The molecular and phenotypic spectrum of <i>CLCN4</i>‐related epilepsy

He, Haiqi; Guzman, Raul E.; Cao, Dezhi; Sierra-Marquez, Juan; Yin, Fei; Fahlke, Christoph; Peng, Jing; Stauber, Tobias

doi:10.1111/epi.16906

Cited by 17 publications

(24 citation statements)

References 44 publications

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“…with a developmental and epileptic encephalopathy as highlighted in recent reports [1,11]. The severity of epilepsy, however, does not necessarily correlate with the severity of cognitive impairment.…”

Section: Discussionmentioning

confidence: 96%

“…Xu et al, reported on a female with ID, autistic features and brain abnormalities, with a maternally inherited CLCN4 missense variant where the mother had mild ID [ 8 ]. We recently summarized the published genotypic and phenotypic spectrum [ 9 ], noting that, to date, all CLCN4 variants studied in the Xenopus expression system demonstrated partial or complete loss-of-function (LOF) [ 1 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

et al. 2022

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Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

et al. 2022

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“…Their function is not completely clear, but CLCN Cl − channels are involved in the regulation of excitability by controlling extra-and intracellular ion homeostasis. Dysfunction of some CLCN genes leads to severe neurological disorders, in particular LoF mutations in CLCN4 cause a spectrum of phenotypes including severe DEE with drug-resistant seizures, cognitive and behavioral disorders (494,495). SLC1A2 AND SLC6A1.…”

Section: Synaptic Transportersmentioning

confidence: 99%

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Guerrini

Conti

Mantegazza

et al. 2023

Physiological Reviews

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Developmental and epileptic encephalopathies are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures, EEG abnormalities, on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both non-genetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs, of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.

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“…These larger cohorts lead to a much better genotype–phenotype characterization of these syndromes. In the past 2 years, several single-center and multicentric studies have generated new insights into the electrographic and phenotypic spectrum of the following genetic epilepsies: PIGS-associated early-onset developmental and epileptic encephalopathy [6], Angelman syndrome [7], LAMA-2 -related muscular dystrophy [8], Mowat–Wilson syndrome [9], neurofibromatosis type 1 [10], CLCN4 -related epilepsy [11], Poirier–Bienvenu syndrome [12], and familial cortical myoclonic tremor with epilepsy type 1 [13].…”

Section: Genotype–phenotype Correlationmentioning

confidence: 99%

Updates on the diagnostic evaluation, genotype–phenotype correlation, and treatments of genetic epilepsies

Zimmern

Korff

2022

Current Opinion in Pediatrics

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Purpose of reviewThis article reviews the latest publications in genetic epilepsies, with an eye on publications that have had a translational impact. This review is both timely and relevant as translational discoveries in genetic epilepsies are becoming so frequent that it is difficult for the general pediatrician and even the general child neurologist to keep up.Recent findingsWe divide these publications from 2021 and 2022 into three categories: diagnostic testing, genotype–phenotype correlation, and therapies. We also summarize ongoing and upcoming clinical trials.SummaryTwo meta-analyses and systematic reviews suggest that exome and genome sequencing offer higher diagnostic yield than gene panels. Genotype–phenotype correlation studies continue to increase our knowledge of the clinical evolution of genetic epilepsy syndromes, particularly with regards to sudden death, auditory dysfunction, neonatal presentation, and magnetoencephalographic manifestations. Pyridoxine supplementation may be helpful in seizure management for various genetic epilepsies. There has been interest in using the neurosteroid ganaxolone for various genetic epilepsy syndromes, with clear efficacy in certain trials. Triheptanoin for epilepsy secondary to glucose transporter 1 (GLUT1) deficiency syndrome is not clearly effective but further studies will be needed.

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The molecular and phenotypic spectrum of CLCN4‐related epilepsy

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 17 publications

References 44 publications

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Updates on the diagnostic evaluation, genotype–phenotype correlation, and treatments of genetic epilepsies

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