Background. The recently described FBXL4-related encephalomyopathic mitochondrial DNA depletion syndrome 13 (MTDPS13) manifests with severe encephalopathy, early-onset lactic acidosis, hypotonia, developmental delay and feeding difficulty. Less than 100 cases with FBXL4-related MTDPS13 and 47 pathogenic mutations in the FBXL4 gene have been identified thus far. Here, we describe a patient diagnosed with MTDPS13 with two novel variants of the FBXL4 gene.

Case. A 51-day-old male was admitted with the complaint of bloody stool. His physical examination revealed facial dysmorphic features, developmental delay and truncal hypotonia with lack of head control. Laboratory investigations showed anemia, neutropenia, metabolic acidosis with hyperlactatemia, elevated fumaric acid, 2-ketoglutaric acid in urine and elevated alanine level in plasma which were consistent with mitochondrial dysfunction. Brain magnetic resonance imaging (MRI) showed large ventricles, thin corpus callosum and poor myelination. Drug-resistant epilepsy developed during the clinical follow-up. Ketogenic diet was initiated for intractable epilepsy; which was then interrupted due to severe metabolic acidosis. Compound heterozygous pathogenic variants were detected in the FBXL4 gene [p.Gly258* (c.772G > T, Exon 5)/p.Trp354Ser (c.1061G > C, Exon 6)] with whole-exome sequencing.

Conclusion. We detected two novel variants of the FBXL4 gene. To the best of our knowledge, this is the first case in the literature that presented with gastrointestinal bleeding as an encephalomyopathic form of mitochondrial DNA depletion syndromes and for whom ketogenic diet was initiated due to intractable epilepsy, which was not reported in previous cases.

Keywords: FBXL4, MTDPS13, novel variants