Male patients affected by mosaic PCDH19 mutations: five new cases

Lange, Iris; Rump, Patrick; Neuteboom, Rinze F.; Augustijn, Paul B.; Hodges, Kyndall; Kistemaker, A I; Brouwer, Oebele F.; Mancini, Grazia M.S.; Newman, Hadas; Vos, Yvonne J.; Helbig, Ingo; Peeters-Scholte, Cacha; Kriek, Marjolein; Knoers, Nine V A M; Lindhout, Dick; Koeleman, Bobby P. C.; Kempen, Marjan J. A. van; Brilstra, Eva H.

doi:10.1007/s10048-017-0517-5

Cited by 46 publications

(52 citation statements)

References 31 publications

(40 reference statements)

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“…An affected mosaic male was reported by de Lange et al. () who harbored the same variant (c.1682 C>G; p. p.Pro561Arg) previously observed in two female individuals (de Lange et al., ; Depienne et al., ). This affected male was 24 month old with 78% mosaicism in blood at the time of study.…”

Section: Biological Significancesupporting

confidence: 65%

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

et al. 2019

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The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X‐linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19‐related disorder is known to cause early‐onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. This condition was initially described in 1971 and in 2008 PCDH19 was identified as the underlying genetic etiology. This condition is the result of pathogenic loss‐of‐function variants that may be de novo or inherited from an affected mother or unaffected father and cellular interference has been hypothesized to be the culprit. Heterozygous females are symptomatic because of the presence of both wild‐type and mutant cells that interfere with one another due to the production of different surface proteins, whereas nonmosaic hemizygous males produce a homogenous population of cells. Here, we review novel pathogenic variants in the PCDH19 gene since 2012 to date, and summarize any genotype‐phenotype correlations.

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Section: Biological Significancesupporting

confidence: 65%

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

et al. 2019

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“…It has been postulated that natural mosaicism created by X-inactivation in females accounts for the wide phenotypic variability observed in females with pathogenic PCDH19 variants. Interestingly, some males with mosaic PCDH19 variants present similarly to affected females 20–23 , which further suggests that the mosaic state may be required for expression of many of the core features of this syndrome. The number of diagnosed cases is increasing as recognition of the gene has grown since 2008, and continues to grow as clinical genetic testing becomes more routine.…”

Section: Introductionmentioning

confidence: 97%

PCDH19‐related epilepsy is associated with a broad neurodevelopmental spectrum

et al. 2018

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Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.

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“…Recognition of this disease is rapidly increasing, with greater access to genetic testing for children with infantileonset seizures. 5,6,24,25 Longer-term follow-up of women and mosaic men with PCDH19-GCE will clarify the risk of later-onset psychotic disorders. 22,23 Moreover, the association of psychosis in a woman with a history of seizures in childhood may not be considered as related to an underlying PCDH19 pathogenic variant, even where the variant is known.…”

Section: Psychotic Disorders In Pcdh19-gcementioning

confidence: 99%

“…Currently, there are 9 PCDH19 mosaic males reported in the literature, of whom 7 had behavioral problems, but they are too young (only 3 were aged 13 and 14 years) to determine whether they are at risk of psychosis. 5,6,24,25 Longer-term follow-up of women and mosaic men with PCDH19-GCE will clarify the risk of later-onset psychotic disorders.…”

Section: Psychotic Disorders In Pcdh19-gcementioning

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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Male patients affected by mosaic PCDH19 mutations: five new cases

Cited by 46 publications

References 31 publications

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern

PCDH19‐related epilepsy is associated with a broad neurodevelopmental spectrum

Schizophrenia is a later‐onset feature ofPCDH19Girls Clustering Epilepsy

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