The presenting symptoms of Lafora Disease: An electroclinical and genetic study in five Apulian (Southern Italy) families

Purpose: To elucidate the presenting symptoms of Lafora Disease (LD) to differentiate it from Juvenile Myoclonic Epilepsy (JME). Methods: We collected and evaluated the early electroclinical data of 5 unrelated Apulian (Southern Italy) LD families, 30 LD patients selected from the literature, and 30 Apulian JME patients. Results: The Apulian LD patients presented with generalised tonic-clonic and focal visual seizures, followed by myoclonic seizures and action-postural myoclonus. In these patients, EEG background slowing and occipital epileptiform abnormalities were significantly more evident than in the other groups. Genetic analysis revealed the presence of mutations in the EPM2A gene in 4 families, and in the NHLRC1 gene in the remaining family. In detail, we identified 2 different point mutations in EPM2A and only 1 in NHLRC1, and expanded the molecular spectrum of the EPM2A gene mutations reporting for the first time a patient carrier of the c.243_246del genetic variant. In the previously reported LD cases, generalised tonic-clonic and focal visual seizures and myoclonus were the most frequent symptoms, as confirmed by the first EEGs showing occipital or diffuse epileptiform abnormalities with photosensitivity in the background activity slowing. In the Apulian JME patients, myoclonus appeared earlier, usually at awakening, with diffuse epileptiform abnormalities during sleep and photosensitivity in the normal background activity. The diagnosis of JME was established much earlier than the LD one. During evolution, unlike JME patients, LD patients showed a significant resistance to drugs. Conclusions: Tonic-clonic and focal visual seizures followed by myoclonic seizures and action-postural myoclonus together with EEG background slowing with diffuse and occipital epileptiform abnormalities suggest a diagnosis of LD. An early molecular confirmation allows a better diagnosis, counselling and management of affected patients and their families, and it may be useful to improve the patients' quality of life using, when possible, emerging personalized treatments that may slow the evolution of the disease.