Clinical and molecular phenotype of Aicardi-Goutieres syndrome.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Aicardi syndrome.

Aicardi syndrome (AS) is characterized by a triad of callosal agenesis, infantile spasms and chorioretinal 'lacunae'. It occurs only in individuals with two X chromosomes and is not familial. The outcome of AS is severe, with a high early mortality, considerable morbidity and a generally poor developmental outcome. However, the spectrum of AS seems broader than previously defined with a small proportion of the affected girls only moderately or mildly retarded. Several novel and important features should be added to the classic triad. The brain malformation is complex with cortical migration abnormalities, often cystic formations and sometimes choroid plexus papillomas; the eye anomalies, often feature a coloboma in addition to the lacunae, and focal seizures rather than spasms, are common. AS has been reported in 2 boys, both with an XXY complement, supporting the hypothesis of an X-linked gene lethal early in pregnancy for male conceptuses. A locus at Xp22.3 has been suggested but has not been confirmed. Treatment is only symptomatic.

Hypothalamic hamartoma and epilepsy in children: illustrative cases of possible evolutions.

The progresses of neuroimaging have allowed an earlier detection of hypothalamic hamartoma in children presenting with gelastic or dacrystic seizures. Associated symptoms can include other types of seizures, precocious puberty, and behavioral or cognitive deterioration. Combination of all these features is not constant and, when present, their evolution may be variable. When epilepsy proves intractable, surgery may be a solution but is not without risks. Therefore, it can only be justified on the basis of a considerable degree of certainty on the progressive character of the disorder, both in terms of epilepsy and global development. Even though epilepsy is a major and usually the most important problem, it is not always possible to predict its course and to be able to evaluate its potential effects on development. Available data suggests that deterioration is partly related to the epileptogenic activity. We reviewed data from 16 personal cases and discussed the possible evolutions of the epilepsy syndrome on the basis of 6 illustrative cases and a review of the literature. We point out that seizures may start early in life and evolve either towards a catastrophic encephalopathy or may be transiently severe and will progressively settle down. Intermediate situations also exist as well as cases presenting with a mild epilepsy. In almost all cases cognitive difficulties are present and may be associated with behavioral disturbances. They are of variable severity, usually in relation to the severity of the epilepsy and the evolution of the EEG abnormalities. Some of our cases also illustrate that, in young children whose seizures are limited to "a sensation of a pleasant feeling", "a pressure to laugh" or "smiling", early detection of the hamartoma may still be difficult and the epilepsy pattern may be misdiagnosed as an epilepsy temporal or frontal origin. Detailed analysis of the electro-clinical evolution of representative cases highlights the variable expression of the epilepsy syndrome and renders difficult any dogmatic position on early surgery. However, recent data suggests that a surgical solution must be sought early. Prospective studies are needed to evaluate, not only outcome in terms of control the seizures without unacceptable side effects but also on the evolution of the cognitive and behavioral profile of children with HH and epilepsy are needed.