Rett‐like phenotypes: expanding the genetic heterogeneity to the <i><scp>KCNA2</scp></i> gene and first familial case of <i><scp>CDKL5</scp></i>‐related disease

Allou, Lila; Julia, Sophie; Amsallem, D.; Chehadeh, Salima El; Lambert, Laëtitia; Thévenon, Julien; Duffourd, Yannis; Saunier, Aline; Bouquet, Pierre Marie; Pere, S.; Moustaïne, Aissa; Ruaud, Lyse; Roth, Virginie; Jonveaux, Philippe; Philippe, Christophe

doi:10.1111/cge.12784

Cited by 44 publications

(47 citation statements)

References 41 publications

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“…Though she did not fulfill requirements for a clinical diagnosis of typical or atypical RTT, she met 3/4 of the main criteria and 3/11 of the supportive criteria [19]. Another report mentions an IQSEC2 nonsense mutation in a female with severe ID, developmental regression with loss of acquired language, stereotyped hand movements, and inappropriate laughing/screaming spells [20]. Patient 7 in our cohort has a relatively non-specific profile characterized by global developmental delay and hypotonia.…”

Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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Background. Rett syndrome (RTT) is caused by mutations in methyl-CpG binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. Methods. We performed a retrospective chart review on n=319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup. From this group, we characterized those who (1) possessed features that were compatible with RTT based on clinical judgment (2) subsequently underwent MECP2 sequencing and/or MECP2 deletion/duplication analysis with negative results (3) ultimately arrived at a diagnosis other than RTT with WES. Results. n=7 patients had clinical features overlapping RTT with negative MECP2 analysis but positive WES providing a diagnosis. These 7 patients collectively possessed pathogenic variants in 6 different genes: two in KCNB1 and one each in FOXG1, IQSEC2, MEIS2, TCF4, and WDR45. n=2 (both with KCNB1 variants) fulfilled criteria for atypical RTT. RTT associated features included the following: loss of hand or language skills (n=3; IQSEC2, KCNB1 × 2); disrupted sleep (n=4; KNCB1, MEIS2, TCF4, WDR45); stereotyped hand movements (n=5; FOXG1, KNCB1 × 2, MEIS2, TCF4); bruxism (n=3; KCNB1 × 2; TCF4); and hypotonia (n=7). Conclusion. Clinically-based diagnoses can be misleading, evident by the increasing number of genetic conditions associated with features of RTT with negative MECP2 mutations.

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Section: Discussionmentioning

confidence: 99%

Monogenic disorders that mimic the phenotype of Rett syndrome

et al. 2018

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“…[94][95][96] Many affected patients present with progressive, potentially life-threatening episodic exacerbations, which often necessitate hospitalization in an intensive care setting. [98][99][100] Moreover, autosomal recessive KCNJ10 mutations cause epilepsy, ataxia, sensorineural deafness, and tubulopathy syndrome. 94,96,97 Lasting from minutes to days or even months, such exacerbations are commonly triggered by infection, pyrexia, heightened emotion, stress, and anxiety.…”

Section: Infantile-onset Epileptic Encephalopathies Associated With Smentioning

confidence: 99%

“…Other associations also include autistic features and behavioural issues, sleep disturbance, and hand stereotypies. 153,154 IQSEC2 has an essential role in modulating the cytoskeleton and vesicle transport at the postsynaptic density and hence is a crucial modifier of synaptic plasticity. 140 Similar to MECP2, a number of genes causing epilepsy syndromes with prominent stereotypies encode for transcription factors, or proteins involved in transcriptional regulation.…”

Section: Epilepsy Syndromes Associated With Prominent Stereotypiesmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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“…De novo mutations of KCNA2 have recently been reported in infantile-onset epileptic encephalopathies (EEs) in which infants present with uncontrolled seizures, developmental slowing or regression, and frequent epileptiform activity on EEG. [1][2][3][4][5][6] Inherited mutations have not been described. KCNA2 has not been implicated in common pharmacoresponsive epilepsies such as the genetic generalized epilepsies (GGE), nor has an association with paroxysmal movement disorders been established.…”

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confidence: 99%

“…Of these, a deletion in KCNA2 (CCDS_827.1: c.765_773del; p.255_257del) (figure 1B) was favored because both knockout and ENU-induced Kcna2 mutant mice exhibit seizures and ataxia 12,23 and de novo KCNA2 mutations cause EE. [1][2][3][4][5] The remaining 3 genes in which variants were found (EGR4, MET, RNF19B) have not been implicated in epilepsy or ataxia (table e-2). The KCNA2 variant segregated with all affected individuals (figure 1B).…”

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confidence: 99%

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

Corbett

Bellows

et al. 2016

Neurology

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Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G.A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. Neurology ® 2016;87:1975-1984 GLOSSARY EA 5 episodic ataxia; EE 5 epileptic encephalopathy; GATK 5 genome analysis toolkit; GGE 5 genetic generalized epilepsies; GTCS 5 generalized tonic-clonic seizures; ICCA 5 infantile convulsions choreoathetosis syndrome; RMS 5 root mean square.De novo mutations of KCNA2 have recently been reported in infantile-onset epileptic encephalopathies (EEs) in which infants present with uncontrolled seizures, developmental slowing or regression, and frequent epileptiform activity on EEG.1-6 Inherited mutations have not been described. KCNA2 has not been implicated in common pharmacoresponsive epilepsies such as the genetic generalized epilepsies (GGE), nor has an association with paroxysmal movement disorders been established.Paroxysmal neurologic disorders are often due to disorders of ion channel function. The episodic ataxias (EAs) are usually dominantly inherited and associated with a range of ion channel *These authors contributed equally to this work.

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Rett‐like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5‐related disease

Cited by 44 publications

References 41 publications

Monogenic disorders that mimic the phenotype of Rett syndrome

Monogenic disorders that mimic the phenotype of Rett syndrome

The expanding spectrum of movement disorders in genetic epilepsies

DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

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