EXPLANATION


Barth syndrome is an X-linked recessive condition that classically presents with cardiomyopathy, poor growth, neutropenia, small stature, and skeletal myopathy. It is a rare condition currently estimated to affect one in a million males worldwide. Due to its X-linked recessive classification, it almost exclusively affects males. Neutropenia may be cyclical, intermittent, or sustained and increases the risk of bacterial infections, the second most common cause of death after cardiomyopathy. Skeletal myopathy is usually non-progressive and typically affects the proximal limb muscles.


Patients commonly present during infancy with signs and symptoms of acute dilated cardiomyopathy. In male fetuses, hydrops fetalis, cardiomyopathy, and intrauterine growth fetuses are also typical of Barth syndrome. Often there is a family history of multi-generational fetal loss and/or still births of males. Often, a viral illness is the precipitating event that brings an infant to the hospital with symptoms of heart failure, making the diagnosis of Barth syndrome less obvious. Though dilated cardiomyopathy is the most common cardiac condition seen in young infants and children with Barth Syndrome, hypertrophic, restrictive, and left ventricular non-compaction cardiomyopathy may also be present in some. Patients with Barth syndrome are also at risk for ventricular arrhythmias and sudden death. A prolonged QTc interval on an electrocardiogram is evident in 25%-75% of patients. Infancy and early childhood are periods of high risk for cardiac death. Older children appear to have more stable cardiac function.


Barth syndrome is caused by a genetic defect in the TAFAZZIN gene, located on chromosome Xq28, which encodes an enzyme involved in cardiolipin remodeling. Cardiolipin (CL) is a phospholipid present on the inner mitochondrial membrane that is essential for important functions of the respiratory chain. As a result of the genetic defect, abnormal enzyme activity results in an accumulation of monolysocardiolipin (MCL). An elevation in the MCL:CL ratio is thus present in the blood and tissues of patients with Barth syndrome. An elevated MCL:CL ratio approaches 100% sensitivity and specificity for Barth syndrome. Patients are thus at increased risk of lactic acidosis and hypoglycemia due to mitochondrial dysfunction.


Management of heart failure in Barth Syndrome follows standard guidelines. Transplant is a viable option for end-stage heart failure. Morbidity and mortality after cardiac transplantation is equivalent in Barth syndrome and non-Barth syndrome patients with dilated cardiomyopathy. Skeletal muscle myopathy is generally managed with physical therapy, exercise regimens and devices to aid mobility. Although there are no currently available therapies for Barth Syndrome, elamipretide is a medication that is being reviewed by the Food and Drug Administration to treat Barth syndrome. This peptide molecule localizes to the inner mitochondrial membrane and enhances ATP synthesis.


The pre-anesthetic evaluation of patients with Barth syndrome should include a complete blood count, glucose, and carnitine levels. A recent electrocardiogram and echocardiogram should be reviewed prior to surgery. Excessive preoperative fasting should also be avoided due to the risk of hypoglycemia and lactic acidosis. Succinylcholine is contraindicated due to skeletal myopathy. Cardiac medications should be managed as for any other patient and the usual precautions should be taken if a rhythm management device is present. Sterility, aseptic technique and prophylactic antibiotics are especially important in neutropenic patients. Postoperative ventilation may be necessary for patients with significant skeletal muscle weakness.


Choice A is the correct answer due to the presentation of cardiomyopathy, hypotonia, prolonged QTc, and neutropenia, all features of Barth syndrome. Alport syndrome is a condition in which there is hearing loss and renal disease. The only cardiovascular manifestation is hypertension, secondary to renal disease. X-linked dominant, autosomal dominant and autosomal recessive forms have been described. Thrombocytopenia is associated with Alport syndrome, versus the neutropenia that is associated with Barth syndrome. Duchenne muscular dystrophy is an X-linked recessive disorder with cardiomyopathy, skeletal myopathy, and smooth muscle myopathy. Cardiac failure usually occurs later during this disease and is very unlikely to manifest in infancy as demonstrated in the stem.


REFERENCES


Taylor C, Rao ES, Pierre G, et al. Clinical presentation and natural history of Barth Syndrome: An overview. J Inherit Metab Dis. 2022;45(1):7-16. doi:10.1002/jimd.12422


Thompson R, Jeffries J, Wang S, et al. Current and future treatment approaches for Barth syndrome. J Inherit Metab Dis. 2022; 45(1):17-28. doi: 10.1002/jimd.12453.


Li Y, Godown J, Taylor CL, Dipchand AI, Bowen VM, Feingold B. Favorable outcomes after heart transplantation in Barth syndrome. J Heart Lung Transplant. 2021; 40(10):1191-1198. doi: 10.1016/j.healun.2021.06.017.


Baum VC, O’Flaherty JE. Barth syndrome. In: Baum VC, O’Flaherty JE, eds. Anesthesia for Genetic, Metabolic and Dysmorphic Syndromes of Childhood. 3rd ed. Philadelphia, PA: Wolters Kluwer; 2015:50-51.


Baum VC, O’Flaherty JE. Alport syndrome. In: Baum VC, O’Flaherty JE, eds. Anesthesia for Genetic, Metabolic and Dysmorphic Syndromes of Childhood. 3rd ed. Philadelphia, PA: Wolters Kluwer; 2015:28-29.


Baum VC, O’Flaherty JE. Duchenne muscular dystrophy. In: Baum VC, O’Flaherty JE, eds. Anesthesia for Genetic, Metabolic and Dysmorphic Syndromes of Childhood. 3rd ed. Philadelphia, PA: Wolters Kluwer; 2015:125-127.