Fatal cardiomyopathy and hepatic dysfunction with acute onset due to mitochondrial trifunctional protein deficiency diagnosed by whole exome sequencing

E. Bratila, R. Stanculescu, M. Cirstoiu, D. Comandasu

Abstract: In this paper we report the postmortem identification of a rare disorder of mitochondrial fatty acid β-oxidation in a neonate patient which presented with clinical manifestations of cardiomyopathy and hepatic dysfunction which caused his death. The baby, born by caesarean section at term, presented at the age of eight months following a respiratory viral infection with a severely impaired general condition culminating with multiple organ failure and subsequent death in 10 days. Next-generation-sequencing of genomic deoxyribonucleic acid (DNA) isolated from an archived umbilical cord blood sample revealed two heterozygous point mutations within exons 14 and 15 of the 3-hydroxyacyl-CoA dehydrogenase (HADHA), encoding the α-subunit of the mitochondrial trifunctional protein (MTP), which were subsequently confirmed by targeted polymerase chain reaction and conventional DNA capillary sequencing. MTP is an enzyme complex which catalyzes three steps in mitochondrial β-oxidation of fatty acids: enoyl-CoA hydratase, HADHA/HADHB, and 3-ketoacyl-CoA thiolase. Deficiency of this heterocomplex containing 4α and 4β subunits causes sudden infant and neonate death, Reye-like syndrome, cardiomyopathy, hepatic dysfunction and skeletal myopathy. We determined the molecular basis of the deficiency in our patient with neonatal presentation and later sudden death, and also tested the patient’s parents for the same defect, which turned out to be both heterozygous carriers of a mutation within the HADHA gene, associated with the autosomal recessively inherited fatty acid oxidation disorder called MTP deficiency. After the death of their first infant they gave birth to a second baby, which was also tested for this deficiency and was diagnosed also as a heterozygous carrier for the same HADHA deficiency.
DOI:10.18643/gieu.2015.8

Keywords: mitochondrial trifunctional protein deficiency, infant death, cardiomyopathy, hepatic dysfunction.