Multisystem fatal infantile disease caused by a novel homozygous EARS2 mutation

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features

“…To date, 26 patients are reported with LTBL (12 by Steenweg et al (2012), one by Talim et al (2013), two by Taylor et al (2014), one by Biancheri et al (2015), one by Kohda et al (2016), one by Kevelam et al (2016), one by Danhauser et al (2016), one by Taskin et al (2016), one by G€ ung€ or et al (2016), two by Şahin et al (2016) and two by Pronicka et al (2016)), with our patient being the 26th reported patient. The phenotype of our patient fits the severe group of LTBL patients, mostly due to signs of perinatal presentation of the disease and rapid decline of her clinical status.…”

“…Due to the rapid and fatal disclosure, neuroimaging alone was insufficient to predict the outcome of our patient, but she had signs of neurodevelopment compromise such as hypotonia. She had a fatal course that was similar to patients reported by Talim et al (2013) and Danhauser et al (2016). Unfortunately none of these reports had brain MR reports and images available for comparison, except for corpus callosum dysgenesis and agenesis, described for each patient on brain MR and brain sonogram, respectively.…”

“…Although liver respiratory chain activity was normal, there was evident liver dysfunction. Liver involvement was also described in six additional EARS2 patients, which included one or more of neonatal transient icterus, hepatomegaly, fatty liver and steatosis (Steenweg et al 2012;Talim et al 2013;Taylor et al 2014;Pronicka et al 2016). Post-mortem examination of the liver from the patient reported by Talim et al (2013) also found COXdeficiency.…”

“…In total, only five patients have been reported with homozygous pathogenic EARS2 variants, presenting forms of LTBL with different clinical outcomes. One patient each from Talim et al (2013) and Taylor et al (2014) had a homozygous c.193A>G (p.Lys65Glu) missense change affecting a well conserved residue, and had a severe and fatal form of the disease. The patient presented by Biancheri et al (2015) with a homozygous c.902G>C (p.Gly301Ala) missense change was described as having an intermediate form of LTBL.…”

LARS2 Variants Associated with Hydrops, Lactic Acidosis, Sideroblastic Anemia, and Multisystem Failure

“…A range of compound heterozygous variants in EARS2 result in leukoencephalopathy with thalamus and brainstem involvement and high lactate (Steenweg et al 2013). In one case with a homozygous EARS2 variant in the catalytic domain, the patient had a multisystem fatal disease characterized by severe failure to thrive, intractable lactic acidosis, mitochondrial myopathy, and hepatopathy, resulting in death at 3 months of age (Talim et al 2013). For some genes there appears to be a correlation between the severity of the variant and the outcome of the disease, while in others it appears that other genetic and/or environmental factors contribute to the phenotypic variability.…”