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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},
}