Cardiovascular Structure and Function in the Mucopolysaccharidoses

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.

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

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