In 1922, German investigators Hallervorden and Spatz reported a syndrome of neurologic and pathologic findings in a sibship of 12 individuals, among whom 5 siblings had progressive dysarthria and dementia. At autopsy, the investigators observed brown discoloration of the substantia nigra and the globus pallidus of the affected siblings. Since the initial report, hundreds of individuals with this disorder have been reported, and most have mutations of the PANK2 gene that encodes pantothenate kinase 2. In 2001, this disorder was named pantothenate kinase-associated neurodegeneration, also known as neurodegeneration with brain iron accumulation (OMIM #234200). The brown discoloration of the brains of persons with pantothenate kinase-associated neurodegeneration is caused by the deposition of excessive quantities of iron. This condition occurs in approximately 3 per 1,000,000 people. In a university hospital autopsy series that was evaluated to identify iron overload disorders specifically, only one case of neurodegeneration with brain iron accumulation was found in 10,345 adults (age ≥21 years) and 1337 children (>1 year of age).

Clinical manifestations

There is phenotypic heterogeneity in the clinical presentation of patients who have mutations of the PANK2 gene. The report of an international study published in 2003 describes findings in 186 patients from 145 families, including clinical histories, physical examination findings, laboratory characteristics, extrapyramidal neurologic abnormalities, and magnetic resonance imaging evidence of iron deposition in the basal ganglia.