Journal of the Neurological Sciences 340 (2014) 233–236
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Novel homozygous PANK2 mutation causing atypical pantothenate kinase-associated neurodegeneration (PKAN) in a Cypriot family George A. Tanteles a, Elena Spanou-Aristidou a, Chloe Antoniou b, Violetta Christophidou-Anastasiadou a, Kleopas A. Kleopa b,⁎ a b
Clinical Genetics Department, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus Neurology Clinics, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
a r t i c l e
i n f o
Article history: Received 24 October 2013 Received in revised form 25 February 2014 Accepted 1 March 2014 Available online 11 March 2014 Keywords: Pantothenate kinase-associated neurodegeneration PKAN Neurodegeneration with brain iron accumulation NBIA Pantothenate kinase 2 PANK2
a b s t r a c t Pantothenate kinase-associated neurodegeneration (PKAN) is the commonest, recessively inherited form of neurodegeneration with brain iron accumulation (NBIA) resulting from mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20. PKAN is usually rapidly progressive, presenting in the vast majority in the first decade of life (classic form). A rarer, later onset and slowly progressive (atypical) PKAN form also exists. We present two siblings of Cypriot descent, a 27-year-old man and his clinically asymptomatic younger sister, both of whom were found to be homozygous for a novel c.695ANG (p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. The index patient presented with a 5-year history of slowly progressive gait disturbance, dysarthria, mild axial rigidity and bradykinesia. His brain MRI scan revealed the characteristic “eye-of-thetiger” sign. Atypical genetically confirmed PKAN cases are sparsely reported and should be considered in the differential diagnosis of patients presenting with a progressive extrapyramidal syndrome particularly if the radiographic findings are suggestive of iron accumulation. Effective treatment strategies for PKAN are not currently available and symptomatic therapy is often unsatisfactory. However, early diagnosis including the presymptomatic stage is important for genetic counseling and will be crucial for testing novel therapeutics in the future. © 2014 Elsevier B.V. All rigths reserved.
1. Introduction Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive, complex motor disorders uniformly characterized by intense brain iron deposition and variable presentations ranging from early-onset degeneration with premature fatality to adult-onset Parkinsonism and dystonia. The commonest form, accounting for approximately 35–50% of NBIA cases [1], is pantothenate kinaseassociated neurodegeneration (PKAN-MIM#234200, also known as NBIA1), a recessively inherited disorder caused by bi-allelic mutations in the pantothenate kinase 2 (PANK2) gene [2] on chromosome 20p13 [3]. PKAN can be distinguished from other forms of NBIA on the basis of a characteristic brain MRI imaging pattern which typically reveals a central hyperintensity within a surrounding area of hypointensity in the globus pallidus, particularly on T2-weighted images [4], corresponding to excessive brain iron accumulation. This radiological pattern, referred to as the ‘eye-of-the tiger’ sign [5], is found in the vast majority but not in all individuals with PANK2 mutations [6], it is certainly not pathognomonic for this cohort [7] and it can also be seen in other conditions such as ⁎ Corresponding author at: The Cyprus Institute of Neurology & Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus. Tel.: +357 22 358600; fax: +357 22 392786. E-mail address: [email protected] (K.A. Kleopa).
http://dx.doi.org/10.1016/j.jns.2014.03.001 0022-510X/© 2014 Elsevier B.V. All rigths reserved.
progressive supranuclear palsy, early-onset levodopa-responsive Parkinsonism and cortical–basal ganglionic degeneration [8]. Characteristic MRI findings may be found earlier [9] or lag behind clinical symptoms in mutation positive PKAN patients [10]. The central T2-hyperintensity may be transient and fade with time while the diffuse globus pallidus T2-hypointensity representing abnormal iron deposition appears later and does not fade [9]. At least three clinical forms of PKAN have been described: A classic (early-onset), rapidly progressive and clinically remarkably homogeneous form seen in the majority of cases, an atypical (lateronset), slowly progressive form [1] and HARP (Hypobetalipoproteinemia, Acanthocytosis, Retinitis pigmentosa and Pallidal degeneration) syndrome [11]. The clinical features of atypical PKAN vary compared to those seen in the classic form and the age of onset is typically in the first three decades of life (13.7 ± 5.9 years, range: 1–28 years) [1]. Brain MRI changes may precede the manifestation of clinical symptoms [9]. Presenting features usually involve speech problems (dysarthria, palilalia and tachylalia). Psychiatric symptoms are common in the atypical form, often predating any motor features and manifesting as depression, anxiety, emotional lability, tics, obsessive compulsive disorder, or psychosis [12,13]. Progressive cognitive impairment occurs in both the classic and the atypical form. Other presenting features include mild gait abnormalities but motor involvement is generally less severe than
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in classic cases and progresses slowly with loss of ambulation occurring within 15–40 years of onset. Most individuals with atypical PKAN will go on to develop an extrapyramidal phenotype, although the observed features generally tend to be less severe than those seen in the classic form [1]. Retinopathy seems to be rare in atypical disease but has been described. In this article, we present two siblings of Cypriot-descent with an atypical PKAN form, homozygous for a novel PANK2 mutation.
2. Clinical description A 27-year-old man (patient 1), the oldest of four siblings was born to healthy third-cousin parents (Fig. 1). He had an unremarkable childhood with normal acquisition of developmental milestones and enjoyed good general health up until about the age of 22 years when he started developing gait difficulties. He attended college where he studied computer programming but interrupted his studies two years later because of his difficulties. His gait instability was slowly progressive over a few years. He gradually also developed a degree of dysarthria, concentration difficulties and leg stiffness and presented to our Neurology Clinic at the age of 27 years. On examination at this age, he had mild bradyphrenia but was able to read and write without difficulty. There was no difficulty with calculation or short term memory. His mini-mental state examination score was 30/30. He had mild dysarthria and palilalia and on cranial nerve examination extra-ocular movements were full without nystagmus. Tongue and soft palate were strong at midline. There were no visual field deficits. His vision and hearing were intact. On motor examination, he had no involuntary movements. There was mild bradykinesia of both hands and feet and marked axial rigidity. He had brisk reflexes but these were not pathological and plantar responses were flexor. There was no cerebellar dysfunction. His gait was remarkable for leg spasticity, slight toe walking and moderate instability. Romberg's test was negative. He denied any sensory loss. Investigations included a full blood count, biochemistry, liver and thyroid function tests, plasma ceruloplasmin, urinary copper and an autoimmune screen, all of which were either normal or negative. There was no evidence of acanthocytosis. Review of his brain MRI scan (performed at the age of 25 years) revealed bilateral peripheral hypointensity in the globi pallidi with a central focus of gliosis. This finding was consistent with a typical “eye-of-the-tiger” sign (Fig. 2A–C). Ophthalmological assessment did not reveal a pigmentary retinopathy. Our initial impression was that of a slowly progressive, mostly extrapyramidal syndrome suggestive of a neurodegenerative disease as can be seen with NBIA and more specifically PKAN. Mutation analysis by direct sequencing of the entire coding region of the PANK2 gene along with multiplex ligation-dependent probe amplification (MLPA) analysis revealed homozygosity for a novel c.695ANG
Fig. 1. Pedigree of the Cypriot family with two of four siblings with PKAN born to third cousin parents. The second male child, designated with a question mark, declined genetic testing. Arrow points to the index patient.
(p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. Carrier status was confirmed in the healthy parents. The patient progressed slowly over the last 6 years. On his latest examination at the age of 33 years, he mainly had trunk rigidity, dystonia with athetotic hand movements, moderate dysarthria, dysphonia, palilalia, dysphagia and concentration difficulties. He also had saccadic eye movements. He was unable to walk without support, and his gait was characterized by en block posture with impaired balance and a tendency to fall backwards, lacking postural reflexes. There was also bradykinesia and bilateral lower limb spasticity and hyper-reflexia. There was no evidence of cerebellar dysfunction or focal muscle atrophy. He denied any sensory loss. Symptomatic treatment with levodopa showed no benefit and baclofen up to 3× daily had only a minor effect on his leg stiffness. Following genetic counseling, two out of his three younger siblings opted for genetic testing looking at the familial PANK2 mutation. One of his two sisters tested negative for any mutated alleles. His other sister (patient 2) was tested at the age of 26 years and found to be homozygous for the same PANK2 mutation identified in her brother, although she had been asymptomatic up to that point. Currently, she reports no neurological symptoms. She works as a police officer and she is fully functional. On initial examination of patient 2 at the age of 26 years, her mental status was normal. There were no cranial nerve deficits. There was no mobility disturbance, no rigidity, bradykinesia or tremor. Her balance was preserved. There was no muscle weakness or atrophy. Reflexes however were brisk especially in the lower limbs and plantar responses were equivocal. There was no objective sensory loss. There was no cerebellar dysfunction and her gait was normal. MRI of the brain at the same age revealed early changes in the globi pallidi on T2-weighted images indicating a slight excess in iron deposition with one central focus of hyperintensity (Fig. 2D–F). 3. Discussion We report the first family from Cyprus with PKAN and a novel mutation in the PANK2 gene, presenting with a late onset, atypical form. Atypical PKAN cases present at an older age and exhibit milder extrapyramidal signs and a slower disease progression compared to the classic form. A small number of reports of late adult-onset cases with bi-allelic PANK2 mutations have been published [1,2,12,14–21]. Our patient's phenotypic presentation was compatible with atypical PKAN in terms of the age of onset, initial symptoms and signs, slowly progressive nature and radiological findings. Specifically, both gait disturbances and speech problems have more commonly been recognized as presenting features in atypical PKAN cases. PANK2 codes for an enzyme called pantothenate kinase 2 involved in coenzyme A (CoA) biosynthesis. The first step is the phosphorylation by PANK2 of pantothenate (or vitamin B5) to 4′-phosphopantothenate [22]. Brain iron accumulation is believed to result from loss of PANK2 function leading to lower 4′-phosphopantothenate levels and accumulation of cysteine-containing substrates which may autoxidize to generate free radicals causing cell damage [2,23]. Mutations have been identified in all seven exons of the PANK2 gene [24] and seem to cluster in the catalytic core domain which consists of about 355 residues [23]. Missense mutations (majority of identified variants) can either lead to early or late PKAN forms. The novel c.695ANG (p.Asp232Gly) missense mutation identified in homozygous form in exon 2 of the PANK2 gene in this family leads to an amino acid change from asparagine (Asp) to glycine (Gly) at position 232 in the PANK2 protein (Suppl. Fig. 1). Codon 232 is highly conserved throughout mammalian species and in silico analysis (Mutation Taster available at http://www.mutationtaster.org/) predicts with high probability that this amino acid change is pathogenic. Current treatment for all NBIA disorders is essentially symptomatic and primarily aimed at the dystonia which can be both extremely
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Fig. 2. MRI findings in the two siblings with the D232G PANK2 mutation. MRI images including T1-weighted (A, D), T2-weighted (B, E) and diffusion weighted (DWI) from the symptomatic brother (P1) and asymptomatic sister (P2) with the novel homozygous D232G mutation. The characteristic “eye-of-the-tiger” sign in the globus pallidus can be seen (arrows) resulting from slightly high signal intensity on the T1W images (A) and low signal intensity of the T2W surrounding an area of hyperintensity (B) consistent with a central focus of gliosis. Symmetrical diffusion abnormalities (C) are also seen. Similar but milder abnormalities are seen in the asymptomatic sibling (D–F) suggesting earlier stages of excess iron deposition.
distressing and debilitating to the affected individual and their families. Anticholinergic medications or benzodiazepines may help reduce rigidity, dystonia, and tremor, while baclofen administered orally or intrathecally is used to treat dystonia [25]. Favorable outcomes were reported in a series of patients with secondary dystonia (one with PKAN) receiving intra-ventricularly administered baclofen [26]. Parkinsonism can be managed with dopaminergic agents. Intramuscular botulinum toxin A injections have been used to treat dystonia. Deep brain stimulation (DBS) of the globus pallidus is used clinically with increasing frequency with some beneficial evidence [27]. Finally, a small phase II pilot trial with iron chelation using deferiprone which crosses the blood–brain barrier has been performed in a PKAN cohort and showed significant reduction in pallidal iron as measured by MRI, although the clinical status did not change [28]. Our patient has so far responded only minimally to symptomatic treatments. Early detection at the presymptomatic stage is therefore important to allow early and effective treatments of this disease in the future. PKAN is a rare genetic disorder most commonly seen in childhood and adolescence but it should be considered in the differential diagnosis of adult patients with a history of a progressive extrapyramidal syndrome. Characteristic MRI findings should prompt genetic testing. Optimal treatment strategies are not known, and to date therapies are directed at the specific manifestations of the disease. Further research is required to shed more light on the apparent phenotypic breadth of this disorder.
Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2014.03.001. Conflict of interest All authors declare no conflict of interest. Acknowledgments We would like to thank the patients for consenting to this publication. References [1] Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. Genetic, clinical, and radiographic delineation of Hallervorden–Spatz syndrome. N Engl J Med 2003;348(1):33–40 [Epub 2003/01/03]. [2] Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden–Spatz syndrome. Nat Genet 2001;28(4):345–9 [Epub 2001/08/02]. [3] Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, et al. Homozygosity mapping of Hallervorden–Spatz syndrome to chromosome 20p12.3-p13. Nat Genet 1996;14(4):479–81. [4] 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;70(18):1614–9 [Epub 2008/04/30]. [5] Sethi KD, Adams RJ, Loring DW, el Gammal T. Hallervorden–Spatz syndrome: clinical and magnetic resonance imaging correlations. Ann Neurol 1988;24(5):692–4 [Epub 1988/11/01].
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[6] Zolkipli Z, Dahmoush H, Saunders DE, Chong WK, Surtees R. Pantothenate kinase 2 mutation with classic pantothenate-kinase-associated neurodegeneration without ‘eye-of-the-tiger’ sign on MRI in a pair of siblings. Pediatr Radiol 2006;36(8):884–6 [Epub 2006/06/08]. [7] Kumar N, Boes CJ, Babovic-Vuksanovic D, Boeve BF. The “eye-of-the-tiger” sign is not pathognomonic of the PANK2 mutation. Arch Neurol 2006;63(2):292–3 [Epub 2006/02/16]. [8] Guillerman RP. The eye-of-the-tiger sign. Radiology 2000;217(3):895–6 [Epub 2000/12/09]. [9] Hayflick SJ, Penzien JM, Michl W, Sharif UM, Rosman NP, Wheeler PG. Cranial MRI changes may precede symptoms in Hallervorden–Spatz syndrome. Pediatr Neurol 2001;25(2):166–9 [Epub 2001/09/12]. [10] 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;42(4):159–62 [Epub 2011/08/31]. [11] Ching KH, Westaway SK, Gitschier J, Higgins JJ, Hayflick SJ. HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration. Neurology 2002;58(11):1673–4 [Epub 2002/06/12]. [12] Diaz N. Late onset atypical pantothenate-kinase-associated neurodegeneration. Case Rep Neurol Med 2013;2013:860201 [Epub 2013/05/02]. [13] Pellecchia MT, Valente EM, Cif L, Salvi S, Albanese A, Scarano V, et al. The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration. Neurology 2005;64(10):1810–2 [Epub 2005/05/25]. [14] del Valle-Lopez P, Perez-Garcia R, Sanguino-Andres R, Gonzalez-Pablos E. Adult onset Hallervorden–Spatz disease with psychotic symptoms. Actas Esp Psiquiatr 2011;39(4):260–2 [Epub 2011/07/20]. [15] Vasconcelos OM, Harter DH, Duffy C, McDonough B, Seidman JG, Seidman CE, et al. Adult Hallervorden–Spatz syndrome simulating amyotrophic lateral sclerosis. Muscle Nerve 2003;28(1):118–22 [Epub 2003/06/18]. [16] Antonini A, Goldwurm S, Benti R, Prokisch H, Ebhardt M, Cilia R, et al. Genetic, clinical, and imaging characterization of one patient with late-onset, slowly progressive, pantothenate kinase-associated neurodegeneration. Mov Disord 2006;21(3):417–8 [Epub 2005/11/04]. [17] Seo JH, Song SK, Lee PH. A novel PANK2 mutation in a patient with atypical pantothenate-kinase-associated neurodegeneration presenting with adult-onset Parkinsonism. J Clin Neurol 2009;5(4):192–4 [Epub 2010/01/16].
[18] Aggarwal A, Schneider SA, Houlden H, Silverdale M, Paudel R, Paisan-Ruiz C, et al. Indian-subcontinent NBIA: unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms. Mov Disord 2010;25(10):1424–31 [Epub 2010/07/16]. [19] Egan RA, Weleber RG, Hogarth P, Gregory A, Coryell J, Westaway SK, et al. Neuroophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden–Spatz syndrome). Am J Ophthalmol 2005;140(2):267–74 [Epub 2005/07/19]. [20] Hartig MB, Hortnagel 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;59(2):248–56 [Epub 2006/01/27]. [21] Thomas M, Hayflick SJ, Jankovic J. Clinical heterogeneity of neurodegeneration with brain iron accumulation (Hallervorden–Spatz syndrome) and pantothenate kinaseassociated neurodegeneration. Mov Disord 2004;19(1):36–42 [Epub 2004/01/27]. [22] Leonardi R, Zhang YM, Rock CO, Jackowski S. Coenzyme A: back in action. Prog Lipid Res 2005;44(2–3):125–53 [Epub 2005/05/17]. [23] Hong BS, Senisterra G, Rabeh WM, Vedadi M, Leonardi R, Zhang YM, et al. Crystal structures of human pantothenate kinases. Insights into allosteric regulation and mutations linked to a neurodegeneration disorder. J Biol Chem 2007;282(38):27984–93 [Epub 2007/07/17]. [24] Kurian MA, McNeill A, Lin JP, Maher ER. Childhood disorders of neurodegeneration with brain iron accumulation (NBIA). Dev Med Child Neurol 2011;53(5):394–404 [Epub 2011/04/13]. [25] Gregory A, Hayflick SJ. Pantothenate kinase-associated neurodegeneration Gene Reviews™ [Internet]. Seattle, WA: University of Washington; 1993. [26] Albright AL, Ferson SS. Intraventricular baclofen for dystonia: techniques and outcomes. Clinical article. J Neurosurg Pediatr 2009;3(1):11–4 [Epub 2009/01/06]. [27] Castelnau P, Cif L, Valente EM, Vayssiere N, Hemm S, Gannau A, et al. Pallidal stimulation improves pantothenate kinase-associated neurodegeneration. Ann Neurol 2005;57(5):738–41 [Epub 2005/04/27]. [28] Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: results of a phase II pilot trial. Mov Disord 2011;26(9):1756–9 [Epub 2011/05/11].
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Novel homozygous PANK2 mutation causing atypical pantothenate kinase-associated neurodegeneration (PKAN) in a Cypriot family George A. Tanteles a, Elena Spanou-Aristidou a, Chloe Antoniou b, Violetta Christophidou-Anastasiadou a, Kleopas A. Kleopa b,⁎ a b
Clinical Genetics Department, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus Neurology Clinics, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus
a r t i c l e
i n f o
Article history: Received 24 October 2013 Received in revised form 25 February 2014 Accepted 1 March 2014 Available online 11 March 2014 Keywords: Pantothenate kinase-associated neurodegeneration PKAN Neurodegeneration with brain iron accumulation NBIA Pantothenate kinase 2 PANK2
a b s t r a c t Pantothenate kinase-associated neurodegeneration (PKAN) is the commonest, recessively inherited form of neurodegeneration with brain iron accumulation (NBIA) resulting from mutations in the pantothenate kinase 2 (PANK2) gene on chromosome 20. PKAN is usually rapidly progressive, presenting in the vast majority in the first decade of life (classic form). A rarer, later onset and slowly progressive (atypical) PKAN form also exists. We present two siblings of Cypriot descent, a 27-year-old man and his clinically asymptomatic younger sister, both of whom were found to be homozygous for a novel c.695ANG (p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. The index patient presented with a 5-year history of slowly progressive gait disturbance, dysarthria, mild axial rigidity and bradykinesia. His brain MRI scan revealed the characteristic “eye-of-thetiger” sign. Atypical genetically confirmed PKAN cases are sparsely reported and should be considered in the differential diagnosis of patients presenting with a progressive extrapyramidal syndrome particularly if the radiographic findings are suggestive of iron accumulation. Effective treatment strategies for PKAN are not currently available and symptomatic therapy is often unsatisfactory. However, early diagnosis including the presymptomatic stage is important for genetic counseling and will be crucial for testing novel therapeutics in the future. © 2014 Elsevier B.V. All rigths reserved.
1. Introduction Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive, complex motor disorders uniformly characterized by intense brain iron deposition and variable presentations ranging from early-onset degeneration with premature fatality to adult-onset Parkinsonism and dystonia. The commonest form, accounting for approximately 35–50% of NBIA cases [1], is pantothenate kinaseassociated neurodegeneration (PKAN-MIM#234200, also known as NBIA1), a recessively inherited disorder caused by bi-allelic mutations in the pantothenate kinase 2 (PANK2) gene [2] on chromosome 20p13 [3]. PKAN can be distinguished from other forms of NBIA on the basis of a characteristic brain MRI imaging pattern which typically reveals a central hyperintensity within a surrounding area of hypointensity in the globus pallidus, particularly on T2-weighted images [4], corresponding to excessive brain iron accumulation. This radiological pattern, referred to as the ‘eye-of-the tiger’ sign [5], is found in the vast majority but not in all individuals with PANK2 mutations [6], it is certainly not pathognomonic for this cohort [7] and it can also be seen in other conditions such as ⁎ Corresponding author at: The Cyprus Institute of Neurology & Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus. Tel.: +357 22 358600; fax: +357 22 392786. E-mail address: [email protected] (K.A. Kleopa).
http://dx.doi.org/10.1016/j.jns.2014.03.001 0022-510X/© 2014 Elsevier B.V. All rigths reserved.
progressive supranuclear palsy, early-onset levodopa-responsive Parkinsonism and cortical–basal ganglionic degeneration [8]. Characteristic MRI findings may be found earlier [9] or lag behind clinical symptoms in mutation positive PKAN patients [10]. The central T2-hyperintensity may be transient and fade with time while the diffuse globus pallidus T2-hypointensity representing abnormal iron deposition appears later and does not fade [9]. At least three clinical forms of PKAN have been described: A classic (early-onset), rapidly progressive and clinically remarkably homogeneous form seen in the majority of cases, an atypical (lateronset), slowly progressive form [1] and HARP (Hypobetalipoproteinemia, Acanthocytosis, Retinitis pigmentosa and Pallidal degeneration) syndrome [11]. The clinical features of atypical PKAN vary compared to those seen in the classic form and the age of onset is typically in the first three decades of life (13.7 ± 5.9 years, range: 1–28 years) [1]. Brain MRI changes may precede the manifestation of clinical symptoms [9]. Presenting features usually involve speech problems (dysarthria, palilalia and tachylalia). Psychiatric symptoms are common in the atypical form, often predating any motor features and manifesting as depression, anxiety, emotional lability, tics, obsessive compulsive disorder, or psychosis [12,13]. Progressive cognitive impairment occurs in both the classic and the atypical form. Other presenting features include mild gait abnormalities but motor involvement is generally less severe than
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in classic cases and progresses slowly with loss of ambulation occurring within 15–40 years of onset. Most individuals with atypical PKAN will go on to develop an extrapyramidal phenotype, although the observed features generally tend to be less severe than those seen in the classic form [1]. Retinopathy seems to be rare in atypical disease but has been described. In this article, we present two siblings of Cypriot-descent with an atypical PKAN form, homozygous for a novel PANK2 mutation.
2. Clinical description A 27-year-old man (patient 1), the oldest of four siblings was born to healthy third-cousin parents (Fig. 1). He had an unremarkable childhood with normal acquisition of developmental milestones and enjoyed good general health up until about the age of 22 years when he started developing gait difficulties. He attended college where he studied computer programming but interrupted his studies two years later because of his difficulties. His gait instability was slowly progressive over a few years. He gradually also developed a degree of dysarthria, concentration difficulties and leg stiffness and presented to our Neurology Clinic at the age of 27 years. On examination at this age, he had mild bradyphrenia but was able to read and write without difficulty. There was no difficulty with calculation or short term memory. His mini-mental state examination score was 30/30. He had mild dysarthria and palilalia and on cranial nerve examination extra-ocular movements were full without nystagmus. Tongue and soft palate were strong at midline. There were no visual field deficits. His vision and hearing were intact. On motor examination, he had no involuntary movements. There was mild bradykinesia of both hands and feet and marked axial rigidity. He had brisk reflexes but these were not pathological and plantar responses were flexor. There was no cerebellar dysfunction. His gait was remarkable for leg spasticity, slight toe walking and moderate instability. Romberg's test was negative. He denied any sensory loss. Investigations included a full blood count, biochemistry, liver and thyroid function tests, plasma ceruloplasmin, urinary copper and an autoimmune screen, all of which were either normal or negative. There was no evidence of acanthocytosis. Review of his brain MRI scan (performed at the age of 25 years) revealed bilateral peripheral hypointensity in the globi pallidi with a central focus of gliosis. This finding was consistent with a typical “eye-of-the-tiger” sign (Fig. 2A–C). Ophthalmological assessment did not reveal a pigmentary retinopathy. Our initial impression was that of a slowly progressive, mostly extrapyramidal syndrome suggestive of a neurodegenerative disease as can be seen with NBIA and more specifically PKAN. Mutation analysis by direct sequencing of the entire coding region of the PANK2 gene along with multiplex ligation-dependent probe amplification (MLPA) analysis revealed homozygosity for a novel c.695ANG
Fig. 1. Pedigree of the Cypriot family with two of four siblings with PKAN born to third cousin parents. The second male child, designated with a question mark, declined genetic testing. Arrow points to the index patient.
(p.Asp232Gly) missense mutation in exon 2 of the PANK2 gene. Carrier status was confirmed in the healthy parents. The patient progressed slowly over the last 6 years. On his latest examination at the age of 33 years, he mainly had trunk rigidity, dystonia with athetotic hand movements, moderate dysarthria, dysphonia, palilalia, dysphagia and concentration difficulties. He also had saccadic eye movements. He was unable to walk without support, and his gait was characterized by en block posture with impaired balance and a tendency to fall backwards, lacking postural reflexes. There was also bradykinesia and bilateral lower limb spasticity and hyper-reflexia. There was no evidence of cerebellar dysfunction or focal muscle atrophy. He denied any sensory loss. Symptomatic treatment with levodopa showed no benefit and baclofen up to 3× daily had only a minor effect on his leg stiffness. Following genetic counseling, two out of his three younger siblings opted for genetic testing looking at the familial PANK2 mutation. One of his two sisters tested negative for any mutated alleles. His other sister (patient 2) was tested at the age of 26 years and found to be homozygous for the same PANK2 mutation identified in her brother, although she had been asymptomatic up to that point. Currently, she reports no neurological symptoms. She works as a police officer and she is fully functional. On initial examination of patient 2 at the age of 26 years, her mental status was normal. There were no cranial nerve deficits. There was no mobility disturbance, no rigidity, bradykinesia or tremor. Her balance was preserved. There was no muscle weakness or atrophy. Reflexes however were brisk especially in the lower limbs and plantar responses were equivocal. There was no objective sensory loss. There was no cerebellar dysfunction and her gait was normal. MRI of the brain at the same age revealed early changes in the globi pallidi on T2-weighted images indicating a slight excess in iron deposition with one central focus of hyperintensity (Fig. 2D–F). 3. Discussion We report the first family from Cyprus with PKAN and a novel mutation in the PANK2 gene, presenting with a late onset, atypical form. Atypical PKAN cases present at an older age and exhibit milder extrapyramidal signs and a slower disease progression compared to the classic form. A small number of reports of late adult-onset cases with bi-allelic PANK2 mutations have been published [1,2,12,14–21]. Our patient's phenotypic presentation was compatible with atypical PKAN in terms of the age of onset, initial symptoms and signs, slowly progressive nature and radiological findings. Specifically, both gait disturbances and speech problems have more commonly been recognized as presenting features in atypical PKAN cases. PANK2 codes for an enzyme called pantothenate kinase 2 involved in coenzyme A (CoA) biosynthesis. The first step is the phosphorylation by PANK2 of pantothenate (or vitamin B5) to 4′-phosphopantothenate [22]. Brain iron accumulation is believed to result from loss of PANK2 function leading to lower 4′-phosphopantothenate levels and accumulation of cysteine-containing substrates which may autoxidize to generate free radicals causing cell damage [2,23]. Mutations have been identified in all seven exons of the PANK2 gene [24] and seem to cluster in the catalytic core domain which consists of about 355 residues [23]. Missense mutations (majority of identified variants) can either lead to early or late PKAN forms. The novel c.695ANG (p.Asp232Gly) missense mutation identified in homozygous form in exon 2 of the PANK2 gene in this family leads to an amino acid change from asparagine (Asp) to glycine (Gly) at position 232 in the PANK2 protein (Suppl. Fig. 1). Codon 232 is highly conserved throughout mammalian species and in silico analysis (Mutation Taster available at http://www.mutationtaster.org/) predicts with high probability that this amino acid change is pathogenic. Current treatment for all NBIA disorders is essentially symptomatic and primarily aimed at the dystonia which can be both extremely
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Fig. 2. MRI findings in the two siblings with the D232G PANK2 mutation. MRI images including T1-weighted (A, D), T2-weighted (B, E) and diffusion weighted (DWI) from the symptomatic brother (P1) and asymptomatic sister (P2) with the novel homozygous D232G mutation. The characteristic “eye-of-the-tiger” sign in the globus pallidus can be seen (arrows) resulting from slightly high signal intensity on the T1W images (A) and low signal intensity of the T2W surrounding an area of hyperintensity (B) consistent with a central focus of gliosis. Symmetrical diffusion abnormalities (C) are also seen. Similar but milder abnormalities are seen in the asymptomatic sibling (D–F) suggesting earlier stages of excess iron deposition.
distressing and debilitating to the affected individual and their families. Anticholinergic medications or benzodiazepines may help reduce rigidity, dystonia, and tremor, while baclofen administered orally or intrathecally is used to treat dystonia [25]. Favorable outcomes were reported in a series of patients with secondary dystonia (one with PKAN) receiving intra-ventricularly administered baclofen [26]. Parkinsonism can be managed with dopaminergic agents. Intramuscular botulinum toxin A injections have been used to treat dystonia. Deep brain stimulation (DBS) of the globus pallidus is used clinically with increasing frequency with some beneficial evidence [27]. Finally, a small phase II pilot trial with iron chelation using deferiprone which crosses the blood–brain barrier has been performed in a PKAN cohort and showed significant reduction in pallidal iron as measured by MRI, although the clinical status did not change [28]. Our patient has so far responded only minimally to symptomatic treatments. Early detection at the presymptomatic stage is therefore important to allow early and effective treatments of this disease in the future. PKAN is a rare genetic disorder most commonly seen in childhood and adolescence but it should be considered in the differential diagnosis of adult patients with a history of a progressive extrapyramidal syndrome. Characteristic MRI findings should prompt genetic testing. Optimal treatment strategies are not known, and to date therapies are directed at the specific manifestations of the disease. Further research is required to shed more light on the apparent phenotypic breadth of this disorder.
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