Charlie is an international research group, looking for better and more effective treatment for patients with PDE and GA1.

CHARLIE is a research project for lysine metabolism disorders. Examples of these disorders are Pyridoxine-dependent Epilepsy (PDE) and Glutaric Aciduria type 1 (GA1). Without treatment, patients with these disorders often get serious neurological complaints and need continuous care. However, the available treatment does not relief all symptoms. And the diet that needs to be followed is often burdensome and has a major impact on the patients’ quality of life.

In the CHARLIE project, physicians and patients collaborate on research into better treatment. Physicians are going to investigate how damage to the brain can be prevented, if at all. And they may investigate new ways for developing gene therapy for GA1. Patients will indicate which treatment they receive and what does and does not go well. What do they miss in their treatment and the support they receive? What can be improved and how? What should be taken into account if a new treatment is being developed and subsequently becomes available? By investigating these issues, the effect of therapy can be identified for each patient and treatment can be tailored individually.

Current treatments for PDE and GA1 do not suffice. That is why researchers in the field of PDE and GA1 have joined forces. They work together in the CHARLIE project to further unravel these diseases. Only when the disease mechanisms are known solutions come in sight for developing treatment to reduce or repair the disease symptoms.

The two diseases, though very different have some things in common:

  • The dietary treatment strategy for both is aimed at lysine/protein restriction and/or arginine supplementation, the latter as competitive inhibitor over the blood brain barrier as lysine and arginine use the same cationic transporter.
  • Lysine is an essential amino acid which cannot be completely removed from the diet. Thus, lysine reduction does not eliminate, but at best mitigates neurologic impairments. The role of arginine supplementation (an the form in which arginine is taken by patients) makes it difficult to evaluate the effect of it in the real world.

Both diseases also have different symptoms and outcomes for patients.

In both PDE and GA1, something goes wrong in the breakdown of lysine. Lysine is an amino acid, a kind of building block for proteins in the body. Once lysine is no longer needed, it is broken down by various enzymes. This provides energy.

PDE and GA1 are caused by an error in the DNA. The DNA serves as a collection of building instructions for making proteins in the body. These building instructions are called the mRNA. If there is an error in the DNA, the building instructions are no longer correct and a non-functional protein is formed. In PDE and GA1, the DNA error causes one of the enzymes that breaks down lysine to stop working. As a result, lysine can no longer be broken down.

The lysine breakdown process evolves in several steps. The first step involves the AASS enzyme. The subsequent steps involve the ALDH7A1 and GCDH enzymes. During this breakdown process so-called intermediate products are formed. But in PDE and GA1, the ALDH7A1 enzyme and the GCDH enzyme, respectively, no longer work. As a result, the breakdown of lysine is halted, causing the intermediate products to accumulate in the cells. This is especially harmful to the brain cells. As most PDE and GA1 patients do not have the same DNA error, the protein is broken down in a different way each time. It is therefore difficult to develop a drug to treat all PDE or GA1 patients.

In the CHARLIE project, different strategies will be used. The enzyme responsible for the accumulation of the intermediate products that causes damage to the brain will be inactivated. The resulting accumulation of lysine has been shown not to be harmful: people with dysfunctional AASS show no symptoms. So, with this strategy, it no longer matters which DNA error causes the ALDH7A1 or GCDH enzyme to stop working. We thus hope to be able to treat all PDE and GA1 patients with one and the same drug.

Also, gene replacement therapy is pursued in CHARLIE in first instance only for GA1 and perhaps later for PDE.

No one knows the burden of disease and treatment better than the patient. CHARLIE therefore wants to identify the needs of patients so that together better treatment can be sought. One way of doing this is by asking patients which complaints affect them the most. This is called a PRO, a Patient-Reported Outcome. Another tool is called a PREM, a Patient-Reported Experience Measure. This can be used to measure the experiences of patients.

Four patient organizations in the United States, Germany, Spain and The Netherlands collaborate in CHARLIE:


These four organizations are the start of a network for both diseases that can reach and engage more patients. PDE and GA1 are rare diseases. As a result, each patient is an expert by experience. The knowledge of these patients can help to improve future treatment. By completing the questionnaires that will be linked to this website you may be able to help as well.

The patient organizations involved want to work on mutual understanding with scientists and doctors on the experienced unmet needs of patients living with PDE and GA1.
More information about PDE and GA1 can also be found on the websites of the above 4 patient organizations. In addition, you can find care pathways for patients for the two diseases in multiple languages in the next tab.

An anonymous survey to answer questions about the needs of patients. Please participate!

Within CHARLIE researchers in six countries work every day to learn more about the diseases PDE and GA1. The ultimate goal is to be able to offer patients more and better treatment options. Patient involvement is an important aspect of the CHARLIE-project.

Therefore, an online- survey about the needs and opinions of patients and caretakers is waiting to be completed. We hope that many patients and caretakers will participate in the survey. The survey is totally anonymous.

The survey is available in four languages: English, German, Spanish and Dutch. We hope that scientists, patients and caretakers will spread the word, so that many patients are able to contribute their opinions.

If you are a patient with PDE or GA1, the parent of a patient or a patient representative and you want to participate, please contact us via info[at]charlie.science or button below

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Personal story from Núria

Author: Albert Carbonell, father of Núria and affiliated to the Spanish patient association FAMILIA GA1

Núria is our second daughter and she is now four years old. She is a very happy and funny girl who loves music, dancing, and playing with her older sister Joana, who is six years old. She is becoming more aware every day of the importance of controlling her diet and health in her daily life, and she is now more comfortable with her medication routines and emergency protocols when she is sick. With her strength and energy, she has shown us that it is possible to enjoy and be happy while being parents of a child with GA1.

During her first two years of life, she couldn't go to kindergarten on the advice of her medical team to reduce the risk of infections that could cause sequelae. But now, for the second year, she can happily attend school and even bring her food and medicine, and she continues growing without symptoms.

For us, reaching this point has not been easy. When we were called to be informed about the result of the heel prick test, fear and uncertainty took over. The first days, months, and years were tough. We began to familiarize ourselves with specialists, routines, medications, and emergency protocols. At first, we felt like we spent the whole day focused only on making sure Núria took the amino acid formula bottles. She hated them because of the bad taste, but they were essential to ensure she got the minimum calorie intake and to approach the next day with peace of mind. It was hard to live with the anxiety of following these guidelines correctly and also the protocols explained by the doctors. In fact, Montse left her job as a doctor during the first two years of Núria's life to focus on her care.

During the first year, we were hospitalized eleven times. The admissions lasted about five days on average, and both Núria and us did not cope well with the blood tests, the nasogastric tube placement... and every time we returned home, it took us days to return to our normal routine.

But over time, fortunately, the hospital admissions have become less frequent, and Núria has been eating better every day, gradually incorporating new foods into her diet. We have also learned to incorporate appropriate logistics into our family outings, always carrying her backpack with reports, medications, and emergency protocols. We can even celebrate that, at four years old, we have resumed our hobby taking our first trip away from home, with the precaution of having a nearby GA1 reference center.

Uncertainty will always be present, but we have learned to live with it and enjoy the day-to-day.

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Amber (20) and Marijn (18) - Pyridoxine Dependent Epilepsy (PDE)

Amber (2003) and Marijn (2004) are brother and sister and both have Pyridoxine Dependent Epilepsy. To control the epilepsy associated with the disease, they take pyridoxine (vitamin B6). Amber has been given pyridoxine since birth, Marijn already received it when he was still in his mother's belly. During Amber's pregnancy, her mother felt little earthquakes in her belly. Not with Marijn.

Amber
Amber suffered her first epileptic seizure just hours after she was born.
The doctors got her stable with anti-seizure medication. After another attack, medication was used again. After three days, we had a conversation with the doctor. There we received the message: “We know that Amber has a metabolic disorder, but not which one, and as it is now, she will not live past three months”. But luckily it turned out differently.
Her treating physician had read an article about pyridoxine treatment and decided to try this. The first time Amber was given the drug, she went from a very tense position to a totally relaxed position. But the real test came after 5 days, when she had another epileptic seizure. Amber was immediately given pyridoxine intravenously and came out of the insult almost immediately and this was proof that she had PDE. From that moment on she receives pyridoxine daily.

Marijn
With Marijn it was different. The mother had been taking Pyridoxine since pregnancy, as an experiment (2004). The "earthquakes" that his mother had experienced during Amber's pregnancy did not occur during Marijn's pregnancy. Because there were no suitable tests in 2004, the doctors did not know at birth whether Marijn was ill. But to prevent Marijn from having convulsions, the intake of pyridoxine remained important.
That made him, in terms of development, a completely different child than Amber and he hadn't had an epileptic attack yet. For us as parents, that was a reason to believe that he was not ill. However, after 9 months this turned out to be not true. Marijn stayed behind in development, just like Amber, and then we already knew enough. The doctors could now prove the existence of PDE through blood tests and Marijn also appeared to have PDE.

Medication
Thanks to the medication, Amber and Marijn do not suffer from the epilepsy caused by their metabolic disease. But unfortunately, Marijn has to deal with epileptic seizures in a different way. When Marijn was over a year old, he had his first major attack. This was followed by 3 more attacks at intervals of about a year. At first this was linked to the pyridoxine, but after various investigations it turned out to be frontal epilepsy. That is why Marijn ended up at an epileptic center.
The pediatric neurologist prescribed antiepileptics (Carbamazepine) and he has not had major seizures since that time. At the age of 7 Marijn also suffered from absences for which medication (Ethymal) is required. In addition, he is allergic to various products (peanut, some fruits etc.).

Development
Amber and Marijn are doing well at the moment. Amber is a happy girl and wants to help everyone. She likes to do creative things and has an accommodating character. Marijn has also very friendly but has a different character and stands up for his own will. He also doesn't believe everything and always has a lot of questions. And he has an eye for details. It was hard work to get to this level, because Amber and Marijn have a developmental delay. Amber and Marijn both have a low IQ and a delay in mobility. They have difficulty speaking (Amber; finding words, Marijn; stuttering), require longer processing time and use short sentences. It's simple language. In the past, they have both followed various therapies, which have allowed them to develop more and more to a certain level. They have both followed special education and are now following daytime activities.

Amber and Marijn have grown into two cheerful teenagers who, with their limitations, can run well in the family. They don’t need any special tools, can walk and talk and have a great time together. We focus on the positive things and try to do as many fun things as possible.

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Katie, Glutaric Acidemia, Type 1 - Age 23

By Katie, Arnold, MO

I was diagnosed with Glutaric Aciduria Type 1 when I was 6 years old. The doctors tested me for GA1 because my 15-year-old brother had just got diagnosed. Before I was diagnosed, I had a very normal childhood and ate basically anything that I wanted to. I would complain of stomach aches, but we just thought I was being dramatic. Once I was diagnosed, I started to watch my protein intake a lot more. It was very scary being diagnosed later in my childhood because I was afraid that I would be looked at differently by my friends because I was having to watch what foods I was eating. At the time of my diagnosis, I was doing competitive cheerleading and learning how to do backflips. If someone saw me back then they would have no idea that I had a rare genetic disorder. I was an honor roll student and I took advanced classes throughout grade school to high school. Starting in 2nd grade, I started to be hospitalized at Cardinal Glennon Children’s Hospital in St. Louis, Missouri quite frequently due to throwing up and dehydration. It was tough keeping up with my school work while I was in the hospital, but I managed to keep all my grades up and I kept my friendships at school. Staying in the hospital multiple times throughout the year is what helped me decide that I wanted to be a nurse.

I am now currently a Licensed Practical Nurse and I am currently finishing my RN degree at William Penn University in Oskaloosa, Iowa. I am a part of the first graduating classes from their 4-year nursing program. I just accepted a job as a student nurse on the oncology floor at Cardinal Glennon Children’s Hospital, and I am working with a few of the nurses who took care of me as a child. I am very lucky to have had a normal childhood. I was able to continue doing cheerleading all the way until my senior year of college, and now I am also no longer on a low protein diet. I have learned that this disorder does not define my life. I am lucky to have this disorder because it just makes me unique.

An anonymous survey to answer questions about the needs of patients. Please participate!

Within CHARLIE researchers in six countries work every day to learn more about the diseases PDE and GA1. The ultimate goal is to be able to offer patients more and better treatment options. Patient involvement is an important aspect of the CHARLIE-project.

Therefore, an online- survey about the needs and opinions of patients and caretakers is waiting to be completed. We hope that many patients and caretakers will participate in the survey. The survey is totally anonymous.

The survey is available in four languages: English, German, Spanish and Dutch.

We hope that scientists, patients and caretakers will spread the word, so that many patients are able to contribute their opinions.

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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575.

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