Pantothenate kinase-associated neurodegeneration
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Pantothenate kinase-associated neurodegeneration (PKAN), historically also known as Hallervorden-Spatz syndrome, is an autosomal recessive disorder causing involuntary spasticity and progressive dementia. It is a subset of neurodegeneration with brain iron accumulation (NBIA).
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Classical PKAN tends to have onset before 6 years of age, whereas atypical PKAN manifests at a mean age of 14 years 10. Prevalence is estimated around 1-3 per million 10.
Described features include 9,11:
- progressive dementia
- extrapyramidal signs (rigidity, dystonia, choreoathetosis)
- corticospinal signs (spasticity, hyperreflexia)
- retinitis pigmentosa
The clinical course is usually relentlessly progressive with affected individuals dying in their second or third decade.
The diagnosis is made by a combination of clinical and imaging features, however, genetic testing and full gene sequencing of the PANK2 gene to identify biallelic PANK2 pathogenic variants is considered the gold standard 14.
Reflects areas of iron deposition, mainly in the globi pallidi, substantia nigra, and red nuclei.
CT is of limited utility but often shows calcification the globi pallidi which, however, is non-specific and has a long differential (basal ganglia calcification) 15.
- T2: T2-weighted MRI images often demonstrate hypointense changes in the globus pallidi and pars reticulata of the substantia nigra
- SWI/T2*: shows susceptibility artifact (low signal) in corresponding areas from iron deposition 7
Cortex is usually spared but caudate atrophy may be seen in more advanced cases. The eye of the tiger sign refers to a central T2 relatively hyperintense spot (line) within the hypointense globi pallidi due to gliosis and vacuolisation 3.
- shows decreased NAA peak due to neuronal loss and may show increased myoinositol 8
History and etymology
The condition was previously named after two 20th century German neuropathologists Julius Hallervorden (1882-1965) and, his superior, Hugo Spatz (1888-1969) 1,12
Julius Hallervorden personally examined 697 brains from disabled adults and children who had been murdered as part of the Nazi euthanasia program at the Kaiser-Wilhelm-Institut für Hirnforschung in Berlin-Buch. Hugo Spatz was Director of this division. Thus the alternate name of the condition - pantothenate kinase-associated neurodegeneration - is now preferred by contemporaneous authors 13.
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- 3. Guillerman RP. The eye-of-the-tiger sign. Radiology. 2000;217 (3): 895-6. Radiology (full text) - Pubmed citation
- 4. Hallervorden, H. Spatz: Eigenartige Erkrankung im extrapyramidalen System mit besonderer Beteiligung des Globus pallidus und der Substantia nigra: Ein Beitrag zu den Beziehungen zwischen diesen beiden Zentren. Zeitschrift für die gesamte Neurologie und Psychiatrie, 1922, 79: 254-302.
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- 6. Yang S-K, Hu C-J, Yuan R-Y, Wang H-J, Sheu J-J. 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. J. Exp. Clin. Med. [Internet]. Elsevier; 2012 Feb 1 [cited 2013 Nov 12];4(1):73–4. Journal of Experimental and Clinical Medicine citation
- 7. Bosemani T, Meoded A, Poretti A. Susceptibility-Weighted Imaging in Pantothenate Kinase-Associated Neurodegeneration. J. Pediatr. [Internet]. 2013 Oct 7 [cited 2013 Nov 12]. Pubmed citation
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- 9. Asumal KB, Wasay M, Ali SN. Radiologic features of Hallervorden Spatz Disease. J Pak Med Assoc. 2003;52 (11): 528-30. Pubmed citation
- 10. Kurian MA, Hayflick SJ. Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): review of two major neurodegeneration with brain iron accumulation (NBIA) phenotypes. (2013) International review of neurobiology. 110: 49-71. doi:10.1016/B978-0-12-410502-7.00003-X - Pubmed
- 11. Dashti M, Chitsaz A. Hallervorden-Spatz disease. (2014) Advanced biomedical research. 3: 191. doi:10.4103/2277-9175.140623 - Pubmed
- 12. Van Bogaert L. Julius Hallervorden (1882-1965). (1967) Journal of the neurological sciences. 5 (1): 190-1. Pubmed
- 13. Hughes JT. Neuropathology in Germany during World War II: Julius Hallervorden (1882-1965) and the Nazi programme of 'euthanasia'. (2007) Journal of medical biography. 15 (2): 116-22. doi:10.1258/j.jmb.2007.06-57 - Pubmed
- 14. Allison Gregory, Susan J Hayflick. Pantothenate Kinase-Associated Neurodegeneration. (2017) Pubmed
- 15. Wu YW, Hess CP, Singhal NS, Groden C, Toro C. Idiopathic basal ganglia calcifications: an atypical presentation of PKAN. (2013) Pediatric neurology. 49 (5): 351-4. doi:10.1016/j.pediatrneurol.2013.06.021 - Pubmed