Clustering Epilepsy “CE” is a condition caused by pathogenic variants in the X-chromosome gene PCDH19. PCDH19 encodes the protocadherin-19 protein. This protein is important in individual cell function, cell-cell adhesion and cell-cell communication. Due to the normal X-chromosome inactivation in females or the development of a somatic (postzygotic) pathogenic variant in males, individuals with pathogenic variation in this gene are cellular mosaics. That is, they have some cells that express functional protocadherin-19 protein and some cells that do not express protocadherin-19 protein or express its non-functional form.
Clinical features
PCDH19 pathogenic variants cause a distinctive phenotype for which the name Clustering Epilepsy (CE) has been proposed to aid in early recognition of the distinguishing phenotypic features. Although CE can show marked inter-individual variation in severity, it is readily identifiable clinically. Typically developing girls present with clusters of frequent seizures usually in the first year of life, often triggered by fever. Seizures are typically focal, although bilateral tonic-clonic and tonic seizures may occur. Clusters may be difficult to abort and the epilepsy is often pharmaco-resistant. During the second decade of life (mean 18 years) the epilepsy can improve, with many girls becoming seizure free in adolescence. Developmental course is varied, with many girls showing developmental slowing during childhood. Although some girls have abnormal development from birth (approx. 20%). There may be developmental regression with clusters of seizures. Approximately half of affected individuals have intellectual disability ranging from mild to profound. Comorbid psychiatric disorders are common, most frequently autism spectrum disorder (ASD) and behavioural problems; later onset psychosis occurs in approximately 20% of females. These features also have a significant impact on the quality of life for these individuals and their families.
Prevalence
PCDH19 is considered one of the most clinically relevant genes in epilepsy, second only to SCN1A. The prevalence of CE is estimated to be 1 in 15,000. To date, over 300 individuals with pathogenic variants in PCDH19 are reported in the literature.
Inheritance
PCDH19 pathogenic variants can be de novo or inherited. Females may present as sporadic cases or with a striking family history in which only women have seizures, intellectual disability or ASD. The X-chromosome-linked inheritance pattern observed in families is unique: only females with heterozygous pathogenic variants are affected, whereas males with hemizygous pathogenic variants are unaffected. A hemizygous or “transmitting” male must pass the pathogenic variant onto all his daughters who are likely to be affected. The penetrance (the extent to which the condition is present with the pathogenic variant) is estimated to be 90%.
Sporadic cases are generally the result of a de novo (“new”) pathogenic variant and are observed in approximately half of the reported PCDH19 cases. However, in rare instances, the unaffected father may be mosaic thus increasing the recurrence risk of having another girl with GCE in those families.
Males with a de novo somatic pathogenic variant are mosaic, that is, some of their cells express PCDH19 and others do not. These males exhibit a similar clinical profile (with seizures and intellectual disability) to heterozygous affected females. No significant clinical differences have been observed among individuals with inherited or de novo pathogenic variants. There are two frequent recurrent variants: p.Asn340Ser and p.Tyr366Leufs*10 that have been identified in 25 (20 unrelated) and 30 (11 unrelated) cases, respectively. There are no marked similarities among individuals with the same variant.