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Hallervorden and Spatz reported a rapidly progressive neurodegenerative disease of early onset in a German journal of neurology and psychiatry in 1922. The main clinical features are dystonia, dysarthria and rigidity, rapid progression, and early death. Until recently the diagnosis depended on clinical features and CT or MRI abnormalities in the globus pallidus. Pathologically, there is iron accumulation in the basal ganglia with destruction of the pallidum and substantia nigra. The classic disease is of early onset (infancy or early childhood) and rapidly progressive. Atypical forms present later and progress more slowly.
In 2001 researchers in California and Oregon linked Hallervorden-Spatz syndrome with a defect in the gene (PANK2) on the short arm of chromosome 20 (20p13) encoding the enzyme pantothenate kinase 2 which is important in coenzyme A synthesis. They have now delineated the clinical, genetic, and MRI features (Susan J Hayflick and colleagues.
). By advertising internationally they were able to obtain information about 186 patients from 145 families (123 patients from 98 families had enough clinical information for inclusion in the analysis). Sixty-six patients had classic disease and 57 had atypical forms.
They found that the classic disease was invariably associated with a PANK2 mutation whereas only 35% of families with atypical disease had such mutations. The gene defect was a null mutation (resulting in premature protein termination) in 36 of 92 alleles associated with the classic disease but in only 2 of 31 alleles in patients with atypical disease. Two null mutations invariably meant classic disease. (The other (non-null) mutations were missence mutations causing amino acid substitutions). Two mutations, both missense, (G411R and T418M) accounted for one third of the faulty genes. Although both classic and atypical diseases were generally autosomal recessive the G411R mutation appeared to be dominant in a few patients. Speech problems early in the course of the disease, psychiatric symptoms, and dementia were features particularly of patients with atypical disease and no PANK2 mutation and were rare in the classic disease. MRI scans from 69 patients with PANK2 mutations (65 with classic disease) all showed bilateral hypointensity in the medial globus pallidus on T2-weighted images with an area of hyperintensity at the anterior margins of the hypointensity—an appearance which has been given the name “eye of the tiger” pattern. The scans of 16 mutation-negative patients showed only the hypointensity without the eye of the tiger pattern.
All cases of classic Hallervorden-Spatz disease have a PANK2 mutation. One third of atypical cases have such a mutation. The eye of the tiger pattern on MRI signifies a PANK2 mutation.
↵* In an annotation (Michael Shevell. Ibid: 3–4) a call is made for the name Hallervorden-Spatz syndrome to be dropped. Julius Hallervorden was implicated in a programme of mass murder of disabled people in Nazi Germany and knowingly used the brains of victims as a basis for his reports; his name should not be perpetuated by the use of the eponym. The conditions should be called pantothenate kinase-associated degeneration or neurodegeneration with brain iron accumulation according to whether or not a PANK2 mutation is present.
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