Multiple Mitochondrial Dysfunctions Syndrome (MMDS) is a rare inborn error of metabolism resulting in defects in the late Iron-Sulfur [4Fe-4S] cluster (ISC) biogenesis protein assembly, compromising the mitochondrial capacity to produce energy. These can present as a variety of progressive clinical phenotypes that develop early in life. Subtypes of MMDS include subtype 3, resulting from bi-allelic Iron-Sulfur Cluster Assembly Factor (IBA57) mutations. The latter interacts with other ISC proteins involved in the activation of complex biochemical reactions involved in the Krebs Cycle and the insertion of respiratory complexes in the electron transfer chain. 

SUMMARY OF CASE

A 3 month-old female presented with rapidly progressive encephalopathy, and developmental regression.  Additional features included hypotonia, severe paraplegia, dysconjugate gaze, and respiratory failure. Of note, she was born from consanguineous parents. 

Initial brain MRI demonstrated confluent areas of increased white matter signals with spectroscopy showing a lactate peak with a leukodystrophy pattern. Three weeks later, a repeat MRI showed progression of white matter lesions involving the medulla, bilateral internal capsule, corona radiata, and cervical dorsal spinal cord. Genetic testing revealed a novel homozygous variant of uncertain significance, denoted c.310G>T (p.Gly104Cys) in IBA57. 

Given this patient’s devastatingly rapid progression of neurological symptoms, we hypothesize that this previously unreported variant is clinically pathogenic and associated with an ominous prognosis. Unfortunately, the patient expired weeks after her initial presentation from respiratory failure and arrest. There is currently no cure or effective treatment for this disorder. Understanding the pathophysiology of MMDS and characterizing the spectrum of clinically relevant variants may lead to better diagnostic and therapeutic interventions in the future.