Reply: Early-onset phenotype of bi-allelic GRN mutations
Vincent Huin, Mathieu Barbier, Alexandra Durr, Isabelle Le Ber
RReply: Early-onset phenotype of bi-allelic
GRN mutations
Madam, Sir, Neuray et al. report in this work a series of five new patients from four unrelated families with bi-allelic mutations of
GRN . This work nicely completes the few existing reports of similar cases, and refers to our recent publication describing six homozygous
GRN pathogenic variant carriers with divergent phenotypes and ages at onset (Huin et al.,
GRN mutations. All heterozygous pathogenic
GRN variants reported here were previously associated with frontotemporal dementia (FTD) (Rademakers et al., et al., et al., et al., et al., et al.,
GRN variants. This present study summarizes the clinical features and evolution of early-onset CLN11. We agree with almost all key-points described here. In particular, the correlation between more severe cognitive deterioration with generalized tonic-clonic seizures (and also pharmacologically refractory epilepsy) is a major point associated with a gene responsible of a pure dementia phenotype elsewhere. Epilepsy is frequent among CLN (Mole et al., et al., et al., et al., et al., et al., et al., et al., et al. had (or not) myoclonus, considering their similar pharmacologically refractory epilepsy with disabling evolution. This could be important to better characterize epilepsy associated with CLN11, its prognosis and possible treatment. Neuray et al. emphasize the frequency of focal occipital seizures with visual signs in CLN11. Progressive myoclonus epilepsy with focal occipital seizures described in CLN11 patients is similar to that observed in Lafora disease (OMIM et al.,
GRN variants, even if we do not fully agree with the assumption that all the visual symptoms can be considered as red flags for
GRN testing. Indeed, visual loss leading to progressive blindness is a frequent sign, not specific of CLN11, and even a cardinal feature among most forms of ceroid lipofuscinosis (Mole et al., et al., et al., developed visual hallucinations (Smith et al.,
GRN pathogenic variants have already been reported elsewhere at a homozygous state leading to CLN11: the variations c.813_816del, p.Thr22Serfs*10 (Smith et al., et al., et al., et al., et al., et al., et al., et al., et al., reports valuable findings that lead to better define CLN11 due to bi-allelic
GRN pathogenic variants. Despite the small sample number that does not allow statistical analysis, the authors underlined the occurrence of cognitive deterioration and epilepsy. Further study of the CLN11 families with functional brain imaging and neuropsychological examinations may be highly informative for the understanding and the clinical characterization of this rare disease. uthors:
Vincent Huin, MD, PhD , Mathieu Barbier,PhD , Alexandra Durr, MD, PhD , Isabelle Le Ber, MD, PhD Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neuroscience & Cognition, F-59000 Lille, France AP-HP, National Reference center "rare and young dementias", IM2A, Pitié-Salpêtrière University Hospital, Paris, France
ORCID number:
Vincent Huin = 0000-0001-8201-5406 Mathieu Barbier = 0000-0002-5154-2163 Alexandra Durr = 0000-0002-8921-7104 Isabelle Le Ber = 0000-0002-2508-5181
Competing interests
The authors report no competing interests.
Funding
This work received funding from the VERUM foundation and ‘Investissements d’avenir’ ANR-11-INBS-0011 – NeurATRIS: Translational Research Infrastructure for Biotherapies in Neurosciences. This work was funded by the Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome (to I.L.B., promotion by Assistance Publique – Hôpitaux de Paris) and PHRC Predict-progranulin (to I.L.B., promotion by Assistance Publique – Hôpitaux de Paris).
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