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@ARTICLE{He:892409,
author = {He, Hailan and Guzman, Raul and Cao, Dezhi and
Sierra-Marquez, Juan and Yin, Fei and Fahlke, Christoph and
Peng, Jing and Stauber, Tobias},
title = {{T}he molecular and phenotypic spectrum of {CLCN}4-related
epilepsy},
journal = {Epilepsia},
volume = {62},
number = {6},
issn = {0013-9580},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {FZJ-2021-02067},
pages = {1401-1415},
year = {2021},
abstract = {ObjectiveThis study was undertaken to expand the phenotypic
and genetic spectrum of CLCN4-related epilepsy and to
investigate genotype–phenotype correlations.MethodsWe
systematically reviewed the phenotypic and genetic spectrum
of newly diagnosed and previously reported patients with
CLCN4-related epilepsy. Three novel variants identified in
four patients reported in this study were evaluated through
in silico prediction and functional analysis by Western
blot, immunofluorescence, and electrophysiological
measurements.ResultsEpilepsy was diagnosed in $54.55\%$
(24/44) of individuals with CLCN4-related disorders and was
drug-resistant in most cases. Of 24 patients, 15 had
epileptic encephalopathy and four died at an early age;
$69.57\%$ of patients had seizure onset within the first
year of life. Myoclonic seizures are the most common seizure
type, and $56.25\%$ of patients presented multiple seizure
types. Notably, seizure outcome was favorable in individuals
with only one seizure type. All patients showed intellectual
disability, which was severe in $65.22\%$ of patients.
Additional common features included language delay,
behavioral disorders, and dysmorphic features. Five patients
benefitted from treatment with lamotrigine. Most variants,
which were mainly missense $(79.17\%),$ were inherited
$(70.83\%).$ Whereas frameshift, intragenic deletion, or
inherited variants were associated with milder phenotypes,
missense or de novo variants led to more severe phenotypes.
All evaluated CLCN4 variants resulted in loss of function
with reduced ClC-4 currents. Nonetheless,
genotype–phenotype relationships for CLCN4-related
epilepsy are not straightforward, as phenotypic variability
was observed in recurrent variants and within single
families.SignificancePathogenic CLCN4 variants contribute
significantly to the genetic etiology of epilepsy. The
phenotypic spectrum of CLCN4-related epilepsy includes
drug-resistant seizures, cognitive and language impairment,
behavioral disorders, and congenital anomalies. Notably, the
mutation type and the number of seizure types correlate with
the severity of the phenotype, suggesting its use for
clinical prognosis. Lamotrigine can be considered a
therapeutic option.},
cin = {IBI-1},
ddc = {610},
cid = {I:(DE-Juel1)IBI-1-20200312},
pnm = {524 - Molecular and Cellular Information Processing
(POF4-524)},
pid = {G:(DE-HGF)POF4-524},
typ = {PUB:(DE-HGF)16},
pubmed = {33951195},
UT = {WOS:000647207200001},
doi = {10.1111/epi.16906},
url = {https://juser.fz-juelich.de/record/892409},
}