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Update on Neurodegeneration with Brain Iron Accumulation View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Via Medica Journals n e u r o l o g i a i n e u r o c h i r u r g i a p o l s k a 4 8 ( 2 0 1 4 ) 2 0 6 – 2 1 3 Available online at www.sciencedirect.com ScienceDirect journal homepage: http://www.elsevier.com/locate/pjnns Review article Update on neurodegeneration with brain iron accumulation * Karolina Popławska-Domaszewicz , Jolanta Florczak-Wyspiańska, Wojciech Kozubski Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland a r t i c l e i n f o a b s t r a c t Article history: Neurodegeneration with brain iron accumulation (NBIA) defines a heterogeneous group of Received 27 March 2014 progressive neurodegenerative disorders characterized by excessive iron accumulation in Accepted 6 May 2014 the brain, particularly affecting the basal ganglia. In the recent years considerable develop- Available online 17 May 2014 ment in the field of neurodegenerative disorders has been observed. Novel genetic methods such as autozygosity mapping have recently identified several genetic causes of NBIA. Our Keywords: knowledge about clinical spectrum has broadened and we are now more aware of an overlap NBIA between the different NBIA disorders as well as with other diseases. Neuropathologic point PKAN of view has also been changed. It has been postulated that pantothenate kinase-associated PLA26G neurodegeneration (PKAN) is not synucleinopathy. However, exact pathologic mechanism of NBIA remains unknown. The situation implicates a development of new therapies, which Eye of the tiger sign still are symptomatic and often unsatisfactory. In the present review, some of the main clinical presentations, investigational findings and therapeutic results of the different NBIA disorders will be presented. # 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. Neurodegeneration with brain iron accumulation (NBIA) defines prompted by the considerable development in this field. Some a heterogeneous group of progressive neurodegenerative of the main clinical presentations, investigational findings and disorders characterized by excessive iron accumulation in the therapeutic results of the different NBIA disorders will be brain, particularly affecting the basal ganglia [1]. The pantothe- presented in the following review. nate kinase-associated neurodegeneration (PKAN, previously named as Hallervorden–Spatz disease) and PLA2G6-associated 1. Pantothenate kinase-associated neurodegeneration (PLAN) are the two main syndromes. neurodegeneration (PKAN) – NBIA Type 1 Furthermore, novel genetic methods such as autozygosity mapping have recently identified several other genetic causes of NBIA [2] (Table 1). NBIA syndromes pose a challenge to the The major form of NBIA is pantothenate kinase-associated clinicians due to their complex phenomenology as well as their neurodegeneration (PKAN), previously known as Hallervor- requirement for a comprehensive treatment. This review was den–Spatz disease (HSD). HSD was first described by the * Corresponding author at: Department of Neurology, Przybyszewskiego 49, 60-355 Poznan, Poland. Tel.: +61 869 15 35; fax: +61 8691697; mobile: +48 607 464 090. E-mail address: [email protected] (K. Popławska-Domaszewicz). http://dx.doi.org/10.1016/j.pjnns.2014.05.001 0028-3843/# 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. n e u r o l o g i a i n e u r o c h i r u r g i a p o l s k a 4 8 ( 2 0 1 4 ) 2 0 6 – 2 1 3 207 – Table 1 Neurodegeneration with brain iron accumula- as gait and postural difficulties are usually the most prominent tion (NBIA) [2,79,80]. syndromes [1] with early involvement of oromandibular region by dystonic symptoms and signs [8]. Moreover, NBIA Mutated Chromosomal gene localization parkinsonism, chorea, acanthocytosis, cognitive decline and a dementia might be present. Other common features include Pantothenate kinase-associated PANK2 20p13 neurodegeneration involvement of the corticospinal tract with spasticity, hyper- b (PKAN)/NBIA1 reflexia and pathologic signs, dysarthria and clinical or c PLA2G6-associated PLA2G6 22q12 electroretinographic evidence of pigmentary retinopathy neurodegeneration [1,9]. Egan et al. demonstrated that Adie's-like pupils, vertical (PLAN)/NBIA2, PARK14 saccades, and saccadic pursuits are common, what suggests d Aceruloplasminemia (Acp) CP 3q23 e that midbrain degeneration frequently occurs in PKAN. Neuroferritinopathy FTL 19q13 f Additionally, square wave jerks, poor convergence, abnormal FA2H – Associated FA2H 16q23 Neurdegeneration vertical optokinetic response and inability to suppress the g (FAHN)/SPG35 vestibule-ocular reflex may be present. There was no evidence Kufor-Rakeb Disease ATP13A2 1p36 of optic atrophy [10]. Supranuclear gaze palsy has also been NBIA3/(PARK9) reported in PKAN patient [11]. The loss of ambulation occurs Mitochondrial membrane C19orf12 19q12 within 10–15 years after the onset of the disease [1]. protein associated neurodegeneration (MPAN) h Static encephalopathy of nk nk 3. Atypical PKAN childhood with neurodegeneration in adulthood (SENDA The onset takes place between the second and the third syndrome) decades [1]. Atypical disease is clinically heterogeneous [12]. a Pantothenate kinase 2. Speech difficulties (palilalia, dysarthria) and psychiatric b Neurodegeneration with brain iron accumulation. problems are frequent the initial syndromes. Extrapyramidal c Phospholipase A2. features are generally less severe and more slowly progressive d Ceruloplasmin. e than patients with classic form [1,7]. It has been reported that Ferritin light chain. f Fatty acid 2-hydroxylase. patients with adult onset PKAN often present parkinsonism as g fi Spastic paraplegia. the rst sign whereas early onset individuals seem to have h Not known. dystonia as a presenting feature [7]. Psychiatric syndromes include personality changes with impulsivity and violent outbursts, depression, obsessive-compulsive signs and emo- German neuropathologists Julius Hallervorden and Hugo tional lability [13,14]. The presence of psychotic symptoms has Spatz in 1922 [3]. It should be stressed that because of their also been described in the literature [15–18]; cognitive decline criminal activities during World War II (participating in Nazi and dementia may also develop [1]. Moreover, pyramidal tract T4 program of euthanasia), HSD is now referred to as PKAN [4]. involvement [12], freezing during ambulation and pure PKAN is an autosomal recessive disorder caused by mutations akinesia can be observed [19,20]. Sleep analysis revealed in PANK2 gene [5] which is located on chromosome 20p [6]. The altered sleep architecture with reduced total time of sleep and exact pathologic mechanism of PKAN remains unknown. the lack of slow wave sleep. No significant apnea/hypopnea PANK2 encodes pantothenate kinase 2, which is a regulatory and REM sleep abnormalities – in particular REM sleep enzyme in the coenzyme A (CoA) biosynthesis and catalyzing behavior disorders were detected [21]. Diagnostic criteria for the phosphorylation of pantothenate (vitamin B5), N-pan- PKAN were first proposed by Dooling et al. and based on tothenoyl-cysteine, and pantetheine. CoA plays an essential clinical features [22]. Swaiman revised these after brain MRI role in fatty acid synthesis and energy metabolism. It has been became a valuable diagnostic tool [23,24]. Gregory et al. suggest postulated that decreased level of panthotenate kinase 2 leads that after identification of PANK2 gene and the development of to the accumulation of cysteine-containing neurotoxic sub- the molecular diagnostic tests, obligate and corroborative strates, mostly in the regions with higher energy demand, features should be improved again [25] (Table 2). The such as the basal ganglia [1,5]. Excess amounts of cysteine, development of high-field magnetic resonance imaging chelate iron and form a complex which leads to tissue damage (MRI) in the 80-ties was a significant milestone in the further by promoting oxidative stress [7]. PKAN accounts for approxi- studies of NBIA. Brain MRI allowed for noninvasive demon- mately 50% of cases of NBIA [1]. According to the time of onset, stration of decreased T2 relaxation time caused by iron PKAN has been classified as early onset, rapidly progressive deposition, what correlates with iron accumulation of the classic disease and late onset, slowly progressive atypical brain in postmortem studies. Thus, MRI has become a highly variant. sensitive diagnostic tool for the diagnosis of NBIA [26]. An ‘‘eye of the tiger’’ sign, first described by Sethi et al. in 1988 is a specific MRI pattern, a key diagnostic feature of PKAN [27]. It is 2. Classic PKAN high signal intensity in the center of the globus pallidus interna with low signal intensity in the surrounding region. In the classic form, onset occurs between 3 and 4 years of age. The surrounding hypointensity of the globus pallidus repre- Extrapyramidal dysfunction with prominent dystonia as well sents excess iron deposition and the central hyperintensity is 208 n e u r o l o g i a i n e u r o c h i r u r g i a p o l s k a 4 8 ( 2 0 1 4 ) 2 0 6 – 2 1 3 – Table 2 Diagnostic criteria for PKAN proposed by radiological findings. In later stages of the disease only – Swaiman and Dooling et al. [22 24]. hypointesity of the globus pallidus may be seen. This might be explained by further accumulation of iron deposits, which Obligate features Corroborative features can obscure central hyperintensity [38]. Historically, all Onset in the first three decades Corticospinal tract patients who had HSD/NBIA phenotype and radiological involvement evidence of excess iron accumulation in the globus pallidus Progression of signs and symptoms Progressive intellectual impairment were diagnosed of PKAN. After the identification of mutations Evidence of extrapyramidal Retinitis pigmentosa, in the PANK2 gene on chromosome 20p12.3–p13 the term dysfunction (dystonia, rigidity, optic atrophy pantothenate kinase-associated neurodegeneration (PKAN) tremor, bradykinesia, has been proposed only for patients with confirmed or choreoathetosis) suspected mutations in PANK2.
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