A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and disease severity

Kolc, Kristy L.; Sadleir, Lynette G.; Scheffer, Ingrid E.; Ivancevic, Atma M.; Roberts, Rachel; Pham, Duyen; Gécz, Jozef

doi:10.1038/s41380-018-0066-9

Cited by 105 publications

(186 citation statements)

References 57 publications

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“…The reported mutation types include missense, nonsense, insertion or deletion of bases, splicing, deletion of fragments or whole genes, and deletion of other adjacent genes (Depienne et al, ; Vincent et al, ). Seven of the eight‐point mutations in our study were in exon 1, including four frameshift mutations, two missense mutations, one in‐frame mutation; while one mutation occurred in exon 6, just like the reported mutations which occurred mostly in exon 1 (Kolc et al, ). The intracellular C terminal tail of PCDH19 contains the conserved motifs CM1 and CM2, and the Wiskott–Aldrich syndrome protein (WASP) family (Chen et al, ), these domains anchor on the cytoskeleton and integrate with intracellular signal transduction pathways.…”

Section: Discussionsupporting

confidence: 73%

“…PCDH19 ‐GCE is a special X‐linked inheritance, female heterozygotes are affected (Kolc et al, ), male hemizygotes are not affected, neither dominant inheritance nor recessive inheritance. “Cellular interference” mechanism is the main hypothesis to explain this particular genetic pattern.…”

Section: Discussionmentioning

confidence: 99%

“…PCDH19-GCE is a special X-linked inheritance, female heterozygotes are affected(Kolc et al, 2019), male hemizygotes are not affected, neither dominant inheritance nor recessive inheritance.…”

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confidence: 99%

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Novel and de novo mutation of PCDH19 in Girls Clustering Epilepsy

Liu

et al. 2019

Brain and Behavior

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Background PCDH19 has become the second most relevant gene in epilepsy after SCN1A. Seizures often provoked by fever.MethodsWe screened 152 children with fever‐sensitive epilepsy for gene detection. Their clinical information was followed up.ResultsWe found eight PCDH19 point mutations (four novel and four reported) and one whole gene deletion in 10 female probands (seven sporadic cases and three family cases) who also had cluster seizures. The common clinical features of 16 patients in 10 families included fever‐sensitive and cluster seizures, mainly focal or tonic‐clonic seizures, and absence of status epilepticus, normal intelligence, or mild‐to‐moderate cognitive impairment, the onset age ranges from 5 months to 20 years. Only four patients had multiple or focal transient discharges in interictal EEG. Focal seizures originating in the frontal region were recorded in four patients, two from the parietal region, and one from the occipital region.Conclusion PCDH19 mutation can be inherited or de novo. The clinical spectrum of PCDH19 mutation includes PCDH19 Girls Clustering Epilepsy with or without mental retardation, psychosis, and asymptomatic male. The onset age of PCDH19 Girls Clustering Epilepsy can range from infancy to adulthood. Sisters in the same family may be sensitive to the same antiepileptic drugs. And our report expands the mutation spectrum of PCDH19 Girls Clustering Epilepsy.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Novel and de novo mutation of PCDH19 in Girls Clustering Epilepsy

Liu

et al. 2019

Brain and Behavior

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“…4,13,14 The psychiatric features in childhood and adolescence of severe behavioral problems, obsessional features, and ASD often prove more disabling for patients and families, even though seizures may have abated. The term PCDH19 Girl Clustering Epilepsy has been recently suggested to aid in earlier recognition of this serious disorder.…”

Section: Discussionmentioning

confidence: 99%

“…4,13,14 We examined whether each female had experienced psychosis and serious behavioral problems and the evolution of these symptoms over time. 4,13,14 We examined whether each female had experienced psychosis and serious behavioral problems and the evolution of these symptoms over time.…”

Section: Phenotypingmentioning

confidence: 99%

Schizophrenia is a later‐onset feature ofPCDH19Girls Clustering Epilepsy

et al. 2019

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Summary Objective To investigate the occurrence of psychosis and serious behavioral problems in females with protocadherin 19 gene (PCDH19) pathogenic variants. Methods We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2‐75 years) with PCDH19 pathogenic variants belonging to 35 families. Patients were identified from epilepsy genetics databases in Australia, New Zealand, the United States, and Canada. Neurologic and psychiatric disorders were diagnosed using standard methods. Results Eight of 60 females (13%) from 7 families developed a psychotic disorder: schizophrenia (6), schizoaffective disorder (1), or an unspecified psychotic disorder (1). Median age at onset of psychotic symptoms was 21 years (range 11‐28 years). In our cohort of 39 females aged 11 years or older, 8 (21%) developed a psychotic disorder. Seven had ongoing seizures at onset of psychosis, with 2 continuing to have seizures when psychosis recurred. Psychotic disorders occurred in the setting of mild (4), moderate (2), or severe (1) intellectual disability, or normal intellect (1). Preexisting behavioral problems occurred in 4 patients, and autism spectrum disorder in 3. Two additional females (3%) had psychotic features with other conditions: an adolescent had recurrent episodes of postictal psychosis, and a 75‐year‐old woman had major depression with psychotic features. A further 3 adolescents (5%) with moderate to severe intellectual disability had onset of severe behavioral disturbance, or significant worsening. Significance We identify that psychotic disorders, including schizophrenia, are a later‐onset manifestation of PCDH19 Girls Clustering Epilepsy. Affected girls and women should be carefully monitored for later‐onset psychiatric disorders.

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