In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

Bruni, F., Di Meo, I., Bellacchio, E., Webb, B., Mcfarland, R., Chrzanowska-Lightowlers, Z., et al. (2018). Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. HUMAN MUTATION, 39(4), 563-578 [10.1002/humu.23398].

Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease

Di Meo, Ivano;Ardissone, Anna;Ghezzi, Daniele;
2018

Abstract

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.
Articolo in rivista - Articolo scientifico
cardioencephalomyopathy; mitochondrial disorders; OXPHOS; VARS2;
cardioencephalomyopathy; mitochondrial disorders; OXPHOS; VARS2; Genetics; Genetics (clinical)
English
563
578
16
Bruni, F., Di Meo, I., Bellacchio, E., Webb, B., Mcfarland, R., Chrzanowska-Lightowlers, Z., et al. (2018). Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease. HUMAN MUTATION, 39(4), 563-578 [10.1002/humu.23398].
Bruni, F; Di Meo, I; Bellacchio, E; Webb, B; Mcfarland, R; Chrzanowska-Lightowlers, Z; He, L; Skorupa, E; Moroni, I; Ardissone, A; Walczak, A; Tyynismaa, H; Isohanni, P; Mandel, H; Prokisch, H; Haack, T; Bonnen, P; Enrico, B; Pronicka, E; Ghezzi, D; Taylor, R; Diodato, D
File in questo prodotto:
File Dimensione Formato  
Bruni_et_al-2018-Human_Mutation.pdf

Solo gestori archivio

Tipologia di allegato: Author’s Accepted Manuscript, AAM (Post-print)
Dimensione 2.24 MB
Formato Adobe PDF
2.24 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/205493
Citazioni
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 18
Social impact