Epilepsy and Cognition in GM2-Gangliosidosis B1 Variant – Experience of a Tertiary Hospital

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Introduction: GM2 gangliosidosis B1 variant (GM2B1) is an autosomal recessive disorder due to deficiency of β-hexosaminidase A, leading to the lysosomal storage of GM2 gangliosides in neuronal tissue and neuronal death. Symptoms include progressive motor coordination impairment and neurodegeneration, in children with previously normal development, leading to early death. Objective: Clinical characterization of patients with GM2B1 with a focus on epileptic manifestations. Methods: A descriptive retrospective study was conducted, analyzing clinical records of patients diagnosed with GM2B1 and followed at our Hospital Neuropediatric Department in the decade 2013-2022. Results: Four patients (three female) from three families diagnosed with GM2B1 were identified. The median age at diagnosis was 70 months. The most frequent symptoms at presentation were developmental regression (all children), language impairment (three), and epileptic seizures (two). Enzymatic deficiency in leukocytes and pathogenic variants in the HEXA gene were demonstrated in all cases. The pathogenic variant c.533G>A(p.R178H) in exon 5 was present in seven of the eight alleles. All patients experienced language impairment (Md=42 mos) with complete language loss (Md=78 mos). Loss of walking ability occurred in three patients (Md=96 mos). All patients experienced epileptic seizures during the course of the disease, with a median onset of seizures at 55 months. Initial seizures were classified as atypical absences (two), tonic seizures (one) and myoclonic seizures (one). Electroencephalographic evaluation revealed slow basal rhythm and focal paroxysmal activity in all cases. All were treated with antiseizure medication, two requiring a combination of three drugs. Conclusion: GM2B1 encompasses a wide clinical spectrum, with heterogenous age of symptom onset, clinical presentation and disease progression. Epilepsy is a common comorbidity in GM2B1, with variable seizure type and severity, and may be difficult to control. Timely diagnosis, coupled with multidisciplinary clinical follow-up, is crucial to improve quality of life of patients and enable genetic counseling.