Somatic mosaicism of PCDH19 mutation in a family with low-penetrance EFMR.

The occurrence of epilepsy with mental retardation limited to females (EFMR; MIM 300088) has been recently associated to mutations in the PCDH19 gene, located on chromosome X and encoding for protocadherin 19. EFMR shows a rare X-linked inheritance wherein affected females may be segregating a mutation through unaffected transmitting males (Fabisiak and Erickson Clin Genet 38(5):353-358, 1990; Juberg and Hellman J Pediatr 79:726-732, 1971; Ryan et al. Nat Genet 17(1):92-95, 1997). The description of a pedigree segregating PCDH19 mutations from unaffected mothers to patients (Depienne et al. Hum Mutat 32:E1959-1975, 2011; Dibbens et al. Neurology 76:1514-1519, 2011) complicates disease inheritance and genetic counseling. In the present study, we describe a PCDH19 mutation segregating from an asymptomatic mother to an EFMR patient. In order to correlate the healthy phenotype with the genotype of the transmitting mother, we quantified in a few tissues the level of the mutant allele by real-time PCR, disclosing a somatic mosaicism. This finding has a great impact on genetic counseling.

Familial Ohtahara syndrome due to a novel ARX gene mutation.

Recently, it has been reported that longer expansions of the polyalanine tract of the ARX gene could cause an early infantile encephalopathy with suppression burst pattern and that the length of this repeat region could be related to the severity of the electroclinical picture. We describe the history of two male individuals, born from monozygotic twin sisters, with Ohtahara syndrome (OS) that evolved into West syndrome phenotype and epileptic encephalopathy. In both children, we have found a previously unreported missense mutation in exon 5 of ARX gene (c.1604T>A) resulting in the substitution of a leucine with a glutamine in the aminoacid sequence. The two mothers and the maternal grandmother carry the same mutation which segregates with the disease phenotype in the family. This study confirms that ARX is involved in the pathogenesis of cryptogenic early onset epileptic encephalopathy, such as OS, and suggests that the severity of the electroclinical picture is likely to not exclusively correlate with the extent of expansions of the polyalanine tracts, but rather with the functional effect of different pathogenetic mutations.

Periventricular heterotopia in fragile X syndrome.

The authors describe two unrelated individuals with fragile X syndrome (FXS) due to marked expansion and instability of the CGG trinucleotide repeats within the fragile X mental retardation 1 gene (FMR1) and periventricular heterotopia (PH). This observation suggests that the FMR1 gene is involved in neuronal migration and that abnormal neuronal migration, even beyond the resolution of MRI, contributes to the neurologic phenotype of FXS.

Experience with immunomodulatory treatments in Rasmussen's encephalitis.

The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in the few cases of bilateral disease.