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Previous Volume 348:33-40 January 2, 2003 Number 1 Next

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ABSTRACT

Background Hallervorden–Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding pantothenate kinase 2 (PANK2); these patients are said to have pantothenate kinase–associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden–Spatz syndrome with and without mutations in PANK2.

Methods One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden–Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations.

Results All patients with classic Hallervorden–Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease led to amino acid changes, those in patients with classic disease more often resulted in predicted protein truncation. Patients with atypical disease who had PANK2 mutations were more likely to have prominent speech-related and psychiatric symptoms than patients with classic disease or mutation-negative patients with atypical disease. In all patients with pantothenate kinase–associated neurodegeneration, whether classic or atypical, T₂-weighted magnetic resonance imaging (MRI) of the brain showed a specific pattern of hyperintensity within the hypointense medial globus pallidus. This pattern was not seen in any patients without mutations.

Conclusions PANK2 mutations are associated with all cases of classic Hallervorden–Spatz syndrome and one third of cases of atypical disease. A specific MRI pattern distinguishes patients with PANK2 mutations. Predicted levels of pantothenate kinase 2 protein correlate with the severity of disease.

Source Information

From the Departments of Molecular and Medical Genetics, Pediatrics, and Neurology, School of Medicine, Oregon Health and Science University, Portland (S.J.H., S.K.W., M.A.J., K.H.L.C.); and the Howard Hughes Medical Institute and the Departments of Medicine and Pediatrics, University of California, San Francisco (B.L., B.Z., J.G.).

Address reprint requests to Dr. Hayflick at the Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Mailcode L-103a, Portland, OR 97201-3098, or at hayflick{at}ohsu.edu.

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