Defining Mutation Found in Hallervorden-Spatz Syndrome

Laurie Barclay, MD

January 02, 2003

Jan. 2, 2003 -- It is time to change the name of Hallervorden-Spatz syndrome, based on a report in the Jan. 2 issue of the New England Journal of Medicine. That study showed that all cases of the classic syndrome and many atypical cases had the pantothenate kinase-2 (PANK2) gene mutation, leading the authors to suggest that the syndrome should be termed pantothenate kinase-associated neurodegeneration.

"Hallervorden-Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain," write Susan J. Hayflick, MD, from Oregon Health and Science University in Portland, and colleagues. "The culprit gene (PANK2) encodes a novel pantothenate kinase, a key regulatory enzyme in the biosynthesis of coenzyme A."

Based on clinical assessment, 123 patients from 98 families with a diagnosis of Hallervorden-Spatz syndrome were classified as having classic disease characterized by early onset with rapid progression or atypical disease with later onset and slow progression.

All classic cases and one-third of atypical cases had PANK2 mutations, which typically caused protein truncation in classic cases and amino acid changes in atypical cases. On T1-weighted magnetic resonance imaging, all cases with the PANK2 mutation and none of the cases without this mutation had a specific pattern of hyperintensity within the hypointense medial globus pallidus. Predicted levels of PANK2 protein correlated with disease severity.

"We encourage the use of the term 'pantothenate kinase-associated neurodegeneration' for the majority of patients with Hallervorden-Spatz syndrome who have proved or suspected mutations in PANK2," the authors write. "For the remainder, we propose the term 'neurodegeneration with brain iron accumulation.' "

In an accompanying perspective, Michael Shevell, MDCM, from Montreal Children's Hospital in Quebec, Canada, traces the history of Julius Hallervorden, who identified the syndrome bearing his name. In Nazi Germany, diagnosis of this syndrome or of other causes of chronic disability condemned patients to euthanasia in the interests of "racial hygiene."

"This history concerns the corruption of medicine's core values within the framework of the most malevolent of 20th century totalitarian societies," he writes. "We as physicians are not a profession given to honoring mass murderers. The time has come to abandon the term 'Hallervorden-Spatz syndrome.' "

N Engl J Med. 2003;348(1):3-4, 33-40

Reviewed by Charlotte E. Grayson, MD