OBJECTIVE: Perry syndrome is a rapidly progressive autosomal dominant disorder with Parkinsonism, depression, weight loss, and central hypoventilation. BACKGROUND: So far five mutations in 11 families have been observed: G71R, G71E, G71A, T72P, and Q74P located in exon 2 of the dynactin 1 (DCTN1) gene on chromosome 2p13.1. In functional assays, all of them altered microtubule binding. DESIGN/METHODS: Genealogical, clinical, genetic, and functional studies were performed on three families from Colombia, New Zealand, and the USA. A diaphragmatic pacemaker was implanted in the Colombian family proband to treat her respiratory insufficiency. Dopaminergic therapy was initiated in the majority of the patients. RESULTS: In addition to three available probands, 14 symptomatic relatives from the three families were identified. The cardinal signs of Perry syndrome were present in all three probands with symptomatic disease onset in their sixth decade of life. Parkinsonian signs were mild to moderate with a poor response to dopaminergic treatment. All affected family relatives including the probands from the New Zealand and US families died of respiratory insufficiency. In the Colombian and US families the G71R mutation was identified, whereas in the New Zealand family a novel Y78C mutation was discovered, which also altered microtubule binding. The proband from the Colombian family is alive most likely due to early diagnosis and implantation of a diaphragmatic pacemaker. Follow-up examinations over the period of two years have revealed good function of the diaphragmatic pacemaker without any major complications. The patient has displayed a high grade of independence in her everyday life. CONCLUSIONS: Perry syndrome is a rare condition, but new cases will likely continue to emerge worldwide. Early diagnosis may prevent life-threatening acute respiratory failure. Diaphragmatic pacemakers should be considered as a safe and effective symptomatic treatment option. Parkinsonian features, although always present, may not be disabling. Study Supported by: NINDS P50NS072187, and NS078086, Mayo Clinic Center for Individualized Medicine, Gerstner Family Career Development Award, and Max Kade Foundation.