New RAB3GAP1 mutations in patients with Warburg Micro Syndrome from different ethnic backgrounds and a possible founder effect in the Danish.

Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.

Comparison of three clinical rating scales in Friedreich ataxia (FRDA).

To test the validity and reliability of the scale for the assessment and rating of ataxia (SARA) in Friedreich ataxia (FRDA). SARA is limited to eight items and can be performed rapidly. Ninety-six patients with a molecular genetic diagnosis of FRDA were rated using three different clinical scales, the FRDA Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), and SARA. Despite considerable discrepancies in scale size and subscale structure, SARA total scores were significantly correlated with ICARS (r = 0.953, P < 0.0001) and FARS (r = 0.938, P < 0.0001) total scores. SARA total scores also correlated with the activities of daily living (ADL, r = 0.929, P < 0.0001). Although originally developed for the use in dominantly inherited ataxias, which are primarily ataxias of the cerebellar type, SARA can also be used successfully to assess afferent ataxia, which is the predominant form in FRDA. Because SARA is characterized by high interrater reliability and practicability, SARA is applicable and well suited forclinical trials of FRDA.

Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003.

PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. We provide an update on hepatotoxic side effects in Germany between 1994 and 2003. METHODS: We mailed a questionnaire to all members of the German Section of the International League Against Epilepsy, asking for VPA-induced side effects, especially severe side effects such as hepatopathy. RESULTS: As a result of our questionnaire, we found 31 cases of reversible hepatotoxicity and nine cases of lethal hepatopathies in Germany from 1994 to 2003. CONCLUSIONS: The outcome of patients with severe hepatotoxicity is better than that in the past. The risk of a VPA-induced hepatopathy is not limited to patients younger than 2 years, receiving polytherapy, or patients with congenital or acquired metabolic diseases.