Elsevier

Molecular Genetics and Metabolism

Volume 77, Issues 1–2, September–October 2002, Pages 91-98
Molecular Genetics and Metabolism

Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy

https://doi.org/10.1016/S1096-7192(02)00122-1Get rights and content

Abstract

Type 1 Gaucher’s disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT) ± vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid β-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP > 35 < 50 mm Hg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P<0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50–130 mm Hg) were asplenic compared to only 31% of patients with RVSP < 50 mm Hg (Odds ratio [OR] 28.8, 95% CI 1.6–531.6, P<0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1–4.9, P=0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1–33, P=0.003). Severe PH was ameliorated by ERT ± vasodilators during 4.6±4.0 yr (range 1–12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT ± vasodilators/coumadin should be initiated.

Introduction

Type 1 Gaucher’s Disease (GD) is the most common lysosomal storage disorder. It is most frequent in the Ashkenazi Jewish population, affecting ∼1/800 individuals with a carrier frequency of ∼7% [1]. The defect is an autosomal recessive deficiency of acid β-glucosidase that results in multiorgan accumulation of glucosylceramide-laden lysosomes in the macrophage system [2]. Systemic macrophage activation occurs concomitantly, reflected by elevated circulating angiotensin converting enzyme (ACE) and other serum markers [3], [4]. In addition to well-recognized manifestations of hepatosplenomegaly and marrow infiltration, the pathological macrophages also accumulate in the lungs [5], [6], [7], [8], [9], [10], [11], [12], [13]. There are individual case reports of glycolipid-laden macrophages lining pulmonary capillaries, resulting in pulmonary hypertension (PH) with classic plexogenic vasculopathy [7], [8], [9], [10], [11], [12], [13]. However, the prevalence and the clinical spectrum of PH in type 1 GD are not known nor are the determinants of this phenotype.

There is poor correlation between mutations in acid β-glucosidase gene (GBA) and overall severity of type 1 GD [14]. For example, it has been estimated that homozygosity for N370S, the most common mutation causing GD, can cause such mild manifestations that nearly half of affected individuals may never come to medical attention [15]. But the same genotype can also cause crippling disease manifestations including severe, life-threatening PH [16]. The factors that predispose GD patients to PH are not understood. In this study, we aimed to identify candidate modifiers of GD phenotype that exhibits PH, focusing on asplenia, ACE, and GBA mutations. Splenectomy was recently identified as a risk factor in non-GD patients who underwent lung transplantation for primary, plexogenic PH [17]. Another potential risk factor is ACE, which is secreted abundantly by glucosylceramide-laden macrophages in GD [3], [4]. Polymorphisms in ACE gene and its local expression in the pulmonary vascular wall have been implicated in primary PH [18]. Furthermore, in animal models, ACE inhibitors have been shown to ameliorate PH [19].

Before the recent advent of macrophage-targeted enzyme replacement therapy (ERT) as standard of care, GD was treated symptomatically by performing splenectomy [20], [21]. ERT is highly effective in reversing splenomegaly, hepatomegaly, cytopenia, and marrow infiltration, and preventing infarctive bone crises [22]. Although the effect of ERT on PH is not clear, one GD patient with severe PH responded satisfactorily to vasodilators in combination with ERT [23]. In contrast, fatal acceleration of PH occurred in two patients in whom ERT and adjuvant therapies were interrupted [16]. Nevertheless, it has been suggested that ERT may cause PH [24], [25].

In this communication, we report on the prevalence and clinical spectrum of PH in Type 1 GD. Associated genetic and epigenetic factors are analyzed, as well as the effect of ERT with or without vasodilator/Coumadin therapy.

Section snippets

Patients

The primary study cohort comprised 138 consecutive patients with Type 1 GD referred for routine comprehensive evaluation (Table 1); four patients were excluded due to confounding co-morbidity (aortic stenosis, severe ischemic heart disease, and bacterial endocarditis in two patients) and therefore all subsequent analyses on the prevalence of PH in GD were performed on 134 patients. The mean age of patients was 46 with median 45; 66 were males and 68 were females. Forty-two patients were

Prevalence of echocardiographic PH in Type 1 GD

The distribution of RVSP in the primary study cohort of 134 Type 1 GD patients is depicted in Fig. 1. There was a wide distribution of RVSP in the primary study cohort. The prevalence of asymptomatic PH (RVSP >35<50 mm Hg) was significantly higher in untreated type 1 GD patients compared to those on ERT. (Table 1): 30% in ERT-untreated (12/40 patients) and 7.4% (7/94 patients) in ERT groups, respectively (P<0.001). The mean RVSP in untreated patients (30±10 mm Hg) was significantly higher than those

Discussion

We report a remarkable predisposition for PH in Type 1 GD, spanning the entire spectrum from mild, asymptomatic PH to severe, life-threatening forms of the disease. Our study suggests that development of severe PH is not necessarily an indicator of overall severity of GD but that there are specific genetic determinants (i.e., non-N370S mutation of GBA gene, positive family history of similar phenotype, and ACE I allele) and individual epigenetic modifiers (i.e., splenectomy and female sex) that

Acknowledgements

We express our gratitude to the patients and their families who participated in these studies. We thank Dr. H.I. Palevsky for providing right heart catheter data on patient 6 (Table 1) and Drs. S. Wallenstein and K. Katz for statistical advice. We thank Drs. Robert J. Desnick, Jane Morse, and James L. Boyer for critical review of the manuscript. Assistance of Helen Chung, Karen Lim, Whitney Lomazow, and Nursing staff of the General Clinical Research Center in executing the study is gratefully

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    The study was funded by the National Institutes of Health Grant 5 MO1 RR00071 to the Mount Sinai General Clinical Research Center and in part by a grant from Genzyme Corporation, Boston.

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