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Background Up to 15% of cases of prion diseases are due to the autosomal dominant inheritance of coding PRNP mutations. Objective To describe the unique clinical and genetic findings in a family of East Indian origin with autosomal dominant inheritance of a novel PRNP mutation. Design Detailed neurological examination and sequencing analysis of the MAPT and PRNP genes. Setting Toronto Western Hospital, Toronto, Ontario. Patients Five available members of a family of East Indian origin with a rapidly progressive neurodegenerative disorder characterized by dementia, motor decline, and ataxia. Results We identified a novel Pro105Thr mutation in the PRNP gene in all of the 3 clinically affected family members but not in their unaffected relatives or normal controls. Although 5 of 6 affected family members had a relatively homogeneous phenotype and age at onset (range, 33-41 years), 1 of the 6 patients developed the disease at age 13 years. Conclusions A novel mutation in the PRNP gene was identified in all of the available, clinically affected members of this family with a rapidly progressive neurodegenerative disease. To our knowledge, the propositus represents the youngest individual with inherited prion disease described to date.