscore and W&G scale (Fig. 1), and passed the entrance examinationof the National University School of Medicine 1 year after ERT star-ing, and has been studying in the university having the ERT.

Case 3, as a 30-years-old woman at the ERT starting, whose on-set was at 12 years, appeared as muscle weakness, especially slowdown in running. Her father was diagnosed as late onset Pompedisease (onset at 48 years-old, needed invasive ventilator at50 years-old), and her father’s grandparents were consanguineousmarriage. At 14 years-old, she showed liver dysfunction and slighthepatomegary with her muscle weakness, and diagnosed as Pompedisease by the muscle biopsy. After the diagnosis, the symptom asmuscle weakness progressed slowly, and at 31 years-old, she hasneeded wheel-chair, and felt dysphasia and nocturnal dyspnea.At 36 years-old she had first ERT, on the baseline, her respiratorystate was also almost normal (slight dyspnea at night) and withno other major complication influencing respiration or circulation(Table 1). Since then, she has shown improvement in MMT score(Fig. 1a) and respiratory/swallowing state, but not so much as case2, and no improvement in W&G scale (Fig. 1b). The starting age ofERT (36 years) and her genotype (p.R600C, same as case 1) werethought to have influence for the outcome of ERT.

Case 4, as a 44 years-old man at the ERT starting, whose onsetwas at 17 years-old as liver damage, hyper CK and weakness ofproximal muscle of his legs. At 30 years-old, he has not been able

18 H. Kobayashi et al. / Molecular Genetics and Metabolism 100 (2010) 14–19

to climb the stairs smoothly, and at 34 years-old, he has shownGower’s sign, then diagnosed as Pompe disease by muscle biopsyand enzyme activity. With ERT, he has shown some improvementin respiratory state and MMT score but not so much as case 2, andno improvement in W&G scale (Fig. 1). At the baseline, the respira-tory and general state being almost the same as case 2, his age atthe ERT starting (44 years) has been thought to have influence onthe effect of ERT (Table 1). His parents were cousin and his geno-type was homozygote of c.546G > T, thought to influence that hissymptom progressed very slowly.

For comparing with these cases, we added the average data ofEAP, expanded advanced program by Genzyme corp., n = 5, (all Jap-anese, 2 male and 3 female) including case 1, this group was orga-nized by patients with severe respiratory insufficient (tracheotomy60%) on the baseline, and in this program they started ERT beforethe release for emergency rescue. Their average age of onset was7.8 years-old, therapy-off period was 17 years-old, and BMI onthe baseline was 11.5. The group data of BMI in the EAP was signif-icant lower than the group data in the case 2–4 (p = 0.0028, by Stu-dent t-test).

All patients had neither severe allergic reaction nor complica-tion in the course of ERT, and case 2–4 have had continuous en-zyme replacement of rGAA. case 1 had 200� (12 weeks after ERTstarting), 400� (18 weeks after ERT starting) anti-GAA antibodyby ELISA as enzyme-linked immunosorbent assay, but after thathe had immuno-tolerance with no antibody in his serum (datanot shown).

Discussion

We experienced four Japanese patients, and studied the factorsfor their prognosis comparing these cases. The main difference be-tween the index case and the other 3 cases was the state of base-line including locomotive ability and respiratory state, but otherimportant factors for prognosis were detected in this study.

First of all, for the index case, the BMI was much lower than theother cases, suggesting severe emaciation. According to WHO(World Health Organization), BMI is a simple index ofweight-for-height that is commonly used to classify underweight,overweight and obesity in adults. It is defined as the weight inkilograms divided by the square of the height in meters (kg/m2),18.5–24.99 is normal range, <18.50 underweight, >25.00 over-weight. His body was terribly thin and extremely cachectic. Theduration without ERT of 24 years and early onset was thought tobe resulted in severe and irreversible respiratory and skeletal mus-cle destruction found in the pathology. He has suffered from fre-quent pneumothorax, which is not characteristic for Pompedisease but common end stages of muscular disorder such asDuchenne muscular dystrophy. It is considered to be due to themechanism of too much acceleration of autophagy, as self phago-cyte of his own myocyte, especially type II fiber [8,9]. And thereare some reports of this efficient correlation between prognosisand the interval free of therapy in the case of late onset Pompe dis-ease with ERT [10]. The therapy-off period itself was longest in thecase 3, but the onset was later and his mutation was not severe, wespeculated the progression should be much slower than the case 1.We compare the data of the EAP composed by the patients whohad severe pulmonary insufficient, the average therapy-off periodwas 17 years, which should be not longer than the other cases,but the BMI score of EAP group was significant lower than thescore of the case 2–4, as the group without severe respiratoryinsufficiency (p = 0.0028, by t-test, each data not shown). Ventila-tor dependency has been considered as exclusion criterion in stud-ies on classic infantile Pompe disease, but the first Pompe patientwas reported, who was ventilator-dependent at baseline and after

ERT, eventually became steadily ventilator-free for short periods.The authors reported that improvement in respiratory function ispossible in baseline-ventilated patients if therapy is started beforeoccurrence of significant muscle destruction or significant scoliosis[11,12]. According to this conclusion, BMI score on the baselineshould be the prognostic factor for the late onset Pompe diseasewith ERT, because it is representative factor for the presence of se-vere respiratory insufficiency needed for the invasive ventilation.In another reports, it is concluded that there is little correlation be-tween degree of skeletal muscle weakness and severity of respira-tory insufficiency [13,14]. In our study also, we could not find theco-relation between their locomotion ability (patients includingcase 1 got better in MMT and locomotive ability after ERT) andthe respiratory state in the course of ERT.

In the second place, the mutation of p.R600C was common inJapanese, but the prognosis should not be good because it resultsin the molecular destruction of the GAA. The homozygote ofR600C is reported as one of classic and severe infantile type exhib-iting no a-GAA activity [15]. Tajima et al. reported that the ex-pressed mutant enzyme protein with p.R600C is thought to beunstable and to undergo degradation [16]. The other mutation inthe case 1 of p.M439K was reported as recurrent mutation amongKorean population with late onset Pompe disease, which does notaffect the catalytic site of the GAA, most likely associated with lateonset Pompe disease having some retained enzymatic activity ofGAA [17]. In this study, the patient of case 3 had same mutationof p.R600C, but her prognosis was not so poor as the case 1. Theother mutation of c.546G > T is found in the case 2 and 4 also, a lea-ky splice mutation, leading to the production of a normally splicedtranscript, which responsible for the low level expression of the ac-tive enzyme [18]. And the therapy-off period was much shorterthan that of the index case, and at the start of ERT, she had almostno pulmonary dysfunction rather than rare nocturnal dyspnea,which has improved one year after ERT starting. We thought thesefactors should have synergy effect for the prognosis. And con-versely, the presence of c.546G > T was thought to be the predictivefactor for mild phenotype.

In the third place, his respiratory failure was thought to be dueto primary pulmonary dysfunction, because we detected the pul-monary venous obstruction disease (PVOD) that resulted in severeand continuous pulmonary hypertension (PH). His symptoms astachypnea, high DPG (more than 40 mmHg) or RVH in the UCG,suggested the presence of PH. The pathological findings of kidneyand heart were almost within normal (Fig. 3f and g), suggestingthe renal and right cardiac failure was secondary to severe hypo-tension. PVOD has been reported as the main reason for primarypulmonary hypertension (PPH) and there is no efficient therapy.It is currently classified as a subgroup of pulmonary arterial hyper-tension [19], and occult alveolar hemorrhage has been reported tobe a characteristic feature of PVOD [20]. This is the first report ofPVOD as one of the most important cause of pulmonary hyperten-sion in late onset Pompe disease. We detected no atrophic changein his cardiac muscle (Fig. 3f and g), but RVH and moderate dilata-tion in both ventricles due to Cor pulmonale, suggesting his heartfailure and RVH were secondary to pulmonary hypertension dueto PVOD. He had been suffering from chronic respiratory failureincluding tachypnea, which was supposed to be one of signs ofcontinuous pulmonary hypertension. The pathological findings ofhis lung and intestine was negative in PAS staining, means thatno glycogen accumulation there, suggesting PPH and the mesen-teric artery occlusion was not originally from glycogen accumula-tion but secondary to the vessels obstruction due to hypertrophicendothelium (Fig. 2d). The reason or mechanism of vesselsobstruction remains unclear, although occult involvement ofvascular smooth muscle might play some important roles [21].Recently, glycogen accumulation in the vascular smooth muscle

H. Kobayashi et al. / Molecular Genetics and Metabolism 100 (2010) 14–19 19

of the internal muscular small vessels has been reported. And inthe case 1, the antibody for GAA was detected but resulted in tol-erance after 1 year, and thought to have almost no influence on hisprognosis.

Strothotte et al. reported the data of 44 late onset Pompe dis-ease with ERT for one year [22]. In this report, significant changesfrom baseline in the modified Gower’s test, the CK levels and the6 min walk test, while all other tests were unchanged. They con-cluded GAA treatment seems to stabilize the chronic progressivenatural disease course of Pompe disease, but major effects werenot observed. Including our study, it should be necessary for esti-mate the effect of ERT for late onset Pompe disease for longer thanone year. For predict the prognosis of the patient of late onsetPompe disease with ERT, these factors as BMI on the baseline,genotype as R600C or c.546G > T, and signs of pulmonary hyper-tension were thought to be important information or lessons.The deliberate management and care for late onset Pompe diseaseshould be needed even after the ERT start, especially for severecase including pulmonary dysfunction.

Conflict of interest

Authors as H.Kobayashi, T.Ohashi, Y.Eto, and H.Ida are the mem-ber of the Department of Genetic Disease and Genome Science, TheJikei University School of Medicine, which is Endowed ResearchDivision supported by Genzyme corporation.

Acknowledgments

We sincerely thank Dr. Shigeo Yamaki, the Japanese ResearchInstitute of Pulmonary Vasculature, for detecting PVOD in the spe-cific pathological study of the lung specimen, and Dr. Keiji Hashim-oto, the department of rehabililtation, Jikei university school ofmedicine, for scoring of MMT, arm and leg functional scores, andW&G scales. This study is supported by the grants from the Re-search on Measures for Intractable Diseases, the Ministry of Health,Labour and Welfare in Japan.

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