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 [page 32] [Neurology International 2018; 10:7516] Review Figure 1. T2 weighted Brain magnetic res- onance imaging of the patient that shows hyperintense lesion surrounded by hypointensity in the medial aspect of bilat- eral 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