Early-Onset Mild Type Leukoencephalopathy Caused by a Homozygous EARS2 Mutation

Abstract

Childhood leukoencephalopathies are a broad class of diseases, which are extremely rare. The treatment and classification of these disorders are both challenging. Nearly half of children presenting with a leukoencephalopathy remain without a specific diagnosis. Leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) is a newly described childhood leukoencephalopathy caused by mutations in the gene encoding a mitochondrial aminoacyl-tRNA synthetase specific for glutamate, EARS2 Magnetic resonance images show a characteristic leukoencephalopathy with thalamic and brain stem involvement. Here, we report a different clinical course of LTBL supported by typical MRI features in a Turkish patient who presented with a history of failure to walk. The EARS2 gene mutation analysis identified a c.322C>T transition, predicting a p.R108W change. This is the first reported early-onset mild type LTBL caused by a homozygous EARS2 mutation case in the literature.

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.…”

“…The collective findings of symmetrical signal changes of the deep white matter (usually sparing the periventricular rim), thalami and brainstem together with increased lactate on MRS is the hallmark of LTBL. In patients described with either mild (Biancheri et al 2015;G€ ung€ or et al 2016;Taskin et al 2016;Şahin et al 2016) or severe disease (Steenweg et al 2012;Kevelam et al 2016), the clinical presentation appeared to correlate with the severity of neuroimaging at each stage of this biphasic disease. However, lesions of the main structures involved were not different between patients in each group of severity, except for the significant improvement without new lesions of brain MR/MRS associated with the mild-intermediate forms.…”

“…The relative immature brain associated with a slight delay in myelination limited the evaluation of possible involvement of the cerebral white matter in our patient. Nevertheless, no obvious signal abnormality of the supratentorial white matter was found, namely the spared periventricular rim described in older patients (Steenweg et al 2012;Biancheri et al 2015;Kevelam et al 2016;G€ ung€ or et al 2016;Taskin et al 2016;Şahin et al 2016).…”

“…The patient from Kevelam et al (2016) had a homozygous c.454_456del (p.Lys152del) in-frame deletion of a highly conserved residue, which presented as a severe form of disease, and was alive at the time of publication (aged 18 years). The fifth patient from Taskin et al (2016) had a homozygous c.322C>T (p.Arg108Trp) missense change and presented a mild phenotype. Compound heterozygous changes were identified in three additional patients as part of large-scale WES studies but without specific details of phenotypes for comparison (Kohda et al 2016;Pronicka et al 2016).…”

Brain MRI in mitochondrial disorders

“…The same genetic mutations have shown to cause diseases with variable clinical course. 191 It is worthwhile to look for anatomical factors or patterns on MRI, which determine the variable clinical course in diseases caused by the same mutations. More comprehensive and descriptive imaging studies are available to achieve this.…”