FBXL4-Related Mitochondrial DNA Depletion Syndrome 13 (MTDPS13): A Case Report With a Comprehensive Mutation Review

Abstract

Mitochondrial DNA depletion syndromes (MTDPS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA (mtDNA) maintenance. Among those, FBXL4 mutations result in the encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13; OMIM #615471), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, and persistent lactic acidosis. We report here the case of a Lebanese infant presenting to us with profound neurodevelopmental delays, generalized hypotonia, facial dysmorphic features, and extreme emaciation. Whole-exome sequencing (WES) showed the girl as having MTDPS13 with an underlying FBXL4 missense mutation that has been previously reported only twice in unrelated individuals (c.1303C > T). Comprehensive literature search marked our patient as being the 94th case of MTDPS13 reported to date worldwide, and the first from Lebanon. We include at the end of this report a comprehensive mutation review table of all the pathological FBXL4 mutations reported in the literature, using it to highlight, for the first time, a possible founder effect of Arab origins to the disorder, being most prevalent in patients of Arab descent as shown in our mutation table. Finally, we provide a direct comparison of the disorder's clinical manifestations across two unrelated patients harboring the same disease-causing mutation as our patient, emphasizing the remarkable variability in genotype-to-phenotype correlation characteristic of the disease.

Unusual Presentation of Mitochondrial Depletion Syndrome Related to FBXL4: A Case Report

“…The present case was similar in presentation with Bonnen et al but cardiomyopathy, signs, sensory-neuronal hearing impairment, cataract and optic atrophy were preserved [1]. On the other hand, expected survival time was extended more than infancy and had lower complications (anemia, leukopenia and hypoalbuminemia) like the case reported by Ballout et al (Table 3) [6]. This emphasizes the remarkable variability in genotype-tophenotype correlation characteristic of this disease.…”

“…Among those is FBXL4 mutation. To the best of author's knowledge, this patient represented the 95 th case of Mitochondrial DNA Depletion Syndrome 13 (MTDPS13) related to pathogenic mutation in FBXL4 in a 3 years old Saudi girl worldwide [6]. Majority of this genotype were presented at birth with lactic acidosis, severe hypotonia, encephalopathy, epilepsy, kyphosis/scoliosis, cardiomyopathy, poor neurodevelopmental outcome, growth retardation, mildly craniofacial dysmorphic features, and mortality during infancy [7].…”

“…This article provides a comparison of the presented case with all FBXL4deficient cases, which have been reported in the previous literature to act as a future mutation reference table for updates and association studies [6].…”

Metabolite Genome-Wide Association Study (mGWAS) and Gene-Metabolite Interaction Network Analysis Reveal Potential Biomarkers for Feed Efficiency in Pigs

“…FBXL4 is considered to participate in oxidative phosphorylation, mitochondrial dynamics, cell migration, prostate cancer metastasis, circadian GABAergic cyclic alteration, etc. [35][36][37][38][39]. The association results in pigs found that blood and immune traits were associated with the SNPs of FBXL4 [40].…”

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

“…Skeletal muscle commonly shows mitochondrial dysfunctions with combined deficiencies of multiple OXPHOS complexes and mtDNA depletion. Patient’s fibroblasts typically display fragmented mitochondria and combined deficiencies of multiple OXPHOS complexes [ 98 , 99 , 100 , 101 , 130 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ].…”