Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Katrine M Johannesen, Diana Mitter, Robert Janowski, Christian Roth, Joseph Toulouse, Anne-Lise Poulat, Dorothee M Ville, Nicolas Chatron, Eva Brilstra, Karin Geleijns, Alfred Peter Born, Scott McLean, Kimberly Nugent, Gareth Baynam, Cathryn Poulton, Lauren Dreyer, Dylan Gration, Solveig Schulz, Andrea Dieckmann, Katherine L HelbigAndreas Merkenschlager, Rami Jamra, Anja Finck, Elena Gardella, Helle Hjalgrim, Ghayda Mirzaa, Francesco Brancati, Tatjana Bierhals, Jonas Denecke, Maja Hempel, Johannes R Lemke, Guido Rubboli, Petra Muschke, Renzo Guerrini, Annalisa Vetro, Dierk Niessing, Gaetan Lesca, Rikke S Møller

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

65 Downloads (Pure)

Abstrakt

Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.

Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.

Results: Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.

Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

OriginalsprogEngelsk
TidsskriftNeurology: Genetics
Vol/bind5
Udgave nummer6
Sider (fra-til)e373
ISSN2376-7839
DOI
StatusUdgivet - dec. 2019

Bibliografisk note

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Fingeraftryk Dyk ned i forskningsemnerne om 'Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy'. Sammen danner de et unikt fingeraftryk.

Citationsformater