Protocadherin 19 mutations in girls with infantile-onset epilepsy.

OBJECTIVE: To explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy. METHODS: We studied a cohort of 117 female patients with febrile seizures (FS) and a wide spectrum of epilepsy phenotypes including focal and generalized forms with either sporadic or familial distribution. RESULTS: PCDH19 screening showed point mutations in 13 probands (11%). Mean age at seizure onset was 8.5 months; 8 patients (62%) presented with FS, 4 (33%) with cluster of focal seizures, and 1 with de novo status epilepticus (SE). Subsequent seizure types included afebrile tonic-clonic, febrile, and afebrile SE, absences, myoclonic, and focal seizures. Seven patients (54%) had a clinical diagnosis consistent with Dravet syndrome (DS); 6 (46%) had focal epilepsy. In most patients, seizures were particularly frequent at onset, manifesting in clusters and becoming less frequent with age. Mental retardation was present in 11 patients, ranging from mild (7; 64%) to moderate (1; 9%) to severe (3; 27%). Five patients (38%) had autistic features in association to mental retardation. Mutations were missense (6), truncating (2), frameshift (3), and splicing (2). Eleven were new mutations. Mutations were inherited in 3 probands (25%): 2 from apparently unaffected fathers and 1 from a mother who had had generalized epilepsy. CONCLUSIONS: PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. In our cohort, epileptic encephalopathy with DS-like features and focal epilepsy of variable severity were the associated phenotypes and were equally represented.

Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus.

BACKGROUND: ARX is a paired-type homeobox gene located on the X chromosome that contains five exons with four polyalanine (PolyA) tracts, a homeodomain, and a conserved C-terminal aristaless domain. Studies in humans have demonstrated remarkable pleiotropy: malformation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are associated with missense mutations outside of the homeobox and expansion of the PolyA tracts. OBJECTIVE: To investigate the role of ARX, we performed mutation analysis in 115 boys with cryptogenic ISS. This included two pairs of brothers. RESULTS: We found an expansion of the trinucleotide repeat that codes for the first PolyA tract from 10 to 17 GCG repeats (c.333_334ins[GCG]7) in six boys (5.2%) ages 2 to 14, from four families, including the two pairs of brothers. In addition to ISS, all six boys had severe mental retardation and generalized dystonia that appeared around the age of 6 months and worsened, eventually leading to stable severe quadriplegic dyskinesia within age 2 years. Three children experienced recurrent, life-threatening status dystonicus. In four children brain MRI showed multiple small foci of abnormal cavitation on T1 and increased signal intensity on T2 in the putamina, possibly reflecting progressive multifocal loss of tissue. CONCLUSION: The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.