Background The feasibility of carotid artery intima-media thickness (C-IMT), an established cardiovascular disease marker, as a cardiac risk marker in mucopolysaccharidosis (MPS) patients was explored. Objectives To determine if C-IMT is abnormal in MPS versus unaffected controls, and if C-IMT correlates with coronary artery diameter in MPS. Material and methods Measurements of C-IMT via neck ultrasound and echocardiographic parameters, including coronary artery diameters, were obtained from MPS and control patients, and compared. Results Sixteen MPS subjects (6 MPS I, 6 MPS II, 2 MPS III, 1 MPS VI, 1 MPS VII) and sixteen age, ethnicity, and gender-matched controls were enrolled. Median MPS and control subject ages were 8.3 ± 4.5 and 8.6 ± 4.3 years, respectively (p = 0.73). Mean MPS and control C-IMTs were 0.54 ± 0.070 and 0.48 ± 0.034 mm (p = 0.0029). No differences in left main, left anterior descending, or right coronary artery diameters were seen between MPS and controls. A significant proportion of MPS subjects had mitral insufficiency (14/16; p=0.0002), aortic insufficiency (10/16; p=0.0021), and left ventricular dilatation (7/16, p=0.037) versus controls. C-IMT did not correlate significantly with age, height, weight, coronary measurements, or duration of treatment. Conclusion C-IMT in MPS patients is increased compared to matched controls, likely reflective of arterial intima-medial glycosaminoglycan accumulation. MPS subjects demonstrated a high percentage of left-sided valvular insufficiency and ventricular dilatation. Additional studies should be performed in MPS patients to determine if C-IMT correlates with arterial elasticity, biomarkers of vascular dysfunction, and higher risk of cardiovascular events.

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Background Treatments for mucopolysaccharidoses (MPS) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients. Objectives To determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls. Methods MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery compliance (cCSC), distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory. Results A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (±SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p < 0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm2/mmHg versus 0.16 ± 0.05 mm2/mmHg; adjusted p = 0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p < 0.001). cCSD in MPS patients was lower than control (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically; p = 0.12. Among MPS patients, cCSD showed a significant association with cIMT (p = 0.047), while the association between cIEM and cIMT approached significance (p = 0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients. Conclusions Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.

The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of α-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced α-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of α-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of α-dystroglycan hypoglycosylation in skeletal muscle.

Background-The feasibility of carotid artery intima-media thickness (C-IMT), an established cardiovascular disease marker, as a cardiac risk marker in mucopolysaccharidosis (MPS) patients was explored.