Pantothenate Kinase-Associated Neurodegeneration

Neurology International 2018; volume 10:7516

Pantothenate kinase-associated toms.4-6 This review aims to describe the neurodegeneration: clinical manifestation, pathophysiology and Correspondence: Saeed Razmeh, Yasuj the treatment of PKAN disease. University of Medical Sciences, Kohgiluyeh Clinical aspects, diagnosis and Boyer-Ahmad Province, Yasuj, Shahid and treatments Motahari Blvd, Iran. E-mail: [email protected]

1 2 Materials and Methods Saeed Razmeh, Amir Hassan Habibi, Key words: Pantothenate Kinase-Associated 2 2 Maryam Orooji, Elham Alizadeh, Etiology Neurodegeneration, Neurodegeneration with 3 Karim Moradiankokhdan, The iron normally accumulated in the brain iron accumulation. Behroz Razmeh3 basal ganglia, hippocampus, cerebellar Contributions: the authors contributed equally. 1Yasuj University of Medical Sciences, nuclei and another subcortical region.7 The 2 Yasuj; Iran University of Medical PKAN characterized by a mutation in the Conflict of interest: the authors declare no Sciences, Tehran; 3Kermanshah PANK 2 that codes the pantothenate kinase potential conflict of interest. University of Medical Sciences, 2. Mutations are missense, duplication, Kermanshah, Iran deletion, splice site mutation and deletion of Funding: none. exon.8 This protein kinase is responsible for the phosphorylation of pantothenate and Received for publication: 30 November 2017. this product combine with cysteine. The Revision received: 29 December 2017. Accepted for publication: 4 February 2018. Abstract cysteine increase in the globus pallidus of patients with PKAN that in association with This work is licensed under a Creative iron produce free radicals and cell dama- Pantothenate Kinase-Associated Commons Attribution NonCommercial 4.0 9,10 Neurodegeneration (PKAN) is an autoso- ge. The Mutations of PANK2 also found License (CC BY-NC 4.0). mal recessive disorder characterized by a in patients with HARP (hypoprebetalipo- mutation in the PANK2 gene. The clinical proteinemia, acanthocytosis, retinitis pig- ©Copyright S. Razmeh et al., 2018 presentation may range from only speech mentosa, and pallidal degeneration). The Licensee PAGEPress, Italy disorder to severe generalized dystonia, HARP is rare disease and has mental decli- Neurology International 2018; 10:7516 spasticity, Visual loss, dysphagia and ne, abnormal movement and vision loss.11 doi:10.4081/ni.2018.7516 dementia. The hallmark of this disease is eyes of the tiger sign in the medial aspect of Diagnosis bilateral globus pallidus on T2-weighted Today, the PKAN disease is diagnosed MRI that is a hyperintense lesion surround- by magnetic resonance imaging and con- Classification and presentations ed by hypointensity. Common treatments 12 firmed with the genetic test. Susceptibility It separated into classic and atypical for PKAN disease include anticholinergics, weighted imaging (SWI) and field dependent form. The classic form starts in early child- botulinum toxin, Oral and Intrathecal R2 increase (FDRI) are the choice methods hood with rapid progression of symptoms baclofen, Iron chelation drugs and surgical for the diagnosis of this disease and FDRI is including Parkinsonism, dystonia, cognitive procedures such as ablative pallidotomy or more sensitive than SWI for detection of decline and dementia, dysarthria, spasticity, thalamotomy, Deep brain stimulation. brain iron.13 We can also use the cranial There are many controversies about the seizure, optic atrophy, pigmentary retinopa- sonography that detects the over load of iron thy that disable the patient very sever. pathogenesis and treatment of this disease, 14 in midbrain. The hallmark of this disease in Atypical form of disease has later onset and and in recent years interesting studies have the BRAIN MRI is eye of the tiger sign. The been done on PKAN disease and other sim- less common than classic form and it may eye of the tiger is a hyperintense lesion sur- not be recognized by aging and has milder ilar diseases. This review summarizes the rounded by hypointensity in the medial clinical presentation, etiology, imaging symptoms with slow progression in com- aspect of bilateral globus pallidus on T2- 20,21 modalities and treatment. pared to classic type. The neuropsychi- weighted MRI. Central hyperintensity shows atric disorder includes Obsessive- gliosis in globus pallidus and the surround- Compulsive Disorder (OCD) , depression ing hypointensity showing iron deposition and schizophrenia-like psychosis.22 In study (Figures 1 and 2).15 All of the patients with Introduction that assessed the Intellectual and adaptive eye-of-the-tiger sign don’t have PANK2 behavior functioning 16 children and adults Neurodegeneration with brain iron mutation, Streckera et al. report a patient with PKAN, there is varied cognitive accumulation (NBIA) is a wide number of with multiple system atrophy (MSA) and expression, also there was an inverse corre- neurodegenerative disorders characterized systemic lupus erythematodes that has typi- lation between the onset of the disease and by iron accumulation in the brain, especial- cal Eye of the Tiger sign in T2-weighted the cognitive impairment.23 The ophthalmo- 16 ly basal ganglia, substantia nigari, hip- MRI. Chaw-Liang Chang also reported a logic manifestation is variable and includes 1,2 pocampus and cerebellar nuclei. The typ- patient with cervical dystonia that has Eye of saccadic pursuits, convergence impairment, ical presentation of NBIA disorder includes the Tiger without evidence of PANK2 gene vertical hypermetric saccades, square wave 17 dystonia, Parkinsonism, choreoathetosis, mutation. This sign also reported in a jerks and pigmentary retinopathy.24 mental dysfunction, spasticity, visual distur- patient with mitochondrial membrane pro- bance and bulbar dysfunction.3 The most tein associatedneurodegeneration (MPAN).18 common form of NBIA is PKAN also The brain MRI may be normal in the Early known as NBIA-1 that is an autosomal Stages of Classic Pantothenate Kinase Treatment recessive disorder characterized by a muta- Associated Neurodegeneration and after the tion in the PANK 2 at locus 20 P12.3 This progression of disease, the Eye of the Tiger Medications disease also has various psychiatry symp- sign appear.19 There is currently no suitable therapy

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Figure 1. T2 weighted Brain magnetic resonance imaging of the patient that shows hyperintense lesion surrounded by hypointensity in the medial aspect of bilateral globus pallidus (eye-of-the-tiger).

Figure 2. Susceptibility weighted imaging (SWI) of the PKAN patient that shows hypointense lesion in the medial aspect of bilateral globus pallidus.

for PKAN patients and different available stimulation.33 In PKAN patients that have brain iron accumulation: from genes to drugs don’t effect on disease progression.25 severe dystonia, spasticity and pain, pathogenesis. Semin Pediatr Neurol Dystonia can be profoundly disabling in the intrathecal baclofen (ITB) pump can allevi- 2006;13:182-5. affected patients and progresses over time ate the symptoms.34 Blair Ford et al. shows 2. Thomas M, Hayflick SJ, Jankovic J. and involves many parts of the body. It usu- intrathecal baclofen is more effective if the Clinical heterogeneity of neurodegener- ally treated with anticholinergics, botu- dystonia is associated with spasticity and ation with brain iron accumulation and linum toxin, Oral and Intrathecal baclofen, pain35 it can also use intraventricular. In a pantothenatekinase-associated neurode- benzodiazepines, Clonidine, gabapentin, study of Albright et al on ten patients with generation. Movement Disord 2004; pregabalin, tetrabenazine and other anti- severe generalized secondary and heredode- 19:36-42. spasticity drugs, alone or in combina- generative dystonia, Intraventricular 3. Hogarth P. Neurodegeneration with tion.26,27 Vitamin B5 (pantothenate) may be baclofen was effective on dystonia.36 brain iron accumulation: diagnosis and able to improve PKAN patients by increas- management. J Mov Disord 2015;8:1- ing levels of CoA and recovery of mito- Iron chelation 13. chondrial dysfunction. In mouse models of The drugs currently used include 4. Hayflick SJ, Westaway SK, Levinson PKAN with a high-fat ketogenic diet, this deferiprone, deferoxamine and B, et al. Genetic, clinical, and radi- drug was able to prevent some neurological deferasirox.37 Nowadays, Deferiprone have ographic delineation of PKAN disease. symptoms, But to investigate its effects, attracted the attention of many researchers. N Engl J Med 2003;348:33-40. clinical trial studies should be conducted in It can cross the blood-brain barrier to 5. Gregory A, Polster BJ, Hayflick SJ. 28-30 the future. remove iron and prevent its accumula- Clinical and genetic delineation of neu- tion.38,39 In studies that investigated the rodegeneration with brain iron accumu- Surgery effect of deferiprone on the NBIA patients, lation. J Med Genet 2009;46:73-80. Surgical procedures such as Deep brain the use of this drug was safe and without 6. Pawar Y, Kalra G. A case of PKAN dis- stimulation are now used for PKAN dis- adverse effects. In these studies, ease presenting as catatonic schizophre- ease.The benefit effect of Deep brain stimu- deferiprone reduced iron load in brain nia. Indian J Psychiatry 2013;55:386-9. lation, can occur quickly after surgery, But imaging and in clinical evaluations, variable 7.Hayflick SJ, Westaway SK, Levinsonetal B. Genetic clinical, and due to the progressive nature of the disease, results were obtained which requires further radiographic delineation of PKAN dis- symptoms may reappear after a while and investigation in the future.40,41 the disease progresses again.31,32 In addition ease. New Engl J Med 2003;348:33-40. to Deep brain stimulation, other surgical 8. Levi S, Finazzi D. Neurodegeneration procedures including Ablative pallidotomy with brain iron accumulation: update on or thalmotomy can also be used, although References pathogenic mechanisms. Front these surgical procedures are currently less Pharmacol 2014;5:99. commonly used and replaced by Deep brain 1. Hayflick SJ. Neurodegeneration with 9. Hayﬂick SJ, Westaway SK, Levinson B,

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et al. Genetic, clinical, and radiographic 2015;25:539-51. longstanding severe generalized dysto- delineation of PKAN disease. N Engl J 21. Meyer E, Kurian MA, Hayflick SJ. nia in PKAN disease: case report. J Med 2003;348:33-40. Neurodegeneration with brain iron Neurosurg 2004;100:706-9. 10. Gregory A, Westaway SK, Holm IE, et accumulation: enetic diversity and 32. Balas I, Kovacs N, Hollody K. Staged al. Neurodegeneration associated with pathophysiological mechanisms. Ann bilateral stereotactic pallidothalamoto- genetic defects in phospholipase A(2). Rev Genomics Hum Genet my for life-threatening dystonia in a Neurology 2008;71:1402-9. 2015;16:257-79. child with PKAN disease, Mov Disord 11. Ching KH, Westaway SK, Gitschier J, 22. Loring DW, Sethi KD, Lee GP, Meador 2006;21:82-5. et al. HARP syndrome is allelic with KJ. Neuropsychological performance in 33. Justesen CR, Penn RD, Kroin JS, Egel pantothenate kinase-associated neu- PKAN disease : a report of two cases. RT. Stereotactic pallidotomy in a child rodegeneration. Neurology 2002;58: Neuropsychology 1990;4:191-9. with PKAN disease. Case report, J. 1673-4. 23. Freeman K, Gregory A, Turner A, et al. Neurosurg 1999;90:551-4. 12. Kruer MC, Boddaert N, Schneider SA, Intellectual and adaptive behaviour 34. Albright AL, Barry M, Fasick P, et al. et al. Neuroimaging features of neu- functioning in pantothenate kinase- Continuous intrathecal baclofen infu- rodegeneration with brain iron accumu- associated neurodegeneration. J sion for symptomatic generalized dysto- lation. Am J Neuroradiol 2012;33:407- Intellect Disabil Res 2007;51:417-26. nia [clinical studies]. Neurosurgery 14. 24. Egan RA, Weleber RG, Hogarth P, et al. 13. Schipper HM. Neurodegeneration with Neuroopthamologic and electroreino- 1996;38:934-9. brain iron accumulation — Clinical graphic finding in pantothenate kinase 35. Ford B, Greene P, Louis ED, et al. Use syndromes and neuroimaging. Biochim associated neurodegeneration. Am J of intrathecal baclofen in the treatment Biophys Acta 2012;1822:350-60. Ophtalmol 2005;140:167-274. of patients with dystonia. Arch Neurol 14. Liman J, Wellmer A, Rostasy K, et al. 25. Schneider SA, Bhatia KP, Hardy J. 1996;53:1241-6. Transcranial ultrasound in neurodegen- Complicated recessive dystonia 36. Albright AL, Ferson SS. eration with brain iron accumulation Parkinsonism syndromes. Mov Disord Intraventricular baclofen for dystonia: (NBIA). Eur J Paediatr Neurol 2012;16: 2009;24:490-9. techniques and outcomes. Clinical arti- 175-8. 26. Zorzi G, Zibordi F, Chiapparini L, cle. J Neurosurg Pediatr 2009;3:11-4. 15. Savoiardo M, Halliday WC, Nardocci Nardocci N. Therapeutic Advances in 37. Gomber S, Saxena R, Madan N. N, et al. Hallervorden-Spatz disease: Neurodegeneration With Brain Iron Comparative efficacy of desferrioxam- MR and pathologic findings. Am J Accumulation. Semin Pediatr Neurol ine, deferiprone and in combination on Neuroradiol 1993;14:155-62. 2012;19:82-6. iron chelation in thalassemic children. 16. Strecker K, Hesse S, Wegner F, et al. 27. Cloud LJ, Jinnah H. Treatment strate- Indian Pediatr 2004;41: 21-7. Schneider Eye of the tiger sign in mul- gies for dystonia. Exp Opin 38. Boddaert N, Le Quan Sang KH, Rötig tiple system atrophy. Eur J Neurol Pharmacother 2010;11:5-15. A, et al. Selective iron chelation in 2007;14:e1-2. 28. Kuo YM, Hayflick SJ, Gitschier J. Friedreich ataxia: biologic and clinical 17. Chang CL, Lin CM. Eye-of-the-Tiger Deprivation of pantothenic acid elicits a implications. Blood 2007;110: 401-8. sign is not Pathognomonic of movement disorder and azoospermia in 39. Olivieri NF, Brittenham GM, McLaren Pantothenate Kinase-Associated a mouse model of pantothenate kinase- CE, et al. Long-term safety and effec- Neurodegeneration in Adult Cases. associated neurodegeneration. J Inherit tiveness of iron-chelation therapy with Brain Behav 2011;1:55-6. Metab Dis 2007;30:310. deferiprone for thalassemia major. New 18. Yoganathan S, Sudhakar SV, T. Maya, 29. Brunetti D, Dusi S, Morbin M, et al. Engl J Med 1998;339:417-23 et al. Eye of tiger sign mimic in an ado- Pantothenate kinase-associated neu- 40. Zorzi G, Zibordi F, Chiapparini L, et al. lescent boy with mitochondrial mem- rodegeneration: altered mitochondria Iron-related MRI images in patients brane protein associated neurodegener- membrane potential and defective respi- with Pantothenate Kinase-Associated ation (MPAN). Brain Dev 2016;38:516- ration in Pank2 knock-out mouse 9. model. Hum Mol Genet 2012;21:5294- Neurodegeneration (PKAN) treated 19. Chiapparini L, Savoiardo M, D’Arrigo 305. with Deferiprone: results of a phase II S, et al. The eye-of-the-tiger sign may 30. Brunetti D, Dusi S, Giordano C, et al, pilot trial. Mov Disord 2011;26:1756-9. be absent in the early stages of classic Pantethine treatment is effective in 41. Cossu G, Abruzzese G, Matta G, et al. pantothenate kinase associated neu- recovering the disease phenotype Efficacy and safety of deferiprone for rodegeneration. Neuropediatrics induced by ketogenic diet in a pan- the treatment of pantothenate kinase- 2011;42:159-62. tothenate kinase-associated neurode- associated neurodegeneration (PKAN) 20. Amaral L, Gaddikeri S, Chapman PR, generation mouse model. Brain and neurodegeneration with brain iron et al. Neurodegeneration with brain iron 2014;137:57-68. accumulation (NBIA): results from a accumulation: clinicoradiological 31. Umemura A, Jaggi JL, Dolinskas CA, et four years follow-up. Parkinsonism approach to diagnosis. J Neuroimaging al. Pallidal deep brain stimulation for Relat Disord 2014;20:651-4.

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