Abstracts

Rationale: Epilepsy and paroxysmal dyskinesia are two distinct neurological disorders both characterized by recurrent periods of involuntary movements. These disorders can also coexist in one patient or family, but little is known about the genetics underlying these coexistent disorders. In our study a clinical evaluation and a molecular genetic analysis was performed in a large Belgian family with autosomal dominant exercise-induced paroxysmal dyskinesia and epilepsy.Methods: Detailed clinical questionnaires and interviews were conducted with affected and unaffected family members. Clinical evaluation was performed for most of the affected family members. Genome wide linkage analysis, under the assumption of an autosomal dominant inheritance model with a reduced penetrance of 95%, was performed to localize the disease-causing gene in a 5-generational Belgian family. Candidate genes in this region were screened for mutations to identify the disease-causing gene. Results: Clinical evaluation revealed at least 21 individuals with paroxysmal dyskinesia, epilepsy, or both. For five family members clinical information was not complete. Evidence for linkage of the coexistent paroxysmal dyskinesia and epilepsy phenotype to chromosome 1p was obtained. Mutation analysis of SLC2A1, encoding the GLUT1 protein, revealed the causal mutation segregating with the disease in this family. These results were confirmed by the identification of GLUT1 mutations in other two unrelated patients with comparable phenotypes and by the observation of reduced blood/CSF glucose ratios in all of these patients.Conclusions: The identification of this locus for coexistent paroxysmal dyskinesia and epilepsy and the identification of the GLUT1 mutations provides new insights into the pathophysiology of this disorder. Mutations in GLUT1 also lead to another more severe phenotype, the GLUT1 deficiency syndrome (GLUT1DS), which is characterized by infantile seizures, persistent hypoglycorrhachia, acquired microcephaly and developmental delay. The less drastic reduction of the blood/CSF glucose ratio (hypoglycorrhachia) in our patients, when compared to the GLUT1DS patients, corresponds to the less severe neurological phenotype we observe in our patients. The currently poor understanding of the pathophysiology and biochemistry of paroxysmal dyskinesia often makes the establishment of a satisfactory treatment plan difficult. Since the ketogenic diet is successful for patients with GLUT1DS, this diet could also be beneficial in the treatment of these patients.