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The heart of the matter: Elamipretide in the treatment of Barth syndrome

First diagnosed in 1983 by Dr Peter Barth, Barth syndrome (BTHS) is a genetic disease affecting the X sex chromosome, meaning the disease is commonly passed down from mother to son... The failure of current medications to treat the underlying cause of the disease is well recognised, with most therapies only treating the symptoms. Over the last decade, Dr Hani N Sabbah, Professor of Medicine at Wayne State University and Professor of Medicine Research at Michigan State University, USA, has contributed significantly to the study of this field, highlighting and researching a new drug candidate – elamipretide – that can target the mitochondrial pathology in patients with BTHS.

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 This Microchip Heart Has A Rare Genetic Disease

It doesn’t look much like a heart, but it works—a little bit—like one. Researchers have created a microchip heart that has a rare genetic disease. Using the chip, the researchers were able to learn some basics about the disease, called Barth syndrome, that scientists didn’t know before. These results are a step forward for Barth syndrome research, of course. The syndrome, usually found in boys, causes enlarged, weakened hearts; muscle weakness; and immune system trouble. It has no cure. The research also happens to show off a fascinating application for organs-on-a-chip, a technology that engineers developed in recent years to study human biology in an entirely new way.

 Traditional randomized trials don’t work for ultra-rare diseases like Barth syndrome

Another ultra-rare therapy will soon be subject to the gaze of an FDA advisory committee, with the fate of more than 200 boys diagnosed with Barth syndrome worldwide in the balance. On Thursday, the FDA cardiovascular and renal drugs advisory committee will be reviewing a new drug application for elamipretide hydrochloride injection, submitted by Stealth BioTherapeutics Inc., for the treatment of Barth syndrome. Barth syndrome is a rare, one in a million X-linked genetic disease of the Tafazzin (TAZ) gene, which impacts cardiolipin, an essential lipid in the mitochondria needed for energy creation. The boys affected by Barth syndrome get sick very early in life with cardiac failure and other muscle-related symptoms and, like other ultra-rare diseases, there hasn’t been any therapeutic option available to them. Their only hope is a heart transplant.

Articles of Interest

Born with Barth Syndrome and Beating the Odds

When Barth syndrome was mentioned to us I used the internet to try and gather some information. I was terrified by what I discovered. I remember reading, among other things, that Barth syndrome was associated with high infant mortality. I know it was a little while before I could face doing any more research. I then reached out to the Barth Syndrome Foundation and with that we found instant friends, family, support and acceptance. When your child is very ill friends and family often pull away not knowing what to say or how to act. The experience can be very isolating as it is difficult for others to understand what you are going through. We attended our first Barth syndrome conference in 2006. I think we experienced every emotion – we laughed and we cried, but we learnt so much. The information we gathered at the conference allowed us to come home and advocate for the best care for Cameron.

Our Barth Journey

In 2006, after watching an episode of Discovery Health Channel’s “Mystery Diagnosis” that featured Barth syndrome, I immediately got in contact with the mother of the affected boys featured on the show, Shelley Bowen. She urged me to look further into genetic testing; upon receipt of the earlier results, a mutation had been found on the G4.5/TAZ Gene. Mutations in this gene are known to cause Barth syndrome, the leading genetic cause for infantile dilated cardiomyopathy in boys

Symptoms of Barth syndrome

You’re going to quickly become an expert in this condition. Here are the basics.

Barth Syndrome

Barth syndrome is caused by mutations in the TAZ gene. This gene provides instructions for making a protein called tafazzin. Tafazzin is essential for the production of cardiolipin, a specialized type of fat found in the mitochondria (the energy-producing parts of cells). Mutations in TAZ disrupt the production of cardiolipin, leading to the problems associated with Barth syndrome.

Barth syndrome breakthrough: Rare disease research fueled by determined family and scientists

Because Barth syndrome is rare and life-threatening — most patients eventually require heart transplants — the successful development of the patient-derived mouse model is a major advancement for future research and finding a cure. The model enables scientists to study the disease’s influence on neutrophils, skeletal muscles and the heart in ways that previously seemed impossible.

Barth Syndrome Cardiomyopathy: An Update

Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease.

Barth syndrome: A life-threatening disorder caused by abnormal cardiolipin remodeling

Barth syndrome (BTHS) is a rare X-linked genetic disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, and organic aciduria. The presence and severity of clinical manifestations are highly variable in BTHS, even among patients with identical gene mutations. Currently, less than 200 patients are diagnosed worldwide, but it is estimated that the disorder may be substantially under-diagnosed due to the variable spectrum of clinical manifestations.

Barth syndrome: A potential treatment for a rare disease

Barth syndrome is a rare disorder in males caused by a variant of the gene TAFAZZIN. It affects the metabolism of the fat molecule cardiolipin in mitochondria, resulting in the dysfunction of skeletal muscle and the heart. The syndrome doesn’t have a specific therapy, so patients who suffer from it have health problems their entire lives and are more likely to die as a result of heart problems.

Barth Syndrome: Gene Therapy Offers Hope, But Challenges Remain for Rare Genetic Disorder

Barth syndrome is an X-linked metabolic disorder, affecting only males. It has widespread systemic effects presenting with cardiomyopathy, neutropenia, muscle weakness, stunted growth, exercise intolerance, and abnormal skeletal structures. In many cases, it results in stillbirth. It is strongly related to mutations in the tafazzin gene, also known as TAZ. Currently, only symptomatic treatment exists, and no definite cure has been developed for Barth syndrome.

Current and future treatment approaches for Barth syndrome

Management requires a multidisciplinary approach to the organ-specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted toward remediating the underlying biochemical defect.

The diagnostic odyssey, clinical burden, and natural history of Barth syndrome: an analysis of patient registry data

Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, complex, multi-system X-linked disorder that arises from pathogenic mutations in the gene TAFAZZIN. BTHS is characterized by cardiomyopathy, skeletal myopathy, muscle weakness, and neutropenia. To better understand the natural history and lived experience of affected individuals, the Barth Syndrome Foundation maintains the patient-inputted Barth Syndrome Registry and Repository

Understanding the life experience of Barth syndrome from the perspective of adults: a qualitative one-on-one interview study

Barth syndrome (BTHS, OMIM 302060) is a rare, life-threatening, x-linked genetic disorder that occurs almost exclusively in males and is characterized by cardiomyopathy, neutropenia, skeletal muscle myopathy primarily affecting larger muscles, and shorter stature in youth.

What is Barth Syndrome?

Barth syndrome is a rare, genetic, mitochondrial disorder causing metabolic abnormalities that can lead to an enlarged and weakened heart (cardiomyopathy), muscle weakness and fatigue (skeletal muscle myopathy), low levels of certain white blood cells that can lead to recurrent infections (neutropenia), growth delay that potentially can lead to short stature, and increased levels of 3-methylglutaconic acid in the urine and blood. The disease affects primarily males

Resources

Elamipretide

Barth syndrome, or Barth, is characterized by skeletal muscle weakness, delayed growth, fatigue, varying degrees of physical disability, heart muscle weakness, or cardiomyopathy, low white blood cell count, or neutropenia (which may lead to an increased risk for bacterial infections), and methylglutaconic aciduria (which is an increase in an organic acid that results from abnormal mitochondria function). The incidence of Barth is estimated to be between one in 300,000 to 400,000 births. There are no therapies approved by the FDA or the EMA for treating Barth. We have received Fast Track and Orphan Drug designation from the FDA for the development of elamipretide in this indication. The U.S. Food and Drug Administration (“FDA”) is currently reviewing a New Drug Application (“NDA”) for elamipretide for the treatment of Barth syndrome with a user fee act date in early 2025.

Barth Syndrome Foundation

We work continuously to raise public awareness and generate additional support among individuals, community organizations of similitude, and the medical community. Up-to-date information on Barth syndrome-- from medical issues to daily living issues — is available on-line. We also provide print publications and video coverage of our international scientific, medical and family conferences, and through our website we communicate globally.

Barth Syndrome Foundation of Canada

We are a nation-wide, entirely volunteer-based, charitable organization (registered charity number 86102 2002 RR0001) that works to find treatments, causes and a cure for Barth syndrome (BTHS). While independent, we are an affiliate of the Barth Syndrome Foundation, Inc. (BSF), and together we share a vision for a world in which not one more person shall suffer or perish from Barth syndrome.

Barth Syndrome UK

Saving lives through education, advances in treatment and finding a cure for Barth syndrome

Barth Syndrome

Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur.

Barth Syndrome Clinic

The Barth Syndrome Clinic at Kennedy Krieger Institute is an interdisciplinary clinic dedicated to the diagnosis and treatment of Barth syndrome. Barth syndrome is a rare X-linked genetic disorder caused by the deficiency of a complex lipid called cardiolipin. Because cardiolipin is the major phospholipid of mitochondria, the elements of cells that make energy, many systems in the body can be affected.

BrainFacts.org

Barth syndrome (BTHS) is a rare, genetic disorder of lipid metabolism that primarily affects males. It is caused by a mutation in the tafazzin gene (TAZ, also called G4.5) which leads to decreased production of an enzyme required to produce cardiolipin. Cardiolipin is an essential lipid that is important in energy metabolism.