A new form of alpha-dystroglycanopathy associated with severe drug-resistant epilepsy and unusual EEG features.

We describe two unrelated girls with congenital muscular dystrophy associated with alpha-dystroglycan deficit with no identified genetic defect, both presenting severe drug-resistant epilepsy with predominant myoclonic seizures and an unusual similar EEG pattern. Severe epilepsy has been unusually described in patients with congenital muscular dystrophies, mainly associated with Walker-Warburg, Fukuyama and muscle-eye-brain diseases. [Published with video sequences].

Type I hyperprolinemia and proline dehydrogenase (PRODH) mutations in four Italian children with epilepsy and mental retardation.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder caused by proline oxidase deficiency. This enzyme is encoded by the proline dehydrogenase (PRODH) gene on 22q11. The functional consequences of different PRODH mutations on proline oxidase activity have been characterized in vitro. Few patients with HPI with epilepsy and cognitive/behavioral disturbances have been described so far. We screened four Italian children with HPI presenting epilepsy, mental retardation, and behavioral disorders for PRODH gene mutations, and attempted a genotype-phenotype correlation.

Efficacy of folic acid in children with migraine, hyperhomocysteinemia and MTHFR polymorphisms.

MTHFR gene variants C677T and A1298C seem to be related to an increased risk of migraine. Folates' metabolism could play a role in the pathophysiology of migraine. We supplemented 16 children with migraine, hyperhomocysteinemia, and MTHFR polymorphisms with folic acid and obtained a resolution/reduction of migraine attacks. Although the mechanism leading to these effects has been not made clear, we believe that the use of folic acid needs further investigations in migraineurs with hyperhomocysteinemia and MTHFR variants. A randomized, double-blind, placebo controlled crossover trial is needed to support these findings.

Status gelasticus associated with levetiracetam as add-on treatment.

We report the case of a five-year-old girl, presenting with difficult-to-treat, symptomatic focal epilepsy, who developed status gelasticus following the introduction of levetiracetam as add-on treatment to oxcarbazepine and diazepam. Gelastic seizures were documented by video-EEG and were responsive to i.v. administration of diazepam. A possible causative role of levetiracetam is suggested. Specific susceptibility to some AEDs is also discussed, as this patient, at the age of four years, had presented an episode of non-convulsive status epilepticus, following introduction of tiagabine, in association with vigabatrin and nitrazepam.[Published with video sequences].

Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome.

Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.

Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications.

BACKGROUND: Recent evidence indicates that atypical antipsychotics represent a promising option for the treatment of autistic disorder. In particular, risperidone appears to be effective in treating aggressiveness, hyperactivity, irritability, stereotypies, social withdrawal, and lack of interests. OBJECTIVE: The aim of the present study was to evaluate the effectiveness and tolerability of risperidone in children with autistic disorder and to examine the correlation between plasma levels of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) and the clinical response. METHODS: The effect of treatment with risperidone (0.75-2 mg/day; mean +/- SD dose = 1.26 +/- 0.42 mg/day) was studied for 24 weeks in 20 children (14 boys, 6 girls) ages 3 to 10 years (mean age 6.0 +/- 2.4 years), diagnosed with autistic disorder. Fourteen items selected from the Children's Psychiatric Rating Scale (CPRS-14) and Clinical Global Impression (CGI) were used for behavioral evaluation. Patients were classified as responders if they showed a 25% or greater decrease on CPRS-14 total score at final evaluation compared with baseline and a final CGI rating of 1 or 2. Patients were rated for extrapyramidal side effects on the Abnormal Involuntary Movement Scale (AIMS). Other side effects, including the expected side effects of atypical antipsychotics drugs, were assessed by a checklist. Blood samples for determination of risperidone and its active metabolite 9-OH-risperidone were obtained after 12 weeks, and serum prolactin levels were measured on admission and at weeks 12 and 24. RESULTS: The psychopathological state, as assessed by CPRS, improved significantly over the duration of treatment. The mean CPRS-14 scores decreased significantly from 63.7 +/- 10.0 at baseline to 52.9 +/- 14.3 at week 12 (p < 0.01). At the end of 12 weeks of treatment, 8 patients were considered responders, and 10 patients reached a minimal improvement. No further improvement was observed in the following 12 weeks. In all children, serum prolactin levels increased significantly (p < 0.001) from 166 +/- 88 UI/mL at baseline to 504 +/- 207 UI/mL at week 12 of risperidone treatment. Weight gain and increased appetite were the most common unwanted effects. A mean increase of 3.7 +/- 1.7 kg in body weight was observed at final evaluation as compared with baseline. There was no significant correlation between percent improvement in total CPRS score and the plasma level of risperidone's active fractions (the sum of the risperidone and 9-OH-risperidone plasma concentration). CONCLUSIONS: This study provides further evidence of the beneficial effects of risperidone in children diagnosed with autistic disorder. However, the potential advantages of risperidone should be weighed against the risk of unwanted effects, such as an increase in serum prolactin levels and weight gain. No relation was observed between total plasma risperidone and 9-OH-risperidone concentrations and clinical response.