Presence of the Eye-of-the-tiger Sign on Magnetic Resonance Imaging in a Subject with Atypical Hallervorden-Spatz Syndrome Lacking Pantothenate Kinase 2 Mutation

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CASE REPORT

Presence of the Eye-of-the-tiger Sign on Magnetic Resonance Imaging in a Subject

with Atypical Hallervorden-Spatz Syndrome Lacking Pantothenate Kinase 2

Mutation

Szu-Kuan Yang

1

, Chaur-Jongh Hu

2,3

, Rey-Yue Yuan

3,4

, Hung-Jung Wang

5

, Jau-Jiuan Sheu

3,4 * 1_{Department of Neurology, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan}

2_{Department of Neurology, Taipei Medical University Shuang-Ho Hospital, Taipei County, Taiwan}

3_{Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan} 4_{Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan}

5_{Department of Radiology, Taipei Medical University Hospital, Taipei, Taiwan}

a r t i c l e i n f o

Article history: Received: Feb 9, 2011 Accepted: Sep 1, 2011 KEY WORDS: eye-of-the-tiger sign; Hallervorden-Spatz syndrome; pantothenate kinase 2

Hallervorden-Spatz syndrome (HSS) is generally considered to be a rare neurodegenerative disorder associated with autosomal recessive pantothenate kinase-associated neurodegeneration or neuro-degeneration with brain iron accumulation. The most well-known hallmark of the syndrome is the eye-of-the-tiger sign on the brain magnetic resonance imaging (MRI) scan. Previous studies have highlighted a one-to-one correlation between the MRIﬁndings of the eye-of-the-tiger sign and the presence of a pantothenate kinase 2 (PANK2) mutation, postulating that the MRI appearance is a good diagnostic tool for identifying PANK2 mutation-positive cases. We report an atypical HSS patient without a PANK2 mutation, who had an eye-of-the-tiger sign on MRI, therefore strengthening the notion of genetic and radiological heterogeneity in HSS.

1. Introduction

Hallervorden-Spatz syndrome (HSS) is a heterogeneous group of neurodegenerative disorders characterized by dystonia, parkin-sonism, and iron accumulation in the basal ganglia.1This syndrome is classified by clinical presentations to be either the classic or atypical form. In classic HSS, the disease is usually evident by 10 years of age with rapid progression to severe disability by 20 years of age. The predominant neurological features are dystonia, dysarthria, and rigidity. Cognitive decline and retinal changes are also constant features. In atypical HSS, the onset of extrapyramidal defects is later and the progression is slower. All patients with classic HSS and one-third of those with atypical disease have pantothenate kinase 2 (PANK2) mutations, and are said to have pantothenate kinase-associated neurodegeneration. Hayflick et al reported a one-to-one correlation between the magnetic resonance imaging (MRI)findings of the eye-of-the-tiger sign and the pres-ence of a PANK2 mutation and postulated that the MRI appearance is a good diagnostic tool for identifying PANK2 mutation-positive

cases.2 Herein, we report an atypical HSS patient without a PANK2 mutation, who had an eye-of-the-tiger sign on MRI. 2. Case report

A 38-year-old woman had progressively unsteady gait and frequent instances of falling in the past 5 years. The patient also developed mental deterioration and lost the ability to take care of her son. She later experienced depressive mood and suicide attempts. Her past medical and family histories were otherwise unremarkable. The neurological examination showed cognitive impairment, limb hyperreﬂexia, postural instability and bilateral feet dystonia. The patient had a normal peripheral blood smear, hemogram, biochemical and lipid pro_{ﬁle, and serum copper and ceruloplasmin.} A 1.5-T brain MRI scan showed abnormal iron deposition in the bilateral globus pallidi and substantia nigra. Within the globus pallidi, there was a central hyperintense signal demonstrating an eye-of-the-tiger sign on T2-weighted images (Figure 1). Screening the entire coding sequence of the PANK2 gene revealed no mutation.

3. Discussion

The eye-of-the-tiger sign on the MRI scan contributed to a diag-nosis of HSS for this patient. Early in the course of the disease, the

* Corresponding author. Department of Neurology, Taipei Medical University Hospital, 252 Wu-Hsing Street, Taipei, Taiwan.

E-mail: J.-J. Sheu <[email protected]>

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medial globus pallidi appear hypointense bilaterally on T2-weighted images as a result of iron deposition. The classic eye-of-the-tiger sign is generally present when symmetrical T2 hyper-intensity develops, superimposing upon the hypointense back-ground, presumably due to gliosis, increased water content, and neuronal loss with disintegration, vacuolization, and cavitation of the brain tissue.3,4The pathologicﬁndings of HSS demonstrate that there are areas with different tissue densities within the globus pallidi. The ﬁrst consists of a rather dense tissue containing dystrophic axons, reactive astrocytes, and residual neurons. The second pattern is associated with a rather loose tissue in which the above elements are separated by vacuoles. The area of loose tissue with vacuolization and lesser amounts of iron in the medial part of the globus pallidi corresponds to the area of high signal intensity in the T2-weighted images.5Baumeister et al reported a classic HSS patient who had lost the eye-of-the-tiger sign during the course of

the disease and postulated progressive atrophy leading to resorp-tion of the cavitated areas.6 We speculate that the presence or absence of T2 hyperintensity in the medial globus pallidi is deter-mined by a dynamic process between the degree of iron deposition and vacuole formation in this loose area. During the course of the disease, the eye-of-the-tiger sign is present in conditions of less iron deposition and more vacuole formation, and absent in condi-tions of more iron deposition and less vacuole formation.

Hayﬂick et al studied 123 patients from 98 families with a diagnosis of HSS, concluding that all patients with MRIﬁndings of the eye-of-the-tiger sign, whether classic or atypical, had PANK2 mutations.2However, Valentino et al reported a classic HSS patient who, despite having the eye-of-the-tiger sign, lacked the PANK2 mutation.7 _{Thus, the one-to-one correlation between PANK2}

mutations and the eye-of-the-tiger sign can no longer be accepted in classic HSS patients. Mutations in the PANK2 gene lead to a deﬁciency of cysteine dioxygenase and subsequent cysteine accumulation and iron deposition in the globus pallidi, resulting in free radical generation and oxidative damage in the brain.8,9 However, the relationship between PANK2 mutations, iron depo-sition, and vacuolization in the medial part of the globus pallidi is not clear and awaits further study. Ourﬁndings illustrate that the eye-of-the-tiger sign is also not always associated with mutations in the PANK2 gene in patients with atypical HSS, and strengthen the phenotypic and genetic heterogeneity of HSS.

References

1. Dooling EC, Schoene WC, Richardson Jr EP. Hallervorden-Spatz syndrome. Arch Neurol 1974;30:70e83.

2. Hayﬂick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KHL, Gitschier J. Genetic, clinical and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348:33e40.

3. Renaud DL, Kotagal S. Pantothenate-kinase associated neurodegeneration (PKAN)“eye of the tiger” sign. Pediatr Neurol 2007;36:70e1.

4. Guillerman RP. The eye-of-the-tiger sign. Radiology 2000;217:895e6. 5. Savoiardo M, Halliday WC, Nardocci N, Strada L, D’Incerti L, Angelini L, Rumi V,

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6. Baumeister FA, Auer DP, Hortnagel K, Freisinger P, Meitinger T. The eye-of-tiger sign is not a reliable disease marker for Hallervorden-Spatz syndrome. Neuro-pediatrics 2005;36:221e2.

7. Valentino P, Annesi G, Ciro Candiano IC, Annesi F, Civitelli D, Tarantino P, Naso F, et al. Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-tiger pattern. Mov Disord 2006;21:252e4.

8. Perry TL, Norman MG, Yong VW, Whiting S, Crichton JU, Hansen S, Kish SJ. Hallervorden-Spatz disease: cysteine accumulation and cysteine dioxygenase deﬁciency in the globus pallidus. Ann Neurol 1985;18:482e9.

9. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayﬂick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001;28:345e9.

Figure 1 T2-weighted magnetic resonance image of the patient showing hypointen-sity with central hyperintenhypointen-sity lesions in the medial globus pallidi.

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