Homozygosity for a 3 bp-deletion in BOLA3 Causes a Severe Cardiac Phenotype in Early Childhood with Lethal Outcome

Background: Due to deficient lipoate synthesis, variants within the BOLA3 gene result in a deficiency of 2-oxoacid dehydrogenases accompanied by defects of the mitochondrial respiratory chain. Patients typically show a severe and progressive multisystem phenotype with hypertrophic cardiomyopathy, white matter lesions, epilepsy, and involvement of visceral organs. Around 25 patients can be found in scientific literature. We describe the first patient with a severe phenotype and homozygosity for a 3 bp-deletion in BOLA3.

Method: We report on two siblings who showed a severe cardiac phenotype at the age of 5 and 8.5 months, respectively, both with a lethal outcome.

Results: Patient 1 presented at the age of 5 months after a seven-dose vaccination in reduced general condition, circulatory failure necessitating resuscitation, severe lactic acidosis of 22 mmol/L, and hyperammonemia. He died on the day of admission. Endomyomyocardial biopsy (EMB) revealed acute lymphocytic parvovirus B19 associated myocarditis with 80,000 copies PVB19 DNA/µg cardiac DNA. Results of genetic studies are pending. Patient 2 presented at the age of 8.5 months with hypertrophic cardiomyopathy, severely impaired pump function, rapidly developing myocardial failure, lactic acidosis of 10 mmol/L, and hyperglycinemia of 574.7 µmol/L. Sudden bradycardia requiring resuscitation was followed by implantation of venoarterial extracorporeal membrane oxygenation. As EMB was suspicious for noncompaction cardiomyopathy with unlikely recovery, a biventricular assist device was implanted to avoid failure of the right ventricle and to prepare for a heart transplant (Htx). In addition, a focal lymphocytic myocarditis was observed with CD3+ T-cells (30/mm²). At that point in time, genetic testing identified homozygosity for a 3-bp deletion (c.220_222del; p.[Glu74del]) within BOLA3. This diagnosis and associated prognosis militated against further pursuit of the plan for Htx, and the patient died after termination of life support.

Conclusion: We report a patient with homozygosity for a 3-bp deletion and sudden early lethal outcome. His genetic variant has once been described in heterozygous expression, then associated with a milder phenotype. Both siblings show the typical manifestation of an iron-sulfur (Fe-S) cluster disorder, affecting many mitochondrial functions.

Publication History

Article published online:
12 February 2022