Brain MRI in Neurodegeneration with Brain Iron Accumulation with and without PANK2 Mutations ============================================================================================ * S.J. Hayflick * M. Hartman * J. Coryell * J. Gitschier * H. Rowley ## Abstract **BACKGROUND AND OBJECTIVE:** Patients with a clinical diagnosis of neurodegeneration with brain iron accumulation (NBIA, formerly called Hallervorden-Spatz syndrome) often have mutations in *PANK2*, the gene encoding pantothenate kinase 2. We investigated correlations between brain MR imaging changes, mutation status, and clinical disease features. **METHODS:** Brain MRIs from patients with NBIA were reviewed by 2 neuroradiologists for technical factors, including signal intensity abnormalities in specific brain regions, presence and location of atrophy, presence of white matter abnormality, contrast enhancement, and other comments. *PANK2* genotyping was performed by polymerase chain reaction amplification of patient genomic DNA followed by automated nucleotide sequencing. **RESULTS:** Sixty-six MR imaging examinations from 49 NBIA patients were analyzed, including those from 29 patients with mutations in *PANK2*. All patients with mutations had the specific pattern of globus pallidus central hyperintensity with surrounding hypointensity on T2-weighted images, known as the eye-of-the-tiger sign. This sign was not seen in any studies from patients without mutations. Even before the globus pallidus hypointensity developed, patients with mutations could be distinguished by the presence of isolated globus pallidus hyperintensity on T2-weighted images. Radiographic evidence for iron deposition in the substantia nigra was absent early in disease associated with *PANK2* mutations. MR imaging abnormalities outside the globus pallidus, including cerebral or cerebellar atrophy, were more common and more severe in mutation-negative patients. No specific MR imaging changes could be distinguished among the mutation-negative patients. **CONCLUSION:** MR imaging signal intensity abnormalities in the globus pallidus can distinguish patients with mutations in *PANK2* from those lacking a mutation, even in the early stages of disease. Since its introduction into clinical use, brain MR imaging has enabled the premortem diagnosis of Hallervorden-Spatz syndrome,1, 2 now called neurodegeneration with brain iron accumulation (NBIA). Historically, all patients who had radiographic evidence of increased amounts of iron in the globus pallidus were assigned this clinical diagnosis, which we now recognize to include several distinct disorders. Now that the genetic basis of the major form of NBIA has been delineated, brain MR imaging is again proving highly effective in distinguishing among the different forms of this disorder.3 NBIA is a heterogeneous group of disorders characterized by neurodegeneration and excessive iron deposition in the basal ganglia. Patients generally fall into 2 clinical categories: (1) early onset, rapidly progressive (classic) disease or (2) late onset, slowly progressive (atypical) disease. Recently, the defective gene that causes most cases of NBIA was identified.4 This gene, called *PANK2*, encodes a pantothenate kinase that is important in the biosynthesis of coenzyme A from vitamin B5. *PANK2* was shown to be mutated in all cases of classic NBIA and in one third of cases of atypical disease,3 and these patients were designated as having pantothenate kinase-associated neurodegeneration (PKAN, OMIM no. 234200). No genetic or pathogenic basis for the remainder of atypical NBIA cases has been determined. In NBIA, the diagnostic MR imaging feature is signal hypointensity in the globus pallidus on T2-weighted imaging, which correlates with the accumulation of iron that is observed on pathologic examination. A range of other brain MR imaging changes have been reported in patients with this diagnosis, including the pattern designated as the eye-of-the-tiger sign, which combines high signal intensity in the center of the globus pallidus interna with low signal intensity in the surrounding region.2 We have shown that there is an absolute correlation between the presence of a mutation in *PANK2* and the eye-of-the-tiger sign3; that is, all patients with the *PANK2* mutation have this MR imaging pattern, which also is not seen in any mutation-negative patients. In the current study, we investigated correlations between brain MR imaging changes, *PANK2* genotype, and clinical disease features. ## Methods Brain MR imaging studies were collected from NBIA patients after informed consent for a protocol that had been approved by the Institutional Review Boards of Oregon Health & Science University or University of California San Francisco. The MR images were interpreted by 2 neuroradiologists who were blinded to patient disease status and all clinical information except age, which was sometimes available from the films. Imaging data that were collected for this study included magnetic field strength in Tesla, pulse sequences used, signal intensity (scored as hypointense, isointense, or hyperintense) in specific brain regions (including globus pallidus interna and externa, substantia nigra, thalamus, putamen, and caudate) on T1- and T2-weighted studies, presence of the eye-of-the-tiger sign, presence and location of atrophy, presence of white matter abnormality, and enhancement on gadolinium contrast study. We operationally defined “T2-weighted” as a technique with repetition time of >2000 ms and echo time of >60 ms, based on a conventional spin-echo, fast spin-echo, or turbo spin-echo pulse sequence. “T2*-weighted” sequences were defined as those with low flip angles acquired with a gradient echo technique designed to accentuate T2* susceptibility effects. Because this was a retrospective collection of clinical cases, the exact MR parameters varied from site to site. The readers’ analysis reported here took into account an appreciation of sequence, timing parameters, and field strength in determining normal versus abnormal signal intensity characteristics. It is important to recognize that the imaging findings described were robust and not dependent on subtle changes in sequence parameters or even field strength. The examples shown in the figures are representative cases done at 1.5T by using sequences and parameters widely used throughout the world. Some of the MR images were previously reviewed for the presence of the eye-of-the-tiger sign and reported.3 *PANK2* genotype data were obtained by using published methods.4 Statistical analyses were performed by using an on-line tool ([http://www.georgetown.edu/faculty/ballc/webtools/web_chi.html](http://www.georgetown.edu/faculty/ballc/webtools/web_chi.html)). ## Results Radiographic data from 66 independent studies were collected on 49 patients who carried the diagnosis of NBIA, including 2 studies from each of 13 patients and 3 studies from 2 patients each. Fourteen image sets included only T2-weighted scans. The earliest studies were performed in 1988 on a 0.3T unit. Two studies were done on 0.5T scanners, and the remainder (94%) were done on 1.5T units. Patients ranged in age from 1.5 to 59 years at the time of the examination. Of the 49 persons studied, 29 patients from 21 families had mutations in *PANK2*. All patients with a *PANK2* mutation demonstrated a specific pattern on T2-weighted imaging called the eye-of-the-tiger sign,2 which was evident on studies performed on 0.3T, 0.5T, and 1.5T units (Fig 1). This sign, which consists of T2- signal hypointensity in the globus pallidus with a central region of T2-hyperintensity, was not observed in studies from any of the 20 patients without the mutation. Instead, these patients had only signal hypointensity in the globus pallidus. ![Fig 1.](http://www.ajnr.org/https://ajnr-sso.highwirestaging.com/content/ajnr/27/6/1230/F1.medium.gif) [Fig 1.](http://www.ajnr.org/content/27/6/1230/F1) **Fig 1.** Eye-of-the-tiger sign (*arrows*). This 10-year-old boy with the *PANK2* mutation shows MR features characteristic of PKAN. The T1-weighted images appear normal, but high signal intensity can be seen in the globus pallidus on proton attenuation (PD), T2-weighted fluid-attenuated inversion recovery (FLAIR), and T2-weighted images in both the axial and coronal planes. With increasingly heavier T2 weighting (PD