The “Eye-of-the-Tiger” Sign may be Absent in the Early Stages of Classic Pantothenate Kinase Associated Neurodegeneration

Abstract

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disorder associated with brain iron accumulation. The brain MRI abnormality consists of T₂ hypointensity in the globus pallidus with a small hyperintensity in its medial part, called the “eye-of-the-tiger” sign. We report on 2 patients affected by PKAN, in whom MRI examination did not demonstrate the “eye-of-the-tiger” sign in the early stages; the typical abnormalities were detected only in the following examinations. Case 1 is a 4-year-old boy first studied at age 2 years for psychomotor delay. The brain MRI was normal. In the following 2 years, the motor impairment progressed. The second brain MRI at age 4 years demonstrated the “eye-of-the-tiger” sign. Molecular analysis of the PANK2 gene revealed a missense mutation F228S in exon 2 in homozygosis. Case 2 is a 6-year-old boy first studied at age 2 years because of psychomotor delay. His brain MRI did not demonstrate abnormalities in the globus pallidus. In the following years spastic-dystonic tetraparesis became evident. A brain MRI at age 4 years demonstrated the “eye-of-the-tiger” sign. Molecular analysis of the PANK2 gene revealed a missense mutation in exon 5 (N501I). Our 2 cases demonstrate that the observation of a normal globus pallidus in the early stage of the disease does not exclude the diagnosis of classic PKAN.

Key words

brain iron accumulation - PKAN - eye-of-the-tiger sign

• References

• 1 Angelini L, Nardocci N, Rumi V et al. Hallervorden-Spatz disease: clinical and MRI study of 11 cases diagnosed in life. J Neurol 1992; 239: 417-425
• 2 Brouwer OF, Laboyrie PM, Peters ACB et al. Follow-up magnetic resonance imaging in Hallervorden-Spatz disease. Clin Neurol Neurosurg 1992; 94 (Suppl) S57-S60
• 3 Dooling EC, Schoene WC, Richardson Jr EP. Hallervorden-Spatz syndrome. Arch Neurol 1974; 30: 70-83
• 4 Gallucci M, Cardona F, Arachi M et al. Follow-up MR studies in Hallervorden-Spatz disease. J Comput Assist Tomogr 1990; 14: 118-120
• 5 Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009; 46: 73-80
• 6 Hartig MB, Hortnagel K, Garavaglia B et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol 2006; 59: 248-256
• 7 Hayflick SJ, Penzien JM, Michl W et al. Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome. Pediatr Neurol 2001; 25: 166-169
• 8 Hayflick S, Westaway S. Pantothenate kinase mutation without “eye-of-the-tiger” sign. Pediatr Radiol 2006; 36: 1329
• 9 Hayflick SJ, Westaway SK, Levinson B et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003; 348: 33-40
• 10 Kruer MC, Hiken M, Gregory A. Novel histopathologic findings in molecularly-confirmed panthotenate kinase-associated neurodegeneration. Brain 2011; 134: 947-958
• 11 Kruer MC, Paisán-Ruiz C, Boddaert N et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 2010; 68: 611-618
• 12 McNeil A, Birchall D, Hayflick SJ et al. T₂* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology 2008; 70: 1614-1619
• 13 Mutoh K, Okuno T, Ito M et al. MR imaging of a group I case of Hallervorden-Spatz disease. J Comput Assist Tomogr 1988; 12: 851-853
• 14 Savoiardo M, Halliday WC, Nardocci N et al. Hallervorden-Spatz disease: MR and pathologic findings. AJNR Am J Neuroradiol 1993; 14: 155-162
• 15 Sethi KD, Adams RJ, Loring DW et al. Hallervorden-Spatz syndrome: Clinical and magnetic resonance imaging correlations. Ann Neurol 1988; 24: 692-694
• 16 Zhou B, Westaway SK, Levinson B et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001; 28: 345-349
• 17 Zolkipli Z, Dahmoush H, Saunders DE et al. Pantothenate kinase 2 mutation with classic pantothenate-kinase-associated neurodegeneration without “eye-of-the-tiger” sign on MRI in a pair of siblings. Pediatr Radiol 2006; 36: 884-886
• 18 Zorzi G, Zibordi F, Chiapparini L et al. Iron-related MR images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 2011; May 6, DOI: 10.1002/mds.23751.