PCDH19 gene-related<unk>  is a highly variable and rare epileptic syndrome, characterized by the early-onset of seizure clusters, with a range of 4 – 60 months, and an average onset at 12.9 months. Other aspects, such as varying degrees of cognitive impairment and behavioral and psychiatric problems, are also common, but are not essential for diagnosis of PCDH19 gene-related<unk> . PCDH19 gene-related<unk>  shares several clinical features with other early-onset epileptic encephalopathies, such as Dravet Syndrome, Generalized<unk>  with febrile seizures plus (GEFS+), FIRES (febrile infection–related<unk>  syndrome) Lennox-Gastaut syndrome or<unk>  of unknown origin. However, the disorder has a distinct evolution of symptoms, and is associated with specific genetic mutations of the PCDH19 gene. Seizures The hallmark characteristic of PCDH19 gene-related<unk>  is early-onset cluster seizures that often cause cyanotic spells, which start in infancy or early childhood. The onset of the first cluster of seizures usually coincides with a fever (febrile seizures), however subsequent seizures may be febrile or afebrile. The seizure clusters are generally brief seizures, lasting 1–5 minutes, often accompanied by fearful screaming observed in 63% of girls. These cluster seizures can occur more than 10 times a day over several days, with varying amounts of time between seizure clusters. Over time, children with PCDH19 gene-related<unk>  tend to exhibit multiple seizure types, including focal, generalized tonic-clonic, tonic, atonic, myoclonus, and absence seizures. In a small study of 35<unk> patients with PCDH19 gene-related<unk> , rare episodes of status epilepticus occurred in about 30% of patients in the early course of the disorder. In PCDH19 gene-related<unk> , the seizures are often refractory to treatment, especially in infancy and childhood. Additionally, seizures are usually characterized by persistence of cluster seizures, with variable frequency. In a study of 35<unk> patients with PCDH19 gene-related<unk> , approximately 30% had become seizure free in the girl's childhood (mean age of 12 years), yet some continued into adulthood. In the same study, a few patients still had recurrent cluster seizures that evolved into status epilepticus in childhood or early adolescence. Developmental problems Beyond early-onset and treatment-resistant cluster seizures, PCDH19 gene-related<unk>  is usually, but not always, associated with cognitive and sensory impairment of varying degrees, and psychiatric and behavioral problems. It is estimated that up to 60 to 75% of the<unk>  have cognitive deficits, ranging from mild to severe<unk><unk> , which do not appear to be related to frequency or severity of seizures. Development over the course of a<unk> patients’ childhood can follow one of three courses: delays from birth that persist into adulthood, normal development and then regression, or normal<unk>  development. It is not yet clear why some people experience delayed<unk>  growth and others regress with<unk> . From the University of Melbourne study, two-thirds of PCDH19 gene-related<unk>  patients have borderline<unk>  functioning or<unk><unk> , while one third have normal intelligence. A connection to depression, autism, obsessive and aggressive behaviors and other disorders has been observed in PCDH19 gene-related<unk> . Approximately 40-60% of girls diagnosed with a PCDH19 mutation are on the autism spectrum. Many of those with PCDH19 gene mutations also exhibit behavioral and psychological problems – including ADHD, aggression, obsessive-compulsive disorder, and anxiety. Other neurological abnormalities may present, including sleep disturbances, ictal apnea, motor deficits, hypotonia, language delay, sensory integration problems and dysautonomia.
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