Cardiac pathology in a patient with a novel pathogenic variant c.703del (p.Ile235SerfsTer4) of the TAFAZZIN gene

Barth syndrome is a mitochondrial disease caused by loss-of-function mutations in the TAFAZZIN gene located on chromosome Xq28 encoding a transacylase essential for cardiolipin remodeling. Most patients develop dilated cardiomyopathy and progressive heart failure within the first year of life with some requiring cardiac transplantation.

A full-term male infant with an anatomically normal heart presented postnatally with cardiogenic shock necessitating VA-ECMO within the second day of life. WGS revealed a pathogenic c.703del (p.Ile235SerfsTer4) variant in the TAFAZZIN gene. While on the waitlist for cardiac transplantation, he was treated with intravenous Elamipretide, a mitochondrially-targeted tetrapeptide interacting with cardiolipin, without significant side effects, started at three weeks old and continued through transplantation. He underwent a successful orthotopic cardiac transplantation at five months of age. The explanted heart showed dilated left ventricle with hypertrabeculation and was remarkable for endocardial fibroelastosis and diffuse sarcoplasmic vacuolization with coarse granularity. Ultrastructurally, mitochondria displayed megaconia and replacement of cristae by circular, vesicular, cylindrical, and fingerprint-like structures. He continues to do well as an outpatient and remains on subcutaneous Elamipretide.

We describe a case of Barth syndrome harboring a novel pathogenic variant of the TAFAZZIN gene exhibiting dilated cardiomyopathy, hypertrabeculation, endocardial fibroelastosis, and prominent mitochondrial abnormality. Elamipretide was well tolerated.