Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: A nationwide survey in Japan

doi:10.1016/j.ymgme.2012.09.004

Molecular Genetics and Metabolism

Volume 107, Issue 3, November 2012, Pages 513-520

https://doi.org/10.1016/j.ymgme.2012.09.004 Get rights and content

Abstract

Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients < 2 years of age and an intelligence quotient (IQ) of ≥ 70. Even after the approval of enzyme replacement therapy for both of MPS I and II, HSCT is still indicated for patients with MPS I severe form (Hurler syndrome). To evaluate the efficacy and benefit of HSCT in MPS II patients, we carried out a nationwide retrospective study in Japan. Activities of daily living (ADL), IQ, brain magnetic resonance image (MRI) lesions, cardiac valvular regurgitation, and urinary glycosaminoglycan (GAG) were analyzed at baseline and at the most recent visit. We also performed a questionnaire analysis about ADL for an HSCT-treated cohort and an untreated cohort (natural history). Records of 21 patients were collected from eight hospitals. The follow-up period in the retrospective study was 9.6 ± 3.5 years. ADL was maintained around baseline levels. Cribriform changes and ventricular dilatation on brain MRI were improved in 9/17 and 4/17 patients, respectively. Stabilization of brain atrophy was shown in 11/17 patients. Cardiac valvular regurgitation was diminished in 20/63 valves. Urinary GAG concentration was remarkably lower in HSCT-treated patients than age-matched untreated patients. In the questionnaire analysis, speech deterioration was observed in 12/19 patients in the untreated cohort and 1/7 patient in HSCT-treated cohort. HSCT showed effectiveness towards brain or heart involvement, when performed before signs of brain atrophy or valvular regurgitation appear. We consider HSCT is worthwhile in early stages of the disease for patients with MPS II.

Highlights

► HSCT showed effectiveness on brain or heart involvements in MPS II patients, when performed before a sign of brain atrophy appear in MRI for brain and before valvular regurgitation appear for heart. ► HSCT showed efficacy on cribriform lesion and ventricular dilatation in MRI of MPS II. ► Cardiac valvular regurgitation was diminished in 32% valves of HSCT-treated patients. ► Urinary GAG in HSCT-treated patients was lower than in ERT-treating patients.

Introduction

Hematopoietic stem cell transplantation (HSCT) is a standard therapy for young patients with mucopolysaccharidosis I (MPS I, Hurler syndrome, OMIM 607014) [1], [2], [3], [4]. HSCT is indicated when MPS I patients are < 2 years of age and show an intelligence quotient (IQ) of ≥ 70. However, HSCT has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome, OMIM 309900) as no obvious efficacy has been shown on the brain involvement of MPS II patients [5], [6], [7], [8].

Enzyme replacement therapy (ERT) for MPS II was approved in the USA and Europe in 2006, and in Japan in 2007. Its efficacy has been demonstrated for visceral organ and soft connective tissue involvement [9], [10], but poor or no efficacy was observed for brain involvement [11], [12] because of poor penetration across the blood–brain barrier. Poor efficacy has also been speculated towards hard connective tissues such as bone and heart valves because of poor vascularity. Moreover, weekly injection can prove inconvenient to patients and their families, and the high cost of treatment is another issue to be taken into consideration.

MPS II is the most frequent type of MPS in Asian patients, accounting for 60% of all MPS types in Japan. Before the approval of ERT, HSCT was indicated for MPS II as a standard therapy in Japan. The efficacy of HSCT on visceral organs was clear and similar to that of ERT [13]. However, efficacy on the brain or heart valves has not been clearly evaluated for either ERT or HSCT.

We present the results of a retrospective evaluation of the efficacy of HSCT on MPS II by collecting the clinical records of the patients with MPS II who received HSCT from 1990 to 2003. We also analyzed the answers to a questionnaire given to two cohorts: HSCT-treated and HSCT-untreated (natural history) MPS II patients.

Section snippets

MPS II classification

Disease severity was evaluated in all patients into four types (A–D) on the basis of chronological development, history of disease onset, initial symptoms, and clinical records before transplantation. Because of the wide spectrum of clinical phenotypes in MPS II, it is important to compare patients within the same type of disease for the evaluation of efficacy. Types A and B are attenuated forms with normal intelligence, while Types C and D are severe forms with mental impairment. MPS II was

Retrospective study from transplanted patient records

Among transplanted patients with MPS, 63% (26/41) had MPS II. The 5-year survival rate after treatment of MPS II was 88.5% during the period from 1990 to 2003. Clinical records were collected for the 21 surviving patients (81%) from eight hospitals: Type A (n = 1), Type B (n = 6), Type C (n = 7), and Type D (n = 7) [Table 1, Table 2]. Donor state, transplantation protocol, and chimeric status are also summarized in Table 2. Two patients with Type B disease (patients 10‐3 and 10‐5) received total body

Discussion

We performed a retrospective study on the long-term efficacy of HSCT in MPS II patients. Efficacy was noted, to some extent, even with respect to brain involvement as long as HSCT was carried out before developmental delay became clinically manifest, without brain atrophy on MRI. The study of ADL from transplanted patient records showed that HSCT-treated patients maintained almost the same levels of speech ability and gait as at baseline or an improvement in most patients (Table 2). The

Conflict of interest

Each author declares no potential conflict of interest, real or perceived.

Acknowledgments

We indebted to the patients and families of the members in The Japanese MPS Family Society for providing answers to the questionnaire. We thank Ms. Miho Tabe in SRL Clinical Laboratory Inc. for providing the data on uronic acid concentrations in HSCT-treated patients. We also thank Drs. Toru Yorifuji, Hiraku Doi, and Takeo Kato, Department of Pediatrics, Kyoto University Graduate School of Medicine, for collecting data from historic clinical records and Dr. Yukio Miki, Department of Radiology,

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Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: A nationwide survey in Japan

Abstract

Highlights

Introduction

Section snippets

MPS II classification

Retrospective study from transplanted patient records

Discussion

Conflict of interest

Acknowledgments

Lancet

J. Pediatr.

J. Pediatr.

Mol. Genet. Metab.

Brain Dev.

Am. J. Cardiol.

Mol. Genet. Metab.

Mol. Genet. Metab.

Blood

Blood

Cord-blood transplants from unrelated donors in patients with Hurler's syndrome

N. Engl. J. Med.

Outcomes of hematopoietic stem cell transplantation for Hurler's syndrome in Europe: a risk factor analysis for graft failure

Bone Marrow Transplant.

Mucopolysaccharidosis I: management and treatment guidelines

Pediatrics