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

Oliveira, Renata Maria Souza; Sommerville, Ewen W.; Thompson, Kyle; Nunes, Jacqueline Targino; Pyle, Angela; Grazina, Manuela; Chinnery, Patrick F.; Diogo, Luísa; Garcia, Paula; Taylor, Robert W.

doi:10.1007/8904_2016_581

Cited by 24 publications

(21 citation statements)

References 18 publications

(57 reference statements)

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“…Increased lactate in brain MRS was also reported. 11 One patient had typical brain MRI features at the age of 8 months, which partially improved at the age of 29 months. A repeat brain MRI demonstrated new increased signal intensity in the left caudate and left globus pallidus in T2 weighted images at the age of 5 years and 10 months.…”

Section: Discussionmentioning

confidence: 96%

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

et al. 2019

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Mitochondrial aminoacyl‐tRNA synthetases play a major role in protein translation, synthesis, and oxidative phosphorylation. We reviewed all patients diagnosed with mitochondrial aminoacyl‐tRNA synthetase deficiencies diagnosed in a single neurometabolic clinic. We report five patients with mitochondrial aminoacyl‐tRNA synthetase deficiencies including DARS2, EARS2, PARS2, and RARS2 deficiencies. Siblings with DARS2 deficiency presented with global developmental delay within the first year of life. DARS2, EARS2, PARS2, and RARS2 deficiencies were identified by whole exome sequencing. We report coagulation factor abnormalities in PARS2 deficiency for the first time. We also report symmetric increased signal intensity in globus pallidi in FLAIR images in brain MRI in EARS2 deficiency for the first time. One patient with RARS2 deficiency had compound heterozygous variants in RARS2. One of those variants was an intronic variant. We confirmed the pathogenicity by mRNA studies. Mitochondrial aminoacyl‐tRNA synthetase deficiencies are diagnosed by molecular genetic investigations. Clinically available non‐invasive biochemical investigations are non‐specific for the diagnosis of mitochondrial aminoacyl‐tRNA synthetase deficiencies. A combination of brain MRI features and molecular genetic investigations should be undertaken to confirm the diagnosis of mitochondrial aminoacyl‐tRNA synthetase deficiencies.

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Section: Discussionmentioning

confidence: 96%

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

et al. 2019

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“…Recently numerous MRI patterns characteristic of mitochondrial disease have been described in addition to Leigh syndrome, and basal ganglia with brainstem involvement. We now include Leukoencephalopathy with brainstem and spinal cord involvement (DARS2), 26 Cavitating leukoencephalopathy (LYRM7), 27 Leucoencephalopathy with thalamus involvement (EARS2), 28 Deep cerebral white matter involvement and corpus callosum agenesis (NUBPL). 29 Moreover, the clinical phenotyping with the use of the MDC provides support for the interpretation of WES findings.…”

Section: Discussionmentioning

confidence: 99%

Revisiting mitochondrial diagnostic criteria in the new era of genomics

Witters

Saada²,

Honzík

et al. 2018

Genetics in Medicine

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PurposeDiagnosing primary mitochondrial diseases (MDs) is challenging in clinical practice. The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying MD and the need for a muscle biopsy. In this new genetic era with next-generation sequencing in routine practice, we aim to validate the diagnostic value of MDC.MethodsWe retrospectively studied MDC in a multicenter cohort of genetically confirmed primary MD patients.ResultsWe studied 136 patients (61 male, 91 nuclear DNA (nDNA) mutations). Forty-five patients (33%) had probable MD and 69 (51%) had definite MD according to the MDC. A muscle biopsy was performed in 63 patients (47%). Patients with nDNA mutations versus mitochondrial DNA mutations were younger (6.4 ± 9.7 versus 19.5 ± 17.3 y) and had higher MDC (7.07 ± 1.12/8 versus 5.69 ± 1.94/8). At a cutoff of 6.5/8, the sensitivity to diagnose patients with nDNA mutations is 72.5% with a positive predictive value of 69.5%. In the nDNA mutation group, whole-exome sequencing could diagnose patients with lower scores (MDC (6.84 ± 1.51/8) compared to Sanger sequencing MDC (7.44 ± 1.13/8, P = 0.025)). Moreover 7/8 patients diagnosed with possible MD by MDC were diagnosed by whole-exome sequencing.ConclusionMDC remain very useful in the clinical diagnosis of MD, in interpreting whole-exome results and deciding on the need for performing muscle biopsy.

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“…This was somewhat surprising given the earlier report of the patient with the c.2726C > T, p.Pro909Leu variant documented decreased levels of IARS2 protein in patient cells [ 5 ]. Despite this, it is well documented that mutation of human mitochondrial ARSs are associated with marked clinical heterogeneity and tissue-specificity, and that cultured skin fibroblasts rarely replicate the functional mitochondrial deficit observed in post-mitotic and clinically-relevant tissues [ 35 – 37 ].…”

Section: Discussionmentioning

confidence: 99%

Expanding the clinical phenotype of IARS2-related mitochondrial disease

et al. 2018

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BackgroundIARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies.MethodsGenomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis.ResultsExome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein.ConclusionsThis study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.Electronic supplementary materialThe online version of this article (10.1186/s12881-018-0709-3) contains supplementary material, which is available to authorized users.

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

Cited by 24 publications

References 18 publications

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

Phenotypes and genotypes of mitochondrial aminoacyl‐tRNA synthetase deficiencies from a single neurometabolic clinic

Revisiting mitochondrial diagnostic criteria in the new era of genomics

Expanding the clinical phenotype of IARS2-related mitochondrial disease

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