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Natural history of Type A Niemann-Pick disease

Possible endpoints for therapeutic trials

From the Departments of Human Genetics and Pediatrics (M.M.M., R.J.D., M.P.W.), Neurology and Pediatric (A.A.), and Ophthalmology (S.B.), Mount Sinai School of Medicine, New York, NY.

Address correspondence and reprint requests to Dr. Margaret M. McGovern, Professor and Vice Chair, Human Genetics, Mount Sinai School of Medicine, Box 1497, 100th Street and Fifth Avenue, New York, NY 10029; e-mail: margaret.mcgovern{at}mssm.edu

Objective: To describe the disease course and natural history of Type A Niemann-Pick disease (NPD).

Methods: Ten patients with NPD-A (six male, four female; age range at entry: 3 to 6 months) were serially evaluated including clinical neurologic, ophthalmologic, and physical examinations, and assessment of development. Laboratory analyses, abdominal and brain ultrasounds, and chest radiographs also were obtained and information on intercurrent illnesses and cause of mortality was collected.

Results: All affected infants had a normal neonatal course and early development. The first symptom detected in all patients was hepatosplenomegaly. Developmental age did not progress beyond 10 months for adaptive behavior, 12 months for expressive language, 9 months for gross motor skills, and 10 months for fine motor skills. Non-neurologic symptoms included frequent vomiting, failure to thrive, respiratory infections, irritability, and sleep disturbance. Neurologic examination at the time of presentation was normal in most patients. Later neurologic examinations revealed progressive hypotonia with loss of the deep tendon reflexes. All patients had cherry red spots by 12 months. The median time from diagnosis to death was 21 months. The cause of death was respiratory failure in nine patients and complications from bleeding in the tenth.

Conclusions: The clinical course in Type A Niemann-Pick disease is similar among affected patients and is characterized by a relentless neurodegenerative course that leads to death, usually within 3 years.

M.M.M. is the recipient of a NIH Mid Career Patient-Oriented Research Career Development Award (K24 RR021991-01) and M.P.W. is the recipient of a NIH Mentored Patient-Oriented Research Career Development Award (K23 RR16052). These studies were supported in part by a grant (5 MO1 RR00071) for the Mount Sinai General Clinical Research Center from the National Center for Research Resources, NIH.

Disclosure: The authors report no conflicts of interest.

Received August 16, 2005. Accepted in final form October 7, 2005.

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