Abstracts

Rationale: Neonatal-onset intractable epilepsy is a rare and severe condition of unknown etiology in many cases. Recently, early-onset intractable epilepsy associated with ponto-cerebellar atrophy has been reported in patients harbouring homozygous mutation in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene. We describe the electroclinical phenotype and epilepsy course in patients with RARS2 mutations. Methods: We retrospectively analyzed the electroclinical features in five patients from three unrelated Italian families with neonatal-onset multifocal seizures and progressively intractable epileptic encephalopathy associated with ponto-cerebellar atrophy and carrying disease-related variants in RARS2.Results: All patients were born after an uneventful pregnancy with a normal neurological examination and head circumference at birth. Follow-up ranged from of 3 to 12 years. In all patients we observed a similar course for the epilepsy,consisting of three stages. Stage I was characterized by neonatal-onset ictal apnea and/or focal clonic seizures involving alternatively both sides of the body, controlled by first-line AEDs. EEG at onset showed a normal or mildly abnormal background with sporadic multifocal epileptiform abnormalities. Within the first year of life, all patients developed an epileptic encephalopathy (Stage II) with cluster of tonic spasms and a burst-suppression EEG pattern and persistence of focal seizures consisting of eye deviation, psychomotor arrest or tonic body contractions. Ictal EEG of spasms showed a high-voltage diffuse slow wave followed by low-amplitude fast activity. The third phase (Stage III) was characterized by the appearance of erratic myoclonic jerks with and without EEG correlate, together with the persistence of multifocal seizures followed by clusters of tonic spasms. Interictal EEG showed an epileptic encephalopathy lacking any physiological features and organization with multifocal slow and epileptiform abnormalities. After the stage I, epilepsy became severe with multiple daily seizures highly resistant to AEDs and steroids. The appearance of seizures and the evolution of epilepsy was paralled by a progressive microcephaly and a virtual absence of psychomotor development. MRI showed a progression of ponto-cerebellar atrophy and cerebral cortical atrophy. While ponto-cerebellar atrophy is a key feature of the disorder, it was not present at onset in 2/5 patients, becoming evident only during the first year of life. Despite RARS2 being a genetic defect of mitochondrial protein synthesis, lactic acidosis was rarely detected after the first months of life. Conclusions: Our results contribute to determine the epilepsy profile associated with RARS2 mutations. Although there is no specific EEG pattern, an epilepsy course can be clearly recognized. The diagnosis is important due to the family recurrence. We emphasize that mutation analysis of RARS2 should be looked for in patients with early-onset multifocal intractable epilepsy associated with ponto-cerebellar atrophy even in the absence of lactic acidosis.