Novel (ovario) leukodystrophy related to AARS2 mutations

Cristina Dallabona, Daria Diodato, Sietske H. Kevelam, Tobias B. Haack, Lee Jun Wong, Gajja S. Salomons, Enrico Baruffini, Laura Melchionda, Caterina Mariotti, Tim M. Strom, Thomas Meitinger, Holger Prokisch, Kim Chapman, Alison Colley, Helena Rocha, Katrin Ounap, Raphael Schiffmann, Ettore Salsano, Mario Savoiardo, Eline M. Hamilton & 8 others Truus E M Abbink, Nicole I. Wolf, Ileana Ferrero, Costanza Lamperti, Massimo Zeviani, Adeline Vanderver, Daniele Ghezzi, Marjo S. Van Der Knaap

Research output: Contribution to journalArticle

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Abstract

Objectives: The study was focused on leukoencephalopathies of unknown cause in order to define a novel, homogeneous phenotype suggestive of a common genetic defect, based on clinical and MRI findings, and to identify the causal genetic defect shared by patients with this phenotype. Methods: Independent next-generation exome-sequencing studies were performed in 2 unrelated patients with a leukoencephalopathy. MRI findings in these patients were compared with available MRIs in a database of unclassified leukoencephalopathies; 11 patients with similar MRI abnormalities were selected. Clinical and MRI findings were investigated. Results: Next-generation sequencing revealed compound heterozygous mutations in AARS2 encoding mitochondrial alanyl-tRNA synthetase in both patients. Functional studies in yeast confirmed the pathogenicity of the mutations in one patient. Sanger sequencing revealed AARS2 mutations in 4 of the 11 selected patients. The 6 patients with AARS2 mutations had childhoodto adulthood-onset signs of neurologic deterioration consisting of ataxia, spasticity, and cognitive decline with features of frontal lobe dysfunction. MRIs showed a leukoencephalopathy with striking involvement of left-right connections, descending tracts, and cerebellar atrophy. All female patients had ovarian failure. None of the patients had signs of a cardiomyopathy. Conclusions: Mutations in AARS2 have been found in a severe form of infantile cardiomyopathy in 2 families. We present 6 patients with a new phenotype caused by AARS2 mutations, characterized by leukoencephalopathy and, in female patients, ovarian failure, indicating that the phenotypic spectrum associated with AARS2 variants is much wider than previously reported.

Original languageEnglish
Pages (from-to)2063-2071
Number of pages9
JournalNeurology
Volume82
Issue number23
DOIs
Publication statusPublished - Jun 10 2014

Fingerprint

Mutation
Leukoencephalopathies
Phenotype
Cardiomyopathies
Alanine-tRNA Ligase
Exome
Frontal Lobe
Ataxia
Neurologic Manifestations
Atrophy
Virulence
Yeasts
Databases
Sequencing

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Dallabona, C., Diodato, D., Kevelam, S. H., Haack, T. B., Wong, L. J., Salomons, G. S., ... Van Der Knaap, M. S. (2014). Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology, 82(23), 2063-2071. https://doi.org/10.1212/WNL.0000000000000497

Novel (ovario) leukodystrophy related to AARS2 mutations. / Dallabona, Cristina; Diodato, Daria; Kevelam, Sietske H.; Haack, Tobias B.; Wong, Lee Jun; Salomons, Gajja S.; Baruffini, Enrico; Melchionda, Laura; Mariotti, Caterina; Strom, Tim M.; Meitinger, Thomas; Prokisch, Holger; Chapman, Kim; Colley, Alison; Rocha, Helena; Ounap, Katrin; Schiffmann, Raphael; Salsano, Ettore; Savoiardo, Mario; Hamilton, Eline M.; Abbink, Truus E M; Wolf, Nicole I.; Ferrero, Ileana; Lamperti, Costanza; Zeviani, Massimo; Vanderver, Adeline; Ghezzi, Daniele; Van Der Knaap, Marjo S.

In: Neurology, Vol. 82, No. 23, 10.06.2014, p. 2063-2071.

Research output: Contribution to journalArticle

Dallabona, C, Diodato, D, Kevelam, SH, Haack, TB, Wong, LJ, Salomons, GS, Baruffini, E, Melchionda, L, Mariotti, C, Strom, TM, Meitinger, T, Prokisch, H, Chapman, K, Colley, A, Rocha, H, Ounap, K, Schiffmann, R, Salsano, E, Savoiardo, M, Hamilton, EM, Abbink, TEM, Wolf, NI, Ferrero, I, Lamperti, C, Zeviani, M, Vanderver, A, Ghezzi, D & Van Der Knaap, MS 2014, 'Novel (ovario) leukodystrophy related to AARS2 mutations', Neurology, vol. 82, no. 23, pp. 2063-2071. https://doi.org/10.1212/WNL.0000000000000497
Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS et al. Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology. 2014 Jun 10;82(23):2063-2071. https://doi.org/10.1212/WNL.0000000000000497
Dallabona, Cristina ; Diodato, Daria ; Kevelam, Sietske H. ; Haack, Tobias B. ; Wong, Lee Jun ; Salomons, Gajja S. ; Baruffini, Enrico ; Melchionda, Laura ; Mariotti, Caterina ; Strom, Tim M. ; Meitinger, Thomas ; Prokisch, Holger ; Chapman, Kim ; Colley, Alison ; Rocha, Helena ; Ounap, Katrin ; Schiffmann, Raphael ; Salsano, Ettore ; Savoiardo, Mario ; Hamilton, Eline M. ; Abbink, Truus E M ; Wolf, Nicole I. ; Ferrero, Ileana ; Lamperti, Costanza ; Zeviani, Massimo ; Vanderver, Adeline ; Ghezzi, Daniele ; Van Der Knaap, Marjo S. / Novel (ovario) leukodystrophy related to AARS2 mutations. In: Neurology. 2014 ; Vol. 82, No. 23. pp. 2063-2071.
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AU - Dallabona, Cristina

AU - Diodato, Daria

AU - Kevelam, Sietske H.

AU - Haack, Tobias B.

AU - Wong, Lee Jun

AU - Salomons, Gajja S.

AU - Baruffini, Enrico

AU - Melchionda, Laura

AU - Mariotti, Caterina

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Prokisch, Holger

AU - Chapman, Kim

AU - Colley, Alison

AU - Rocha, Helena

AU - Ounap, Katrin

AU - Schiffmann, Raphael

AU - Salsano, Ettore

AU - Savoiardo, Mario

AU - Hamilton, Eline M.

AU - Abbink, Truus E M

AU - Wolf, Nicole I.

AU - Ferrero, Ileana

AU - Lamperti, Costanza

AU - Zeviani, Massimo

AU - Vanderver, Adeline

AU - Ghezzi, Daniele

AU - Van Der Knaap, Marjo S.

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