GM2-gangliosidosis (McKusick 268800 and 272800) is a rare hereditary, progressive disorder of ganglioside metabolism caused by deficiency of lysosomal beta-hexosaminidase (EC 3.2.1.52) activity. It is characterized by severe central nervous system involvement. Involvement of the peripheral and autonomic nervous system has been suspected but rarely documented in published case reports in the chronic form of the disease. Four patients, aged 24-29 years, with chronic GM2-gangliosidosis were examined prospectively for evidence of peripheral and autonomic nervous system dysfunction. All had nerve conduction studies, sympathetic skin responses and cardiac monitoring during the head tilt-table test. Three patients had objective evidence of autonomic dysfunction with abnormal sympathetic nervous skin responses and axonal sensorimotor polyneuropathy. None of the patients had evidence of significant cardiovascular autonomic dysfunction on the head tilt-table test. The peripheral and autonomic nervous system may be involved in patients with chronic GM2-gangliosidosis. In some cases, this may be clinically significant. On the other hand, cardiovascular autonomic instability is apparently not a significant problem in young adult patients with the disease.