The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis

Background: Late-onset GM(2) gangliosidosis (LGG) is a rare disease that is often considered in the differential diagnosis of adolescents and young adults who present with multiple realms of neurologic dysfunction. Cognitive disturbances are common but have not been systematically studied. Objective: To determine the natural history of cognitive dysfunction in patients with LGG. Design: Case series and literature review. Setting: Urban tertiary referral clinic. Patients: Individuals with hexosaminidase A deficiency as the origin of LGG. Main Outcome Measures: Cognitive dysfunction, psychiatric symptoms, and cerebellar, upper motor neuron, lower motor neuron, or extrapyramidal symptoms and signs. Results: Historical and examination data from 62 patients were found. Forty-four percent of LGG patients had some degree of cognitive dysfunction. Cognitive dysfunction was associated with a greater number of other elemental neurologic deficits. In 21 patients with acceptable longitudinal information, 8 (38%) had a static cognitive disorder, whereas progressive dementia was evident in 13 patients (62%), including 2 of our cases with serial neuropsychological testing. Neuroimaging often showed nonspecific cerebellar and/or cerebral atrophy. Conclusions: Cognitive dysfunction is a frequent manifestation of LGG. Patients who experience cognitive dysfunction are more likely to have a greater number of other neurologic manifestations of the disease. Cognitive dysfunction may take the form of static encephalopathy, but progressive dementia is more often encountered. The pathogenesis of cognitive dysfunction in this disease is unknown, highlighting the need for further study.