Leukoencephalopathy with thalamus and brainstem involvement and high lactate caused by novel mutations in the EARS2 gene in two siblings

Şahin, Sevim; Cansu, Ali; Kalay, Ersan; Dinçer, Tuba; Kul, Sibel; Çakır, İsmet Miraç; Kamaşak, Tülay; Budak, Gülden Yorgancıoğlu

doi:10.1016/j.jns.2016.04.008

Cited by 16 publications

(11 citation statements)

References 11 publications

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“…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.…”

Section: Discussionmentioning

confidence: 96%

“…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).…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2016

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Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

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

et al. 2016

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“…Solid line indicates dominant mode of inheritance, dashed line indicates recessive mode of inheritance. References: AARS , DARS , HARS , IARS MARS , RARS , S ARS , W ARS , ARS , QARS , GARS , KARS , AARS 2 , CARS 2 , DARS 2 , EARS 2 , FARS 2 , HARS 2 , IARS 2 , LARS 2 , MARS 2 , NARS 2 , PARS 2 , RARS 2 , S ARS 2 , TARS 2 , VARS 2 , WARS 2 , YARS 2 .…”

Section: Mitochondrial Trna Synthetases (Ars2 Genes)mentioning

confidence: 99%

“…A large number of autosomal recessive disorders specifically affect the brain, and result in lesions of certain neuronal cell types. The most typical clinical presentations are leukoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL) due to DARS2 mutations , leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) caused by EARS2 mutations , but other mt‐ARS mutations may also cause white matter lesions. Mutations within the AARS2 gene result in two different phenotypes: late onset ovarian failure and leukodystrophy and infantile mitochondrial cardiomyopathy .…”

Section: Mitochondrial Trna Synthetases (Ars2 Genes)mentioning

confidence: 99%

The role of tRNA synthetases in neurological and neuromuscular disorders

2018

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Aminoacyl‐tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNAs with their cognate amino acids, therefore essential for the first step in protein synthesis. Although the majority of protein synthesis happens in the cytosol, an additional translation apparatus is required to translate the 13 mitochondrial DNA‐encoded proteins important for oxidative phosphorylation. Most ARS genes in these cellular compartments are distinct, but two genes are common, encoding aminoacyl‐tRNA synthetases of glycine (GARS) and lysine (KARS) in both mitochondria and the cytosol. Mutations in the majority of the 37 nuclear‐encoded human ARS genes have been linked to a variety of recessive and dominant tissue‐specific disorders. Current data indicate that impaired enzyme function could explain the pathogenicity, however not all pathogenic ARSs mutations result in deficient catalytic function; thus, the consequences of mutations may arise from other molecular mechanisms. The peripheral nerves are frequently affected, as illustrated by the high number of mutations in cytosolic and bifunctional tRNA synthetases causing Charcot–Marie–Tooth disease (CMT). Here we provide insights on the pathomechanisms of CMT‐causing tRNA synthetases with specific focus on the two bifunctional tRNA synthetases (GARS, KARS).

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“…Pathogenic variants of mt-ARS will affect mitochondrial translation and have been implicated in human neurological disorders of the brain, spinal cord and motor neurons in addition to other symptoms. Some of the most typical presentations are leukoencephalopathy with involvement of the brainstem and spinal cord and high lactate due to mt-aspartyl-tRNA synthetase (DARS2) mutations 150, leukoencephalopathy with thalamus and brainstem involvement and high lactate, caused by mt-glutamyl- tRNA synthetase (EARS2 151). However, there are other mt-ARS mutations which may also produce white matter lesions.…”

Section: Cellular Effects On Different Tissuesmentioning

confidence: 99%

Mitochondrial dysfunction and its role in tissue-specific cellular stress

Pacheu-Grau¹,

Rucktäschel²,

Deckers³

2018

CST

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Mitochondrial bioenergetics require the coordination of two different and independent genomes. Mutations in either genome will affect mitochondrial functionality and produce different sources of cellular stress. Depending on the kind of defect and stress, different tissues and organs will be affected, leading to diverse pathological conditions. There is no curative therapy for mitochondrial diseases, nevertheless, there are strategies described that fight the various stress forms caused by the malfunctioning organelles. Here, we will revise the main kinds of stress generated by mutations in mitochondrial genes and outline several ways of fighting this stress.

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Leukoencephalopathy with thalamus and brainstem involvement and high lactate caused by novel mutations in the EARS2 gene in two siblings

Cited by 16 publications

References 11 publications

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

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

The role of tRNA synthetases in neurological and neuromuscular disorders

Mitochondrial dysfunction and its role in tissue-specific cellular stress

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