Cardiac features and effects of enzyme replacement therapy in Taiwanese patients with Mucopolysaccharidosis IVA

Abstract

BackgroundCardiac abnormalities have been observed in patients with mucopolysaccharidosis (MPS) of any type, with the most documented abnormalities being valvular heart disease and cardiac hypertrophy. However, few studies have focused on the cardiac features of MPS IVA.MethodsWe reviewed the medical records, echocardiograms, and electrocardiograms of 32 Taiwanese patients with MPS IVA (16 males and 16 females; median age, 10.8 years; age range, 1.1 to 29.1 years) as well as the echocardiographic data of six patients who received enzyme replacement therapy (ERT) for 3–6 years.ResultsEchocardiographic examinations (n = 32) revealed mean z scores of left ventricular mass index (LVMI), interventricular septum diameter in diastole (IVSd), left ventricular posterior wall diameter in diastole (LVPWd), and aortic diameter of 0.94, 2.70, 0.39, and 3.26, respectively. Z scores > 2 were identified in 25%, 50%, 29%, and 69% of the LVMI, IVSd, LVPWd, and aortic diameter values, respectively. Diastolic dysfunction [reversed ratio between early and late (atrial) ventricular filling velocity (E/A ratio < 1)] was identified in four patients (13%), however, the ejection fraction was normal (50–75%) in all of the patients. Sixteen patients (50%) had valvular heart disease and most were of mild degree. Fourteen (44%) had valvular stenosis, and 10 (31%) had regurgitation. The z scores of LVMI, IVSd, LVPWd, and aortic diameter, the severity scores of aortic stenosis and regurgitation, and the existence of a thickened interventricular septum were all positively correlated with increasing age (p < 0.05). For the 14 patients with valve thickening, the z scores of LVMI, IVSd and aortic diameter were all larger than those of the 18 patients without valve thickening (p < 0.05). For two patients who started ERT at a younger age (1.4 and 2.8 years, respectively), the z scores for LVMI, IVSd, and LVPWd all decreased after ERT.ConclusionsA large proportion of the patients with MPS IVA had valvular heart disease and cardiac hypertrophy. Cardiac abnormalities worsened with increasing age in accordance with the progressive nature of this disease. ERT appeared to be effective in stabilizing or reducing cardiac hypertrophy, and better results may have been associated with starting ERT at a younger age.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0883-6) contains supplementary material, which is available to authorized users.

Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations

“…GAGs decrease and reduction of organomegaly are well-recognized effects of ERTs: from the clinical point of view these two effects are marginal but demonstrate a sustained biological effect. Clinically more important is the quite universal reduction of left ventricular mass index and of septum hypertrophy, with ejection fraction improvement [40,41,46,49,51,52,74,75,77]. AHI and OSAs, when evaluated, seem to be reduced by ERT, but it is clear that macroglossia and adeno-tonsils hypertrophy are not modified during long-term treatment [36,45,46,49,50,[61][62][63][64].…”

“…Some of these studies are the phase III extension studies and involve the same patients previously enrolled in the Phase III trials [36][37][38][39]71,96,114]. The others are mostly observational studies conducted in a single center on a limited number of cases, or studies performed on data extracted from disease registries [29,34,37,[40][41][42][43][44][47][48][49][50][51][52]70,74,77,84,85,97,116]. Disease registries are a helpful tool to collect data on rare diseases and there is now a huge number of disease registries available for many rare diseases.…”

“…While it is generally acknowledged that long term ERT reduces or at least stabilizes left ventricular mass index and interventricular septal hypertrophy, and improves ejection fraction in MPS I, II, IVA and VI [40][41][42]46,51,[74][75][76][77][78], valve abnormalities causing regurgitation or stenosis are not reduced by ERT [34,36,37,40,41,44,46,47,51,59,[74][75][76][77][78][79]. Only few papers found stabilization or worsening of heart hypertrophy in MPS VI and II patients [34,37,47].…”

Cardiac Evaluation Using Two-Dimensional Speckle-Tracking Echocardiography and Conventional Echocardiography in Taiwanese Patients with Mucopolysaccharidoses

“…Existence of diastolic dysfunction was indicated by a reversed E/A ratio (E/A ratio <1). The severity of valvular stenosis and regurgitation was assessed and graded as follows: 0 (none), 1 (mild), 2 (moderate), and 3 (severe), based on the European Society of Cardiology guidelines [12][13][14][15]35,36]: mild aortic stenosis (AS) = a valve area > 1.5 cm 2 and a mean gradient < 30 mmHg; moderate AS = a valve area of 1.0-1.5 cm 2 and a mean gradient of 30-50 mmHg; severe AS = a valve area < 1.0 cm 2 and a mean gradient > 50 mmHg; mild mitral stenosis (MS) = a valve area > 1.5 cm 2 and a mean gradient < 5 mmHg; moderate MS = a valve area between 1.0-1.5 cm 2 and a mean gradient between 5-10 mmHg; and severe MS = a valve area < 1.0 cm 2 and a mean gradient >10 mmHg. Because the frequency of physiological tricuspid regurgitation is high in the general population, we did not include tricuspid regurgitation as a pathological finding in this study.…”

“…Patients with all MPS types suffer from cardiac abnormalities, including cardiac hypertrophy, cardiac valve thickening, and valvular regurgitation and stenosis. The deformed valves with mitral or aortic leaflet thickening and calcification may lead to valvular stenosis or regurgitation [4][5][6][7][8][9][10][11][12][13][14][15]. GAG accumulation in the spongiosa of cardiac valves, myointima of coronary arteries, and myocardium has been associated with cardiomyopathy and valve defects [16].…”