Introduction

Barth syndrome is a genetic condition that affects boys and is known for causing problems in the way the body makes and uses certain fats in the energy-producing parts of cells, called mitochondria. This can lead to a variety of health issues, including low levels of a type of white blood cell called neutrophils, which are important for fighting infections.

People with Barth syndrome often experience problems such as weak muscles, heart issues like an enlarged heart, delays in physical development and growth, and difficulties with feeding. The condition is caused by mutations in a gene called Tafazzin (TAZ), which leads to a loss of function in this gene. As a result, individuals with Barth syndrome may have difficulties with energy production in their cells, leading to a range of symptoms associated with the condition.

Because Barth syndrome follows an X-linked recessive pattern, it primarily affects boys. Girls can also carry the genetic mutation responsible for the condition but typically do not show symptoms themselves. Early diagnosis and management of Barth syndrome are important for providing appropriate medical care and support to affected individuals.^1,2

Pathophysiology

Barth syndrome arises from mutations in the TAZ gene, affecting cardiolipin, a lipid crucial for mitochondrial function. Normally, cardiolipin has specific fatty acid configurations, especially in high-energy tissues like the heart and muscles. TAZ mutations disrupt this process, reducing the formation of tetralinoleoyl cardiolipin (L4-CL) and increasing intermediate forms like monolysocardiolipins (MLCL).

This imbalance, characterized by a higher MLCL:L4-CL ratio, contributes to mitochondrial dysfunction observed in Barth syndrome. Cardiolipin plays vital roles in maintaining mitochondrial structure, facilitating energy production, and regulating cell death. Dysfunctional cardiolipin leads to mitochondrial abnormalities, affecting cellular energy metabolism and integrity.

Diagnostic tests detecting abnormal cardiolipin profiles aid in Barth syndrome diagnosis, emphasizing the importance of understanding lipid metabolism in mitochondrial disorders.^3,4

Clinical features

Barth Syndrome manifests with muscle weakness, fatigue, and cardiac abnormalities such as cardiomyopathy and arrhythmias. Growth delays and recurrent infections are common, alongside low muscle tone and feeding difficulties in infancy. Some individuals may display subtle facial features and delayed development. Early diagnosis and management are crucial for optimizing quality of life.⁵

Neutropenia

Neutropenia, a condition characterized by low levels of a type of white blood cell called neutrophils, is a common feature in Barth Syndrome (BTHS). It affects around 90% of BTHS patients, but some may have normal neutrophil counts over extended periods. Interestingly, around 30% of cases don't show neutropenia at first. Neutropenia can vary in severity, ranging from chronic and severe to intermittent and unpredictable.

Drops in neutrophil counts are often linked to bacterial infections, ranging from mild respiratory issues to severe sepsis. Diagnosis of BTHS can be challenging as neutrophil counts may normalize during infections. In BTHS, neutropenia is associated with abnormalities in bone marrow and compensatory increases in monocytes.⁶

Understanding the role of Tafazzin in myeloid progenitor cells: implications for neutropenia and infection risk

Recent research has found that when the TAZ gene is suppressed, it leads to an increase in the size of heart muscle cells (cardiomyocyte hypertrophy) along with decreased levels of a lipid called cardiolipin and reduced ATP production in mitochondria, the energy-producing units of cells. However, the effects of TAZ gene loss on myeloid progenitor cells, which are involved in the production of certain types of white blood cells, have been less understood.⁷

To better understand this, researchers developed an experimental model by reducing TAZ gene expression in human myeloid progenitor cells using specific molecules called TAZ-specific shRNAs. They observed that this led to abnormal changes in the mitochondria, including loss of membrane potential and increased cell death (apoptosis) in certain myeloid progenitor cell lines but not in lymphoid cell lines. This cell death was found to be linked to the abnormal release of a protein called cytochrome c from the mitochondria and the activation of a protein called caspase c, which plays a role in cell death processes.⁸

Importantly, when the researchers inhibited the activity of caspase using a specific inhibitor called zVAD-fmk, they observed a significant reversal of the increased cell death in the myeloid progenitor cells. This suggests that Tafazzin, the protein encoded by the TAZ gene, normally acts to prevent cell death in myeloid progenitor cells, and deficiencies in this protein can lead to increased apoptosis of these cells. This, in turn, could contribute to neutropenia (low levels of certain white blood cells) and increase the risk of recurrent bacterial infections in individuals with Barth syndrome.^7,8

Epidemiology

In 2012, the Barth Syndrome Foundation (BSF) knew of 151 living patients worldwide. In the USA, about 10 new cases are found each year, and researchers have identified 71 families affected by the condition. Overall, Barth syndrome is estimated to occur in about 1 in every 300,000 to 400,000 births. It doesn't seem to favour any specific race or ethnic group.⁴

Recent findings

In a study involving 88 patients with Barth syndrome, about 84% of them were found to have low levels of neutrophils, which are crucial for fighting infections. Nearly 44% of these patients had a severe and chronic form of this condition, with repeated measurements showing very low neutrophil counts.

The pattern of neutrophil levels varied among the patients, sometimes appearing intermittently, sometimes chronically, and sometimes following a regular cycle of ups and downs. Additionally, around 75% of the patients experienced elevated levels of another type of white blood cell called monocytes, which can also play a role in the body's immune response.¹

Diagnosis

Diagnosing Barth Syndrome historically relied on identifying a specific trio of symptoms: heart and skeletal muscle issues, neutropenia (low neutrophil levels), and elevated levels of 3-methylglutaconic acid (3-MGCA) in urine. However, this approach had limitations as some patients didn't present with neutropenia, and 3-MGCA levels could be within normal ranges or missed by labs. Recent advancements include a diagnostic test measuring the MLCL:L4-CL ratio, which has shown 100% accuracy in diagnosing Barth Syndrome. This test is more accessible and cost-effective compared to genetic testing.

It's recommended for males with unexplained dilated cardiomyopathy, especially in infancy. Abnormal results can prompt further genetic testing for TAZ mutations. Commercial mutation screening panels for cardiomyopathy often include TAZ mutation screening. Additionally, stored tissue samples can aid retrospective diagnosis through cardiolipin ratio testing or genetic analysis.^4,9

Treatment

Patients with symptomatic neutropenia due to Barth Syndrome are typically treated with subcutaneous granulocyte colony-stimulating factor (G-CSF) and prophylactic antibiotics. G-CSF is usually started at a dose of 2–3 μg/kg/dose, administered either twice weekly or on alternate days, depending on the severity of neutropenia and associated infections.

The goal is to increase the average neutrophil count rather than to normalize it completely, as complete normalization can cause major neutrophilia due to the variable neutrophil counts in Barth Syndrome patients. Treatment with G-CSF often leads to significant symptomatic improvements, such as fewer mouth ulcers, reduced gum soreness, and fewer bacterial infections.¹⁰

Prophylactic antibiotics are commonly used to lower the risk of serious infections, especially in boys who experience intermittent neutropenia and are not on G-CSF. No specific drug or dietary supplement has shown conclusive benefits for Barth Syndrome. The efficacy of pantothenic acid is unproven, and some patients have worsened with L-carnitine supplementation.¹⁰

Managing Barth Syndrome involves a multidisciplinary approach, including care from physiotherapists, occupational therapists, speech and language therapists, psychologists, and educational support workers. Specialized clinics are best suited to provide comprehensive care for patients with this complex disease.⁶

Research gap

Despite significant advances in understanding Barth Syndrome (BTHS), many questions remain unanswered. Key areas of uncertainty include the variability in clinical severity with age among individual patients and between family members, as well as the lack of a clear correlation between genotype and phenotype. The exact mechanism by which altered cardiolipin metabolism leads to BTHS is still not fully understood. This gap in knowledge complicates the understanding of unique BTHS features such as the unpredictable nature of neutropenia, the fluctuating severity of cardiomyopathy, and persistent growth delays.

Summary

Barth Syndrome is a rare genetic disorder affecting boys, characterized by issues with energy production in cells, leading to symptoms like muscle weakness, heart problems, and growth delays. The condition results from mutations in the TAZ gene, impacting cardiolipin metabolism, crucial for mitochondrial function.

Diagnosing Barth Syndrome has improved with advanced tests measuring cardiolipin ratios, offering accurate and cost-effective identification. Treatment mainly involves managing neutropenia with G-CSF and antibiotics to prevent infections. Despite these advances, many questions remain about the variability of symptoms and the exact mechanisms of the disease.

No definitive treatments or dietary supplements have proven effective beyond supportive care. A multidisciplinary approach involving various specialists is essential for comprehensive management. Ongoing research is crucial to better understand and address the complexities of Barth Syndrome, aiming to improve the quality of life for affected individuals.