Clinical features, disease evolution, ocular phenotype and electroretinogram abnormalities in Italian Lafora disease patients: a road to precision therapy

INTRODUCTION: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration,associated with pathogenic variants in EPM2A/EPM2B, encoding laforin and malin, two glycogen metabolism enzymes. Long-term follow-up data of this rare disease are lacking. So we collect the entire Lafora Disease italian population describing the clinical features and genetic findings. Moreover In order to identify a safe non invasive and rapid biological marker of Lafora disease we examined retina anatomy, FAF, SD, OCT, visual acuity and color vision of a particular subgroup of these patients. . METHODS: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale .Spontaneous/action myoclonus severity was scored by the Magaudda Scale. In a subgroups of patients we examined retina color and visual acuty in the ocular department at San Martino‘s institute, in Genova RESULTS: Age range was 12.2-46.2 years (mean:25.53±9.14) for the italian Lafora's population. Age at disease onset ranged from 10 to 22 years (mean:14.04±2.62). Mean follow-up period was 11.48±7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech.An overall slower progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9(35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring thehomozygous p.(D146N) variant. In ten patients Full field ERG analysis revealed generalized ROD bipolar involvement and photoreceptor involvement. CONCLUSIONS: We confirm an overall worse disease outcome with severe deterioration of ambulation and speech in patients harbouring EPM2A variants. However, a slower onset of disabling symptoms in EPM2Bsubjects harbouring the p.(D146N) variant suggests that the LD disease severity canindeed be related to the underlying specific causative variant. Moreover we confirm that LD patients show retinal impairment regardless of their disease stage. The dysfunction grade may be related to disease duration. ERG may be an important tool to detect early stage LD, to evaluate disease progression and eventually a biomarker to assess the efficacy of future treatments.