Sections

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Sections Pantothenate Kinase-Associated Neurodegeneration (PKAN)
Overview
Presentation
DDx
Workup
Treatment
Medication
References

Workup

Approach Considerations

No biochemical markers have been found in pantothenate kinase-associated neurodegeneration (PKAN). Levels of copper, ceruloplasmin, lipids, amino acids, and acanthocytes typically are measured in the blood to exclude other conditions. Radionuclide scan reveals increased iron uptake in the basal ganglia.^[23]

Cultured skin fibroblasts have been reported to accumulate iron (⁵⁹ Fe) transferrin, but the isotope is no longer available for human use.

Increased platelet monoamine oxidase ̶ B activity has been reported.^[24]Bone marrow histiocytes and peripheral lymphocytes may demonstrate the presence of abnormal cytosomes, including fingerprint, granular, and multilaminated bodies.^{[25, 26]}The characteristics of the material suggest the presence of ceroid lipofuscin.

CT scanning

Computed tomography (CT) imaging is not very helpful in the diagnosis of PKAN but may show hypodensity in the basal ganglia and some atrophy of the brain. Calcification in the basal ganglia in the absence of any atrophy also has been described.

SPECT scanning

Iodine-123 (¹²³ I)-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) scanning and (¹²³ I)-iodobenzamide (IBZM)-SPECT scanning also have been used in making the diagnosis of PKAN.^{[27, 28]}

MRI

MRI has increased the likelihood of antemortem diagnosis of PKAN.^{[29, 30, 31]}The image below depicts the typical MRI appearance in PKAN, revealing bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted scanning. These imaging features are fairly diagnostic of PKAN and have been termed the "eye-of-the-tiger sign."^{[30, 31, 32, 33, 34]}

Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Pantothenate kinase-associated neurodegeneration (PKAN). The typical MRI findings include bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of PKAN, have been termed the "eye-of-the-tiger sign." The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition.

A study by McNeill et al concluded that in most cases of PKAN, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2 and T2, fast ̶ spin echo brain MRI.^[31]

Using a 7T MRI to quantify the amount of iron deposition, patients with PKAN were found to have a more than 3-fold higher concentration of iron in the globus pallidus, subthalamic nucleus and internal capsule, compared to normal controls. Patients heterozygous for the PANK2 mutation did not have any findings of iron deposition.^[35]

A recent study of 21 patients with PKAN compared to 21 age-matched controls, showed reductions of fractional anisotropy on diffusion tensor imaging mainly in the periventricular substance surrounding the third ventricle, the medial part of both putamina and in the frontal white matter including the anterior limbs of the internal capsules and the corpus callosum. In the infratentorial region, cerebellar white matter and dorsal parts of the pons and medulla were affected. This new finding indicates that cerebral tissue dysfunction is likely more widespread than previously thought.^[36]

Laboratory Studies

Molecular genetic testing used in PKAN and NBIA comprises testing for PANK2 through sequence or deletion/duplication analysis. When one pathogenic variant (sequence variant or partial- and whole-gene deletion) is identified in a person with an "eye of the tiger" sign on MRI, the diagnosis of PKAN is confirmed.^[37]

Treatment & Management

Neumann M, Adler S, Schluter O, et al. Alpha-synuclein accumulation in a case of neurodegeneration with brain iron accumulation type 1 (NBIA-1, formerly Hallervorden-Spatz syndrome) with widespread cortical and brainstem-type Lewy bodies. Acta Neuropathol (Berl). 2000 Nov. 100(5):568-74. [Medline].
Szumowski J, Bas E, Gaarder K, Schwarz E, Erdogmus D, Hayflick S. Measurement of brain iron distribution in Hallevorden-Spatz syndrome. J Magn Reson Imaging. 2010 Feb. 31(2):482-9. [Medline].
Schneider SA, Hardy J, Bhatia K. Iron Accumulation in Syndromes of Neurodegeneration with Brain Iron Accumulation 1 and 2 - causative or consequential?. J Neurol Neurosurg Psychiatry. 2009 Jan 15. [Medline].
Jankovic J, Kirkpatrick JB, Blomquist KA, et al. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology. 1985 Feb. 35(2):227-34. [Medline].
Grimes DA, Lang AE, Bergeron C. Late adult onset chorea with typical pathology of Hallervorden-Spatz syndrome. J Neurol Neurosurg Psychiatry. 2000 Sep. 69(3):392-5. [Medline].
Cooper GE, Rizzo M, Jones RD. Adult-onset Hallervorden-Spatz syndrome presenting as cortical dementia. Alzheimer Dis Assoc Disord. 2000 Apr-Jun. 14(2):120-6. [Medline].
Saito Y, Kawai M, Inoue K, et al. Widespread expression of alpha-synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protracted clinical course. J Neurol Sci. 2000 Aug 1. 177(1):48-59. [Medline].
Hickman SJ, Ward NS, Surtees RA, et al. How broad is the phenotype of Hallervorden-Spatz disease?. Acta Neurol Scand. 2001 Mar. 103(3):201-3. [Medline].
Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet. 1996 Dec. 14(4):479-81. [Medline].
Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden- Spatz syndrome. Nat Genet. 2001 Aug. 28(4):345-9. [Medline].
Hogarth P. Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord. 2015 Jan. 8 (1):1-13. [Medline].
Perry TL, Norman MG, Yong VW, Whiting S, Crichton JU, Hansen S, et al. Hallervorden-Spatz disease: cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus. Ann Neurol. 1985 Oct. 18 (4):482-9. [Medline].
Hayflick SJ. First scientific workshop on Hallervorden-Spatz syndrome: executive summary. Pediatr Neurol. 2001 Aug. 25 (2):99-101. [Medline].
Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet. 2009 Feb. 46 (2):73-80. [Medline].
Johnson MA, Kuo YM, Westaway SK, Parker SM, Ching KH, Gitschier J, et al. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci. 2004 Mar. 1012:282-98. [Medline].
Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM. Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 2005 Jan 19. 25 (3):689-98. [Medline].
Leoni V, Strittmatter L, Zorzi G, Zibordi F, Dusi S, Garavaglia B, et al. Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PANK2 mutations. Mol Genet Metab. 2012 Mar. 105 (3):463-71. [Medline].
Hayflick SJ. Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans. 2014 Aug. 42 (4):1063-8. [Medline].
Swaiman KF. Hallervorden-Spatz syndrome. Pediatr Neurol. 2001 Aug. 25 (2):102-8. [Medline].
Halliday W. The nosology of Hallervorden-spatz disease. J Neurol Sci. 1995 Dec. 134 Suppl:84-91. [Medline].
Rodriguez-Raecke R, Roa-Sanchez P, Speckter H, Fermin-Delgado R, Perez-Then E, Oviedo J, et al. Grey matter alterations in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN). Parkinsonism Relat Disord. 2014 Sep. 20 (9):975-9. [Medline].
Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. GeneReviews. Jan 2013.
Vakili S, Drew AL, Von Schuching S, Becker D, Zeman W. Hallervorden-Spatz syndrome. Arch Neurol. 1977 Dec. 34 (12):729-38. [Medline].
Zimmerman AW, Stover ML, Grasso JA. Uptake of 59Fe by skin fibroblasts and MAO activity in platelets from patients with Hallervorden-Spatz syndrome. Neurology. 1981. 51:48.
Swaiman KF, Smith SA, Trock GL, Siddiqui AR. Sea-blue histiocytes, lymphocytic cytosomes, movement disorder and 59Fe-uptake in basal ganglia: Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan?. Neurology. 1983 Mar. 33 (3):301-5. [Medline].
Alberca R, Rafel E, Chinchon I, Vadillo J, Navarro A. Late onset parkinsonian syndrome in Hallervorden-Spatz disease. J Neurol Neurosurg Psychiatry. 1987 Dec. 50 (12):1665-8. [Medline].
Hermann W, Reuter M, Barthel H, Dietrich J, Georgi P, Wagner A. Diagnosis of Hallervorden-Spatz disease using MRI, (123)I-beta-CIT-SPECT and (123)I-IBZM-SPECT. Eur Neurol. 2000. 43 (3):187-8. [Medline].
Kang A, Minoshima S. 123I-ioflupane SPECT findings of pantothenate kinase-associated neurodegeneration. Clin Nucl Med. 2014 Sep. 39 (9):849-51. [Medline].
Feliciani M, Curatolo P. Early clinical and imaging (high-field MRI) diagnosis of Hallervorden-Spatz disease. Neuroradiology. 1994 Apr. 36 (3):247-8. [Medline].
Lee JH, Gregory A, Hogarth P, Rogers C, Hayflick SJ. Looking Deep into the Eye-of-the-Tiger in Pantothenate Kinase-Associated Neurodegeneration. AJNR Am J Neuroradiol. 2018 Jan 25. [Medline].
McNeill A, Birchall D, Hayflick SJ, Gregory A, Schenk JF, Zimmerman EA, et al. T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation. Neurology. 2008 Apr 29. 70 (18):1614-9. [Medline].
Sethi KD, Adams RJ, Loring DW, el Gammal T. Hallervorden-Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol. 1988 Nov. 24 (5):692-4. [Medline].
Delgado RF, Sanchez PR, Speckter H, Then EP, Jimenez R, Oviedo J, et al. Missense PANK2 mutation without "eye of the tiger" sign: MR findings in a large group of patients with pantothenate kinase-associated neurodegeneration (PKAN). J Magn Reson Imaging. 2012 Apr. 35 (4):788-94. [Medline].
Chiapparini L, Savoiardo M, D'Arrigo S, Reale C, Zorzi G, Zibordi F, et al. The "eye-of-the-tiger" sign may be absent in the early stages of classic pantothenate kinase associated neurodegeneration. Neuropediatrics. 2011 Aug. 42 (4):159-62. [Medline].
Dusek P, Bahn E, Litwin T, Jabłonka-Salach K, Łuciuk A, Huelnhagen T, et al. Brain iron accumulation in Wilson disease: a post mortem 7 Tesla MRI - histopathological study. Neuropathol Appl Neurobiol. 2017 Oct. 43 (6):514-532. [Medline].
Stoeter P, Roa-Sanchez P, Speckter H, Perez-Then E, Foerster B, Vilchez C, et al. Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study. Parkinsonism Relat Disord. 2015 Jun. 21 (6):577-81. [Medline].
Hartig MB, Hörtnagel K, Garavaglia B, Zorzi G, Kmiec T, Klopstock T, et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation. Ann Neurol. 2006 Feb. 59 (2):248-56. [Medline].
Lin CI, Chen KL, Kuan TS, Lin SH, Lin WP, Lin YC. Botulinum toxin injection to improve functional independence and to alleviate parenting stress in a child with advanced pantothenate kinase-associated neurodegeneration: A case report and literature review. Medicine (Baltimore). 2018 May. 97 (20):e10709. [Medline].
Liu Z, Liu Y, Yang Y, Wang L, Dou W, Guo J, et al. Subthalamic Nuclei Stimulation in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN). Neuromodulation. 2017 Jul. 20 (5):484-491. [Medline].
Orellana DI, Santambrogio P, Rubio A, Yekhlef L, Cancellieri C, Dusi S, et al. Coenzyme A corrects pathological defects in human neurons of PANK2-associated neurodegeneration. EMBO Mol Med. 2016 Oct. 8 (10):1197-1211. [Medline].
Rohani M, Razmeh S, Shahidi GA, Alizadeh E, Orooji M. A pilot trial of deferiprone in pantothenate kinase-associated neurodegeneration patients. Neurol Int. 2017 Dec 11. 9 (4):7279. [Medline].
Christou YP, Tanteles GA, Kkolou E, Ormiston A, Konstantopoulos K, Beconi M, et al. Open-Label Fosmetpantotenate, a Phosphopantothenate Replacement Therapy in a Single Patient with Atypical PKAN. Case Rep Neurol Med. 2017. 2017:3247034. [Medline].
Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report. J Neurosurg. 1999 Mar. 90 (3):551-4. [Medline].
Mikati MA, Yehya A, Darwish H, Karam P, Comair Y. Deep brain stimulation as a mode of treatment of early onset pantothenate kinase-associated neurodegeneration. Eur J Paediatr Neurol. 2009 Jan. 13 (1):61-4. [Medline].
Castelnau P, Cif L, Valente EM, Vayssiere N, Hemm S, Gannau A, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol. 2005 May. 57 (5):738-41. [Medline].
Hogarth P, Kurian MA, Gregory A, Csányi B, Zagustin T, Kmiec T, et al. Consensus clinical management guideline for pantothenate kinase-associated neurodegeneration (PKAN). Mol Genet Metab. 2017 Mar. 120 (3):278-287. [Medline].
Santana M, Alvarez F, Baez A, Roa-Sanchez P, Stoeter P. Neurologic improvement after a hypercaloric diet in two patients with pantothenate kinase-associated neurodegeneration. The Journal of Rare Disorders. 2015. 3:45.

Media Gallery

Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Pantothenate kinase-associated neurodegeneration (PKAN). The typical MRI findings include bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of PKAN, have been termed the "eye-of-the-tiger sign." The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition.

of 1

Author

Philip A Hanna, MD Associate Professor of Neuroscience, JFK Neuroscience Institute at JFK Medical Center, Hackensack Meridian School of Medicine at Seton Hall University

Philip A Hanna, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Coauthor(s)

Neeta Garg, MD, DM Assistant Professor, Department of Neurology, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Neeta Garg, MD, DM is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Esther Fischer, MD Resident Physician, Department of Neurology, JFK Neuroscience Institute, JFK Medical Center, Hackensack Meridian School of Medicine at Seton Hall University

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Alliance, Bioserenity, Ceribell, Eisai, Greenwich, LivaNova, Neurelis, Neuropace, Nexus, RSC, SK life science, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Alliance, Aquestive, Bioserenity, Eisai, Greenwich, LivaNova, Neurelis, SK life science, Sunovion<br/>Received research grant from: Cerevel, LivaNova, Greenwich, SK biopharmaceuticals, Takeda.

Acknowledgements

Nestor Galvez-Jimenez, MD, MSc, MHA Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Brian L Gerhardstein, MD, PhD Staff Physician, Department of Neurology, New Jersey Neuroscience Institute, JFK Medical Center

Disclosure: Nothing to disclose.

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Sections Pantothenate Kinase-Associated Neurodegeneration (PKAN)
Overview
Presentation
DDx
Workup
Treatment
Medication
References

Pantothenate Kinase-Associated Neurodegeneration (PKAN) Workup

Approach Considerations

CT Scanning and MRI

CT scanning

SPECT scanning

MRI

Laboratory Studies

Pantothenate Kinase-Associated Neurodegeneration (PKAN) Workup

Approach Considerations

CT Scanning and MRI

CT scanning

SPECT scanning

MRI

Laboratory Studies

References

Tables

Contributor Information and Disclosures

What would you like to print?