Laronidase replacement therapy improves myocardial function in mucopolysaccharidosis I

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Abstract

We assessed whether laronidase (recombinant human α-l-iduronidase) replacement therapy could improve left ventricular (LV) myocardial function in a 49-year-old woman with mucopolysaccharidosis I (MPS I) and valvular heart disease. After 6 months of laronidase treatment, the concentration of urinary uron acid decreased by 78.8%. Hepatosplenomegaly improved and LV weight decreased by 19.6%. LV ejection fraction assessed by two-dimensional echocardiogram did not change after laronidase treatment. However, in two-dimensional ultrasound speckle tracking imaging method, LV myocardial longitudinal strain (shortening ratio) increased from − 13.2 to − 17.4%. LV myocardial radial strain (thickening ratio) increased from 26.6 to 83.4%. LV myocardial torsion increased from + 6 to + 18°. These indexes of myocardial function were normalized after laronidase treatment. Thus, our findings were a first report that laronidase treatment had a beneficial effect on LV myocardial function in an adult patient with MPS I.

Introduction

Mucopolysaccharidosis I (MPS I) is an autosomal recessive inherited disorder caused by mutations in the gene encoding α-l-iduronidase located on chromosome 4p16.3 [1]. The α-l-iduronidase is a lysosomal enzyme involved in the degradation of glycosaminoglycans (GAG) [2]. The GAGs accumulation in cells and tissues results in their organic dysfunction including joint disorder, hepatosplenomegaly, clouding of the cornea, degradation of retina, and cardiovascular disorders including valvular heart diseases, mental retardation, navel herniation, and respiratory disorder [3]. MPS I is phenotypically heterogeneous. Historically, MPS I is classified into three clinical syndromes including Hurler, Hurler–Scheie, and Scheie. Hurler disease shows a most severe phenotype expression. Hurler–Scheie disease is intermediate in phenotype expression. Scheie disease shows mild clinical manifestations with a sometimes normal life span. In these three MSP-1 phenotypes, the mental retardation is the most differentiating factor. Hurler disease shows the severest mental retardation. In contrast, Scheie disease is the lightest mental phenotype and frequently shows normal intelligence quotient (IQ). Hurler–Scheie type is an intermediate IQ phenotype.

Enzyme replacement therapy with recombinant human α-l-iduronidase, laronidase, has an etiology-specific treatment by delivering sufficient α-l-iduronidase for the prevention of GAG accumulation in patients with MPS I [4]. Laronidase treatment has shown safety and efficacy in animal and human studies [5], [6], and is shown to improve respiratory function and physical capacity by reducing GAG storage in patients with MPS I [7]. However, the previous studies demonstrated that laronidase treatment did not affect the left ventricular (LV) ejection fraction in patients with MPS I [8], [9]. In the past decade, two-dimensional (2D) ultrasound speckle tracking imaging method has enabled noninvasive measurements of LV myocardial function including myocardial strain and torsion [10], [11], [12], [13]. Therefore, we assessed by 2D speckle tracking imaging method whether laronidase treatment improves LV myocardial function in a patient with MPS I and valvular heart disease.

Section snippets

Case report

The patient is a 49-years-old woman with MPS I (Scheie) who was diagnosed at 35 years of age with the deficient activity of the enzyme α-l-iduronidase. At 11 years of age, she had initial clinical symptoms including stiffness and deformities of joints, hepatosplenomegaly and umbilical herniation. At 20 years of age, she had clouding of the bilateral corneas. At 33 years of age, degradations of retinal pigmentosa were emerged, leading to amblyopia. Moreover, since she had congestive heart failure

Clinical findings after laronidase treatment

The clinical findings on joint movements, vision and 6 min waking were not improved after enzyme replacement treatment (ERT). However the findings of urinary uronic acid concentration, 2-D speckle-tracking echocardiogram, and the weights of liver and spleen were improved after ERT. Time course of physiological findings before and after laronidase treatment was shown in Fig. 1. The concentration of urinary uron acid was 75 mg/g creatinine before laronidase treatment. After 3 months of treatment,

Discussion

Our patient was diagnosed with MPS I owing to the deficient activity of the enzyme α-l-iduronidase. Since she had developed severe manifestations and complications of MPS I including congestive heart failure due to aortic and mitral regurgitations, she had surgical operation with double valvular replacement. However, she had unfortunately a small amount of paravalvular leakage at the site of aortic prosthetic valve, leading to chronic heart failure and paroxysmal atrial fibrillation. Therefore,

Limitations

The incredible change of thickening ratio was not well explained because the number of case is only one patient. The analysis of a large number of cases might be needed.

Acknowledgments

We thank Yukie Hori, Hiroyoshi Ryu, Masaaki Kanahara and Masaji Honda for their technical assistance, and Emiko Shiotani for her excellent secretarial assistance.

References (18)

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    There was an improvement in the LV GLS value during the period (13.2%–17.4%), whereas the ejection fraction measured by conventional echocardiography did not change. Additionally, the patient showed left ventricular mass reduction (189–152 g), reduction in glycosaminoglycan levels in urine (75–38 mg/g of creatinine), and reduction in hepatosplenomegaly (evaluated by computed tomography).15 In 2014, Lee et al. performed an experimental study in genetically modified mice with the model of cardiomyopathy associated with Hunter syndrome (MPS type II), before and after the use of ERT, and observed cardiac function improvement according to the circumferential and radial strain measurements at the end of the analyzed period (9.44%–12.41% and 16.91%–28.91%, respectively).16

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