A Mild Phenotype of Mitochondrial DNA Depletion Syndrome Type 13 with a Novel FBXL4 Variant

Abstract

Mitochondrial DNA depletion syndromes (MDDS) are a group of rare genetic disorders caused by defects in multiple genes involved in mitochondrial DNA maintenance. Among these, FBXL4 gene variants result in encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), which commonly presents as a combination of failure to thrive, neurodevelopmental delays, encephalopathy, hypotonia, a pattern of mild facial dysmorphisms, and persistent lactic acidosis. To date, 53 pathogenic FBXL4 variants and 100 cases have been described in the literature. In the present case report, we report on a 4.5-year-old boy with MTDPS13 and a novel variant. The patient had a history of antenatal hydrocephalus, severe developmental delay and mental motor retardation with psychomotor delay, severe hypotonia, mild left ventricular hypertrophic cardiomyopathy, mild facial dysmorphism, and elevated lactate levels. Symptoms suggested mitochondrial myopathy; subsequently, whole-exome sequencing was performed and a novel homozygous variant FBXL4 (NM_012160.4): c.486T>G (p.Tyr162Ter) was identified. While most of the patients with FBLX4 gene mutation have severe clinical manifestation and die at a very young age, clinical progress of our case was milder than previously reported. MDDS are very rare and can present with many different clinical signs and symptoms. In this report, we identified a novel pathogenic variant in the FBXL4 gene. This report shows that patients with FBLX4 gene mutations may present with a milder clinical phenotype than previously reported.

Keywords: Encephalopathy; FBXL4; Mitochondrial DNA depletion; Myopathy, MTDPS13; mtDNA depletion syndrome.

Fig. 1

a Pedigree of the patient. b Facial frontal view of our patient at age 4.5 years showing prominent and broad forehead and a metopic ridge, thick eyebrows, short palpebral fissures, epicanthic folds, a broad nasal bridge, smooth philtrum, a small chin, and strabismus.

Fig. 2

Brain magnetic resonance spectroscopic imaging findings of our patient at the age of 1 year was obtained at intermediate echo-time by single-voxel 1H magnetic resonance spectroscopy of the right basal ganglia (red square). An inverted doublet lactate peak at 1.3 ppm was defined.

Fig. 3

Screenshot of a novel homozygote FBXL4 (NM_012160.4) c.486T>G mutation analysis by IGV 2.3 (Broad Institute) software. The sequence is represented by colored letters with adenine in green, cytosine in blue, guanine in yellow, and thymine in red (A, C, G, T).