Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys.

Fragile X syndrome (FXS) is the leading cause of inherited mental retardation, due to expansion and methylation of the CGG sequence at the 5' UTR of the FMR1 gene. Around 90% of affected boys present with attention deficit hyperactivity disorder (ADHD), while this percentage is lower in FXS girls (35-47%). Treatment of these behavioral symptoms is critical for many families. In an attempt at identifying drugs capable of restoring the activity of the FMR1 gene, we investigated the use of valproic acid (VPA), a well-known antiepileptic drug, also used as a mood stabilizer and in migraine therapy. It is described as an inhibitor of histone deacetylase (HDAC) and, possibly, as a DNA demethylating agent. In an in vitro study we observed that treatment of lymphoblastoid cells from FXS patients with VPA caused a modest reactivation of FMR1 transcription and increased levels of histone acetylation, confirming the histone hyperacetylating effect, but not its putative DNA demethylating activity. On the basis of these findings, we decided to evaluate the in vivo efficacy of VPA on ADHD symptoms in FXS patients. We observed an improvement in the adaptive behavior, defined as the performance of daily activities required for personal and social competence, due to a significant reduction in hyperactivity after VPA treatment. This treatment could be considered as an alternative to that with stimulants, whose efficacy in patients with FXS needs to be confirmed by further studies.

Cerebral palsy and intrauterine growth in single births: European collaborative study.

BACKGROUND: Cerebral palsy seems to be more common in term babies whose birthweight is low for their gestational age at delivery, but past analyses have been hampered by small datasets and Z-score calculation methods. METHODS: We compared data from ten European registers for 4503 singleton children with cerebral palsy born between 1976 and 1990 with the number of births in each study population. Weight and gestation of these children were compared with reference standards for the normal spread of gestation and weight-for-gestational age at birth. FINDINGS: Babies of 32-42 weeks' gestation with a birthweight for gestational age below the 10th percentile (using fetal growth standards) were 4-6 times more likely to have cerebral palsy than were children in a reference band between the 25th and 75th percentiles. In children with a weight above the 97th percentile, the increased risk was smaller (from 1.6 to 3.1), but still significant. Those with a birthweight about 1 SD above average always had the lowest risk of cerebral palsy. A similar pattern was seen in those with unilateral or bilateral spasticity, as in those with a dyskinetic or ataxic disability. In babies of less than 32 weeks' gestation, the relation between weight and risk was less clear. INTERPRETATION: The risk of cerebral palsy, like the risk of perinatal death, is lowest in babies who are of above average weight-for-gestation at birth, but risk rises when weight is well above normal as well as when it is well below normal. Whether deviant growth is the cause or a consequence of the disability remains to be determined.