Cardiovascular Structure and Function in the Mucopolysaccharidoses

This study's investigators previously demonstrated the potential utility of non-invasive carotid ultrasonography to calculate carotid intima media thickness (cIMT) and stiffness (as measured by the three parameters, carotid cross-sectional distensibility [cCSD], carotid cross-sectional compliance [cCSC], and carotid incremental elastic modulus [cIEM]) in people with mucopolysaccharidoses (MPS).

Investigators also studied arterial gene expression in animal models of MPS, and identified upregulation of a number of markers potentially tied to atherosclerosis and inflammation. These include the atherosclerotic marker known as Clusterin (CLU), Cathepsin S, Elastin, and the inflammatory cytokines interleukin 1-α, interleukin 1-β, interleukin 2, and interleukin 6. Other studies have identified elevation in circulating tumor necrosis factor-α correlating with pain and physical disability in certain mucopolysaccharidoses.

Since these studies are cross sectional, and not longitudinal, this study aims to annually measure these previously studied biomarkers (carotid measurements, circulating cytokines, cathepsin S, elastin, and CLU) in a large cohort of MPS patients. This study is a 3-year, prospective, anonymized, longitudinal assessment of cardiovascular structure, function, and circulating biomarkers in patients with mucopolysaccharidoses.

Study Overview

• Status: Active, not recruiting
• Conditions: Inflammation; Mucopolysaccharidoses; Cardiac Disease; Carotid Disease
• Intervention / Treatment: Diagnostic test: Carotid ultrasonography; Diagnostic test: Echocardiography, transthoracic; Procedure: Venipuncture

Detailed Description

Specific Aims

1. Annually assess cardiac and carotid structure and function utilizing ultrasonography, in patients with mucopolysaccharidoses
2. Annually measure circulating levels of clusterin, elastin, cathepsin S, lipids, and cytokines in patients with mucopolysaccharidoses

Target enrollment 30 subjects at CHOC Children's Hospital

Study Protocol

Screening

1. Study Investigators will identify eligible patients to participate in the study from their current patient population and future referrals.
2. Eligible patients will be provided with study information on the study during their standard of care metabolic clinic visit.

Informed Consent

1. Informed consent will be obtained following the requirements set forth by 21 CFR 50.25.
2. Patients interested in the study will be provided the informed consent document. The document will be reviewed in a private quiet room and ample time for questions will be provided. The patient can keep a copy of the consent if they wish to discuss the study with friends and family. Consent will only be obtained once the patient has had time to ask questions and is aware that the study is completely voluntary.

Initial entry

1. Information regarding age, sex, MPS diagnosis (including genetic mutation and enzymatic levels, if possible) will be obtained
2. Height and weight will be obtained. If patient has had a recent (within 3 months) evaluation at CHOC Children's with height and weight, those parameters may be used

3. Medical records will be obtained specifically focusing upon

   1. the genetic and/or enzymatic testing used to confirm the MPS diagnosis
   2. the treatment status (treated or not) and duration of treatment (calculated by the difference between date of first carotid imaging and date of first treatment)

4. Carotid ultrasonography will be obtained

   1. Study takes 10 - 15 minutes to complete
   2. Subject will be asked to lay still and quietly during procedure
   3. Blood pressure and heart rate will be obtained during the study
   4. Results will be digitized and stored on CD

5. Echocardiography will be obtained

   1. Study takes 15 - 20 minutes to complete
   2. Subject will be asked to lay still and quietly during procedure
   3. Results will be digitized and stored on CD

6. Venipuncture / phlebotomy

   1. 10 mL of blood total will be drawn (5 mL in a blue top citrate tube, 5 mL in a purple top EDTA tube). Measurements of cytokines, clusterin, lipidomics, cathepsin S protease, and elastin (previously identified potential biomarker candidates) will be performed.
   2. Blood will preferably be drawn via venipuncture, but if patient has a port-a-cath already implanted and is having blood drawn via port-a-cath for clinically required reasons, then study-related blood draw via port-a-cath can take place concurrently with clinically required blood draws.

Annual studies Procedures 2), 4), 5), and 6) will be repeated on an annual basis for a total of three years

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

Study Locations

• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Any patient with a diagnosis of mucopolysaccharidosis who provides informed consent is eligible for this study. Mucopolysaccharidoses are a group of inherited metabolic disorders involving abnormal degradation of glycosaminoglycans. There are 11 different genes which, when altered, can give rise to a mucopolysaccharidosis. People with this diagnosis can develop significant cardiovascular disease (left ventricular hypertrophy, valvular dysfunction, aortic root dilatation, arterial wall thickening and stiffness).

Description

Inclusion Criteria:

1. Any patient with a molecularly confirmed diagnosis of mucopolysaccharidosis is eligible to enroll in this study
2. Parental / patient informed consent

Exclusion Criteria:

1. Any reason that the investigators would deem a patient unable to participate in this study
2. Inability to participate in the assessments required for this study

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular Event	A cardiovascular event is defined by new onset of clinically significant aortic or mitral valve disease, aortic root dilatation, cardiomyopathy, reduction in cardiac contractile function, myocardial ischemia, myocardial infarction, or cerebrovascular accident	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	Change of age of subject (unit: years)	3 years
Height	Change of height of subject (unit: meters)	3 years
Weight	Change of weight of subject (unit: kilograms)	3 years
Blood pressure	Change in systolic and diastolic blood pressure over the duration of the study (unit: millimeters of mercury)	3 years
Carotid structure	Change in carotid intima media thickness over the duration of the study (mm).	3 years
Carotid stiffness	Change in carotid cross-sectional distensibility over the duration of the study (unit: %). This metric is acquired in the carotid ultrasound, and measures the stiffness of the carotid artery via quantitation of the difference between end-systolic and end-diastolic carotid diameter.	3 years
Cardiac structure (left ventricle)	Change in left ventricular mass index over the duration of the study (unit: grams / m2 body surface area). This metric is acquired in the echocardiogram, and quantitates the amount of myocardium in the left ventricle.	3 years
Cardiac structure (aortic root diameter)	Change in aortic root measurement over the duration of the study (unit: mm). This metric is acquired in the echocardiogram, and quantitates the width of the aortic root.	3 years
Mitral valve function	Assessment of changes in mitral valve function over the duration of the study (unit: 4 point Likert scale from 0 [none] to 4 [severe]). This metric is acquired during the echocardiogram, and assess the degree of mitral valve insufficiency.	3 years
Aortic valve function	Assessment of changes in aortic valve function over the duration of the study (unit: 4 point Likert scale from 0 [none] to 4 [severe]). This metric is acquired during the echocardiogram, and assess the degree of aortic valve insufficiency.	3 years
Inflammatory biomarkers (Tumor Necrosis Factor - alpha)	Change in plasma TNFa over the duration of the study.	3 years
Inflammatory biomarkers (Cathepsin S)	Change in plasma Cathepsin S over the duration of the study. (Unit: mcg/L)	3 years
Inflammatory biomarkers (Elastin)	Change in plasma Elastin levels over the duration of the study. (Unit: ng/mL)	3 years
Inflammatory biomarkers (Clusterin)	Change in plasma clusterin levels over the duration of the study. (Unit: mcg/mL)	3 years
Inflammatory biomarkers (lipidomics)	Change in plasma lipid levels over the duration of the study. (Unit: mcmol/L)	3 years

Collaborators and Investigators

• Sponsor: Children's Hospital of Orange County
• Collaborators: Ultragenyx Pharmaceutical Inc
• Investigators: Principal Investigator: Raymond Wang, M.D., CHOC Children's Hospital

Publications and helpful links

General Publications

• Wang RY, Covault KK, Halcrow EM, Gardner AJ, Cao X, Newcomb RL, Dauben RD, Chang AC. Carotid intima-media thickness is increased in patients with mucopolysaccharidoses. Mol Genet Metab. 2011 Dec;104(4):592-6. doi: 10.1016/j.ymgme.2011.09.004. Epub 2011 Sep 10.
• Wang RY, Braunlin EA, Rudser KD, Dengel DR, Metzig AM, Covault KK, Polgreen LE, Shapiro E, Steinberger J, Kelly AS. Carotid intima-media thickness is increased in patients with treated mucopolysaccharidosis types I and II, and correlates with arterial stiffness. Mol Genet Metab. 2014 Feb;111(2):128-32. doi: 10.1016/j.ymgme.2013.11.001. Epub 2013 Nov 12.
• Wang RY, Rudser KD, Dengel DR, Braunlin EA, Steinberger J, Jacobs DR, Sinaiko AR, Kelly AS. The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls. Int J Mol Sci. 2017 Mar 15;18(3):637. doi: 10.3390/ijms18030637.
• Wang RY, Rudser KD, Dengel DR, Evanoff N, Steinberger J, Movsesyan N, Garrett R, Christensen K, Boylan D, Braddock SR, Shinawi M, Gan Q, Montano AM. Abnormally increased carotid intima media-thickness and elasticity in patients with Morquio A disease. Orphanet J Rare Dis. 2020 Mar 17;15(1):73. doi: 10.1186/s13023-020-1331-y.

Study record dates

Study Major Dates

• Study Start (Actual): October 13, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: July 15, 2021
• First Submitted That Met QC Criteria: September 21, 2021
• First Posted (Actual): October 1, 2021

Study Record Updates

• Last Update Posted (Estimated): January 7, 2026
• Last Update Submitted That Met QC Criteria: January 5, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: biomarker; cardiac; cardiovascular; observational; longitudinal; mucopolysaccharidosis; carotid
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Inflammation; Heart Diseases; Mucopolysaccharidoses; Investigative Techniques; Therapeutics; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Diagnostic Imaging; Diagnostic Techniques, Cardiovascular; Heart Function Tests; Cardiac Imaging Techniques; Ultrasonography; Phlebotomy; Blood Specimen Collection; Echocardiography; Ultrasonography, Carotid Arteries
• Other Study ID Numbers: 200107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Since we are the sole site, we do not have any plans to share individual data at this point. Once the study has completed data collection and analysis, data will be shared in aggregate.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No