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Exploring Barth Syndrome: Why does this genetic mutation change the course of life?
Bath syndrome (BTHS) is a rare but severe X-linked genetic disorder caused by changes in phospholipid structure and metabolism. The disease may affect multiple body systems, is particularly characterized by a pronounced cardiomyopathy in young children, and can be fatal. The syndrome is diagnosed almost exclusively in males.
Symptoms
The main features of Barth syndrome include cardiomyopathy (dilated or hypertrophic, possibly with left ventricular hypoplasia and/or endocardial fibroelastosis), neutropenia (chronic, cyclic, or intermittent ), muscle dysplasia and weakness, growth retardation, exercise intolerance, Heart lipid disorder, and 3-methylglutaric aciduria. These symptoms manifest themselves in different ways at birth. Most children are hypotonic at birth and show signs of cardiomyopathy within a few months of birth. Even with adequate nutrition, the disease progresses in the first year. The growth rate will also slow down.
Many people with Barth syndrome experience accelerated growth during puberty, and most achieve normal adult height.
Causes
The primary cause of Barth syndrome is a mutation in the tafazzin gene (TAZ). This gene is highly expressed in heart and skeletal muscle, and its product, Taz1p, functions as an acyltransferase in the metabolism of complex lipids. Any type of TAZ mutation (missense, nonsense, deletion, frameshift, and/or splice mutation) is strongly associated with Barth syndrome. Furthermore, the gene is located on the long arm of chromosome X at Xq28, thus presenting an X-linked nature to the disease. Some asymptomatic female carriers may go undetected for many years, but their offspring have a 50% chance of inheriting the mutated gene, causing males to develop Barth syndrome and females to become carriers.
Diagnosis
Early diagnosis of Barth syndrome is critical but difficult. The clinical presentation of this disease is extremely variable, with the only common feature being the early onset of overt cardiomyopathy. Diagnosis usually requires several tests, including blood tests (neutrophil, white blood cell count), urinalysis (increased urine organic acid levels), cardiac ultrasound (to check for abnormalities in heart structure and function), and, when there is a reasonable suspicion, In the case of Barth syndrome, genetic sequencing was performed to verify the TAZ gene status.
TreatmentThere is currently no cure for Barth syndrome, but some symptoms can be successfully managed. The University of Florida is currently conducting a clinical trial of AAV9-mediated TAZ gene replacement therapy, and preliminary studies show considerable promise. However, further research and clinical trials are needed before this gene therapy can be approved by the FDA. In the fall of 2024, the Cardiovascular and Renal Drugs Advisory Committee voted 10-6 that elamipretide is effective for this rare disease caused by mutations in the TAZ gene.
Elamipretide has been proposed as a first-in-class mitochondrial protector that could theoretically improve cardiomyocyte function, particularly in the hearts of Barth syndrome patients.Epidemiology
Because Barth syndrome is X-linked, it occurs primarily in males. The incidence of this syndrome has been reported to be estimated in the range of 1:140,000 to 1:300,000 - 1:400,000. Although cases of Barth syndrome have been reported on every continent, the incidence of the disease is likely greatly underestimated due to the complexity of early diagnosis.
History
Barth syndrome is named after Dr. Peter Barth, a Dutch pediatric neurologist who discovered the syndrome in 1983 and described it as a genetic trait rather than a contagious disease.
While there is increasing awareness of Barth syndrome, with many patients showing significant improvement after puberty, research into potential gene therapies continues. To what extent can such a genetic mutation affect a person's life?
