Study FAQs

What is the purpose of this study?

The purpose of this study is to look at the ability of BH4 (also known as Kuvan®, sapropterin dihydrochloride, or tetrahydrobiopterin) to work in ways other than helping break down the amino acid phenylalanine in patients with phenylketonuria (PKU). We think BH4 therapy could affect the way the body reacts after eating a meal high in fat and sugar.

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Who is eligible to participate?

We are enrolling participants in three different groups:

  • Patients with PKU who responded to BH4 therapy
  • Patients with PKU who did not respond to BH4 therapy
  • Healthy controls who do not have PKU

Eligibility will be based on your study group. You may be eligible if you:

  • Are 10-45 years of age
  • Do not have a history of a chronic disease (excluding PKU)
  • Do not smoke
  • Are not pregnant or breastfeeding

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What will be asked of me if I participate in this study?

If you choose to participate, you will be asked to come in for a study physical examination and either one or two meal challenge study visits (see below for explanation). At the meal challenge study visit(s) we will ask you to eat a specially designed meal. We will take a small sample of blood every other hour and measure your endothelial function (the way your blood vessel reacts to stress; see General Question #8 and 9) twice over the course of 6 hours.

  • If you are in the group of PKU patients who responded to BH4 therapy, you will be asked to attend a study physical examination and one meal challenge study visit. At the meal challenge, you will be asked to take your prescribed daily dose of BH4 with the meal.
  • If you are in the group of PKU patients who did not respond to BH4 therapy, you will be asked to come in for a study physical and two study visits: once while not taking BH4 and once after taking BH4 (20mg/kg/day) for 2 weeks.
  • If you are in the healthy control group, you will be asked to attend a study physical examination and one meal challenge study visit.

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What information will be collected about me as part of this study?

The following information will be collected about you for the purposes of this study:

  • Health information from your physician and/or medical charts
  • Results from physical examination, including blood and urine tests
  • Demographic questionnaire
  • Health questionnaire
  • Dietary practices questionnaire and 3-day diet records
  • Research center admission measurements (such as height, weight, blood pressure, etc)
  • Oxidative stress indices at the baseline blood draw of each meal challenge
  • Measurement of a blood oxidative stress marker and amino acid profile every other hour throughout each meal challenge
  • Two endothelial function tests performed at baseline and hour 3 of the meal challenge

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Why do I have to eat the meal provided in the study?

Every day your body responds to the food that you eat. Scientists have found that if you change the composition of the meal (i.e. the type of fat, how much sugar, etc) you can create a measurable short-term effect on a marker of oxidative stress and endothelial function. We will be using a specially designed meal to see if BH4 can prevent these measureable effects. The meal has been specially formulated to be low in phenylalanine to be appropriate for all potential participants and is made from ingredients found at your local grocery store! The meal has been specially formulated to be low in phenylalanine to be appropriate for all potential participants and is made from ingredients found at your local grocery store!

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Will I be able to see the results of the tests you run?

The tests we will be running will be for research purposes only. Some of the tests we will be running do not have clinical significance at this time and will not necessarily change your health practices. You will not be able to see the results of these tests.

There will be some routine clinical tests that will occur during the screening physical examination and at the study visit(s) such as a metabolic panel, a complete blood count, measurement of certain vitamins and a mineral, and blood phenylalanine concentration. You will be able to see your results from these routine clinical tests.

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What will it cost to participate?

All laboratory tests and examinations will be covered by our research funds. There will be no cost to you to participate in this study, aside from the cost of transportation to and from study-related visits.

We recognize that involvement in this study will require at least a day's worth of your time. You will be compensated $50 for your participation in each of the meal challenge study visit(s).

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Where will the study take place?

Our research office is located in the Emory Human Genetics Clinic located at the 2165 North Decatur Road, Decatur, GA 30033. You may be consented and/or fill out questionnaires at this location.

Click here for map

All meal challenge study visit will be conducted at the Emory University Hospital Clinical Interactions Site located at 1364 Clifton Road, Atlanta, GA

Click here for map 30322.

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What do I do if I'm interested in participating?

If you are interested in participating, please contact Teresa Douglas:

Phone (404) 778-8629
Email teresa.d.douglas@emory.edu
Address 2165 North Decatur Rd.
Decatur, GA 30033

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You're looking for unaffected controls. Can my family member participate?

The "unaffected control" group is meant to represent the general population. While we would love have your family members as participants in this research study, we want to make sure that they have a low risk of carrying the DNA that carries the error that lead to your PKU. For this reason, we cannot enroll biological first- or second-degree relatives. This includes a PKU participant's parents, children, siblings, half-siblings, grandparents, aunts, uncles, nieces, or nephews.

Due to their lower chance of carrying the DNA, we can enroll more distant blood relatives such as first and second cousins. If a relative is not related to you by blood (for example through marriage or adoption), they may be eligible to participate in the study. If

If you have any questions about who may be eligible for the healthy unaffected control group, please contact Teresa Douglas [(teresa.d.douglas@emory.edu or (404)778-8629)].

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I have a friend who doesn't have PKU. Can they participate in this study?

If your friend meets the inclusion criteria for the study, your friend can participate in the study. We are recruiting participants who do not have PKU, in addition to patients with PKU. Participation is completely voluntary, and if your friend is younger than 18 years of age, we will need his or her parent to agree allow them to participate.

If you know someone without PKU who may be interested in participating, please tell them to directly contact our assistant research coordinator Teresa Douglas[teresa.d.douglas@emory.edu or (404)778-8629)]. All participants, regardless of group, must understand what it means to be a research study participant and give us permission to collect information about them.

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Do I have to participate in this study?

No. Your participation is completely voluntary. Whether or not you participate, your medical management will not be affected.

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I am currently participating in another research study. Can I still participate in this study?

It depends on what type of research study you are participating in. We do not want this study to interfere with your participation in another study, and we don't want your participation in another study to interfere with our study. Please let the study staff know if you are enrolled in any other research study (including clinical trials, registry projects [such as PKUDOS], etc).

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I would like to participate, but will be coming from out of town. Can I still participate?

Yes. We do not currently have the funds to compensate participants for the cost of travel. However, we will work with you to arrange the necessary accommodations for your stay in Atlanta. Please contact Teresa Douglas [(teresa.d.douglas@emory.edu or (404)778-8629)] for more information.

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What will the results of this study mean for the future of PKU and BH4?

This study is a first step to understanding the full impact of BH4 therapy on patients with PKU. The results of this study will help scientists and researchers decide what pathways should be further evaluated in patients who are prescribed BH4.

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What is phenylketonuria?

Phenylketonuria, or PKU, is a genetic disorder in which a person's body can't adequately dispose of the amino acid phenylalanine (a building block of protein). Phenylalanine can accumulate in the blood of these patients and affect their growth and development. To prevent this from happening, people with PKU are instructed to limit the amount of phenylalanine they eat in their diet.

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What is BH4?

BH4 (also known as tetrahydrobiopterin) is a molecule which your body naturally makes. BH4 is important because it plays a helper role in the break down phenylalanine. It also plays a similar helper role in other reactions in the body. Patients with PKU do not lack BH4*.

In 1999, it was found that certain patients with PKU had a decrease in blood phenylalanine concentrations when they were given a pharmacological dose of synthetic BH4. In 2007, the United States approved this synthetic version of BH4 (also called Kuvan® or sapropterin dihydrochloride) for use in patients with PKU. About 30-40% of patients with PKU respond to synthetic BH4 with a decrease in blood phenylalanine concentrations.

*There is a similar disorder called BH4-deficient hyperphenylalaninemia, where BH4 is not properly produced in the body. This disorder is managed differently than PKU.

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How do I know if I'm a resoponder to BH4 therapy?

If you have PKU, you should have the opportunity to try BH4 therapy to see if you respond to the therapy. This process is generally carried out by your metabolic team and consists of measuring your blood phenylalanine concentrations before and after trying BH4.

There are many definitions of how to classify a person as BH4-responsive. This is often based on your metabolic clinic and/or prescribing clinician. For the purposes of this study, a BH4-responder will be defined as a patient who:

  • Experienced at least a 30% decrease in blood phenylalanine concentrations during their clinic's initial BH4 testing protocol
  • Could increase their dietary phenylalanine tolerance by at least 300 mg/day*
  • Could decrease their pre-BH4 medical food needs by at least 25%*
*Diet criteria are not typically used as responsiveness criteria in most clinics. These criteria are subject to case-by-case evaluation based on the patient's metabolic clinic practices and the original diet prescription of the patient.

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Why should I care about how BH4 affects me other than lowering my blood pheylalanine concentrations?

It is believed that when BH4 is given as a drug to patients with PKU, it functions in the pathway that is affected in patients with PKU. However, the structure of the drug may allow it to function in other reactions in your body. So by taking BH4, you may affect these alternative pathways. The only way we can determine if this happens in your body is by conducting a research study.

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What is oxidative stress?

Every day, your body is exposed to and produces a wide range of reactive molecules. Many systems are in place to ensure these molecules are located in the proper place, are in the right amount, and act as they are intended. If these regulatory systems are overwhelmed or impaired, the reactive molecules can accumulate or end up where they are not meant to be. This can result in damage the cellular structures and networks in your body. It is believed that if this damage occurs frequently your body's vital functions can be affected. The body's inability to prevent the effects of excess of reactive molecules is called oxidative stress.

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How does oxidative stress affect someone with PKU?

Oxidative stress in patients with PKU has been evaluated at international clinics. Blood markers that are believed to indicate oxidative damage to lipids and DNA were elevated in PKU patients as compared to unaffected controls.

There is much we still don't know about oxidative stress as it relates to patients with PKU. First, we don't know if what was seen in international clinics applies to patients being treated in the United States. Also, we don't know how new treatments like BH4 therapy affect markers of oxidative stress. Finally, we don't know how dietary intake and changes in blood phenylalanine concentrations affect a person with PKU's oxidative stress status.

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How is oxidative stress measured?

There isn't a single test that will tell a researcher if a person is experiencing oxidative stress. Scientists look at several blood and/or urine markers to get a sense of how the oxidant/antioxidant systems in your body are working. Typically, researchers look at how certain enzymes are functioning and/or the concentrations of biomarkers (molecules in the blood what indicate dysfunction or imbalance).

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What is endothelial function? Why is it important to look at?

The endothelium is the lining of your blood vessels. And important function of the endothelium is to make sure blood is flowing through your blood vessels correctly. The endothelial function can be impaired acutely (after a high fat meal) or chronically, as a result of disease.

We don't know if PKU patients experience endothelial dysfunction. In this study, we will attempt to induce endothelium dysfunction by providing a meal challenge high in fat and sugar. We will see if the drug BH4 can prevent this meal-induced dysfunction in patients with PKU.

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How is endothelial function measured?

There are several ways to measure different aspects of endothelial function. In this study we will be focusing on one type of endothelial function test called flow mediated dilation.

Flow mediated dilation is measured by imaging the blood vessel in your arm while you are at rest. A blood pressure cuff will then be inflated on your arm and left inflated for approximately 5 minutes. Your arm may feel like it's getting tingly or feel like it has fallen asleep during this time, which is normal. When the blood pressure cuff is released the, the blood vessel in your arm will be imaged again as the blood flow returns to normal in your arm. This procedure may have to be repeated in triplicate to get an accurate reading. You will be able to rest between the repeated testing.

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