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1 = 증례보고 == 증례보고 = 대한안과학회지 2013 년제 54 권제 3 호 J Korean Ophthalmol Soc 2013;54(3): pissn: eissn: 야맹증을주소로한 Pantothenate Kinase-Associated Neurodegeneration (PKAN) 1 예 조성호 1 전종근 2 김용우 3 정재호 1 부산대학교의학전문대학원양산부산대학교병원안과학교실 1, 부산대학교어린이병원소아청소년과유전대사분과 2, 부산대학교의학전문대학원양산부산대학교병원영상의학교실 3 목적 : PKAN (Pantothenate Kinase-Associated Neurodegeneration) 은매우드물게보고되고있는철대사장애로인한신경퇴행성질환으로, 저자들은 PKAN 1 예를경험하였기에보고하고자한다. 증례요약 : 6 세여아가야맹과발달지연및보행장애를주소로내원하였다. 신경학적검사상내족지보행, 근육긴장이상, 경직, 구음장애를보였으며, 안저검사상망막색소변성소견을보였고, 망막전위도검사에서막대세포및원뿔세포반응저하가관찰되었다. 뇌자기공명영상촬영에서바닥핵에철침착소견을보여 (eye of the tiger sign), 유전학적검사를시행하여 PKAN 으로진단하였다. 결론 : 안저검사상망막색소변성이관찰되며, 신경학적검사상이상소견및발달장애소견이보일때, PKAN 을감별진단으로염두에두어야할것으로생각한다. < 대한안과학회지 2013;54(3): > Pantothenate Kinase-Associated Neurodegeneration (PKAN, Hallervorden-Spatz syndrome) 은상염색체열성유전질환으로근육이상증, 경직, 구음장애, 파킨슨병, 뇌내철침착, 망막병증, 시신경병증을특징으로하는질환이다. 안구내소견으로는망막색소변성, 시신경위축, 망막신경아교증등이있는것으로알려졌다. PKAN은매우드문대사질환으로알려졌으며, 저자들은야맹증을주소로내원한환아에서발생한망막색소병증과신경학적이상으로진단한 PKAN 1예를경험하였기에이를보고하고자한다. 접수일 : 2012년 3월 16일 게재허가일 : 2013년 1월 2일 증례보고 6세여아가야맹증을주소로내원하였다. 내족지보행, 보행장애, 구음장애, 근육이상증, 강직및경직소견, 발달지연 ( 한국형영유아발달검사에서 gross motor: 57%, social- personal: 70%, language: 91%, cognitive: 91%) 이있었다. 안과검사상교정시력양안모두 0.63이었고, 동공대광 심사통과일 : 2012 년 5 월 22 일 책임저자 : 정재호경남양산시물금읍금오로 20 양산부산대학교병원안과 Tel: , Fax: jaeho0130@naver.com * 이논문의요지는 2012 년대한안과학회제 107 회학술대회에서포스터로발표되었음. 반사는정상이었으며, 구심성동공장애는없었다. 사시는관찰되지않았으나안구운동검사상양안에경도의하전장애를보였다. 전안부검사에서정상이었고, 안저검사상주변부망막탈색소및색소침착과망막색소상피층의광범위한위축소견관찰되었다 (Fig. 1). 망막전위도검사에서암소망막전위도및명소망막전위도에서모두감소형으로측정되어, 막대세포및원추세포의반응소실을확인할수있었으며, 특히, 막대세포의반응소실이더뚜렷한것으로관찰되었다 (Fig. 2). 뇌자기공명영상촬영에서바닥핵에주변부저신호강도, 내부고신호강도소견을보였고 (Fig. 3) 이는대사성질환의소견으로 PKAN, GM1 gangliosidosis 등의질환에서나타날수있으며이를감별하기위해유전자검사를시행하였다. PANK2 유전자염기서열분석결과, PANK2 유전자의 exon3과 4에서돌연변이가나타났으며 (Fig. 4), 임상소견및검사소견을바탕으로환아는 PKAN으로진단되었으며, 현재 pantothenate 200 mg/day, omega-3-fats (fish oil) 경구투여중이며언어치료, 심리치료, 통합감각치료, 물리치료시행중에있다. 고찰 Pantothenate (vit B5) 는생체중요대사경로인삼카르 529

- 대한안과학회지 2013 년제 54 권제 3 호 - A B Figure 1.

Electroretinography demonstrated severe loss of rod and cone responses, prominently reduced in rod response.

1,2 PKAN에서는 Pantothenate kinase 의결핍이발생하면 pantothenate의인산화가이루어지지않아시스테인이축적되게되고, 축적된시스테인은철과결합하게되며조효소 A의생성도이루어지지않게된 Figure 3.

2 - 대한안과학회지 2013 년제 54 권제 3 호 - A B Figure 1. Fundus photographs show scattered bone-spicule formations, peripheral retinal depigmentation, and the retinal vessel changes in both eyes (A, B). 50 mm Figure 2. Electroretinography demonstrated severe loss of rod and cone responses, prominently reduced in rod response. 복실산회로 (Tricarboxilic acid cycle) 의기질로작용되는것으로알려졌고, Pantothenate kinase는 Pantothenate를인산화시켜 cystein과결합후조효소 A의생성에관여하는것으로알려졌다. 1,2 PKAN에서는 Pantothenate kinase 의결핍이발생하면 pantothenate의인산화가이루어지지않아시스테인이축적되게되고, 축적된시스테인은철과결합하게되며조효소 A의생성도이루어지지않게된 Figure 3. Brain MR shows focal high signal intensity within the low signal intensity, in both globus pallidus in T2WI (T2-weighted) & SWI (susceptibility weighted image). 다. 2-4 시스테인과결합한철은특히뇌내에서고에너지효율을요구하는바닥핵에작용하여산소독성라디칼을형성하게되며이러한신경학적손상이뇌와안구에축적되어여러신경학적이상을유발하는것으로알려졌다. 3 Pantothenate Kinase-Associated Neurodegeneration (PKAN, Hallervorden-Spatz syndrome) 은인체내철 (Iron) 대사과정의이상으로발생하는장애로, 신경학적이 530

3 - 조성호외 : PKAN 에서발생한망막색소변성 1 예 - Figure 4. In partial sequence of PANK2 gene, there are c.1154_ 1155 ins(t), c.1319g > C mutation on exon3 and exon 4 (blue arrow). 상및발달지연, 뇌내철침착, 망막색소변성등을보이는상염색체열성유전질환이다. 2-5 PKAN은발현나이에따라 10대이전에발현하는조기유형, 20-30대에발현하는후기유형으로나뉘며조기유형이일반적이다. 조기유형의경우추체외로및피질척수로를침범하여근육이상증, 구음장애, 경직등신경학적이상의급속한진행을보이고, 뇌자기공명영상촬영에서바닥핵내창백핵에저신호강도속고신호강도를보이는이른바 eye of tiger sign이특징적으로관찰된다. 안구소견으로는망막색소변성이흔히나타나며, 환자는조기사망하는것으로알려졌다. 후기유형은 20-30대에발현하여서서히진행하며주로언어장애, 정신장애를유발하고, 망막색소변성은흔하지않은것으로알려졌다. 뇌자기공명영상촬영에서는조기발현유형과동일한양상을보인다. 2,5,6 일반적으로 Pantothenate kinase의발현유전자는 4가지로알려졌다. 그중 PKAN을유발하는유전자는미토콘드리아에작용하는 PANK2 (pantothenate kinase gene) 유전자이며, 이는염색체 20p13에위치하는것으로알려졌다. 2 PKAN의조기유형에서는대부분이 PANK2 유전자에서돌연변이를보였다. 5-9 이증례에서도 PANK2 유전자이상을보였다. PKAN 조기유형및후기유형모두특징적으로뇌자기공명영상 T2 강조영상에서바닥핵내창백핵과흑색질에서저신호강도속고신호강도소견을보이는것으로알려졌으며, 이는바닥핵내철침착과산소독성스트레스에의한조직괴사및부종이있다는것을의미한다. 2,9-13 PKAN에서나타나는안구양상은망막색소변성, 시신경위축, 망막신경아교증등이있는것으로알려졌고, 망막전위도검사및안저검사에서광수용체및외핵층의소실, 다양한정도의망막신경아교증을발견할수있다. 2,5,6,14-17 이는 PANK2 유전자의돌연변이가조효소 A의결손을가져오고, 결국생체막합성의결손을가져오는것에기인한다. 광수용체는지속적으로막성원반 (membranous disc) 을만들기때문에 PANK2 유전자결핍은망막색소변성을유발하게된다. 15,16 Newell et al 18 은망막색소변성이관찰되는 PKAN의조기유형은평균 4.7세에신경학적이상이발병하는것으로보고하였고, 망막색소변성이나타나지않는 PKAN 후기유형은평균 15세에신경학적인이상이발병하는것으로보고하였다. 한편시신경위축및시력소실이 PKAN의첫번째양상으로나타나는경우는드문것으로알려졌다. 17 PKAN은원인유전자와 CoA pathway 의 pantothenate kinase 2의역할에대해많이알려졌으나, 질환의기저원인이명확히밝혀지지않아향후연구결과에따라보다구체적인치료가이루어질것이다. 현재 PKAN의치료는강직과이상운동에 Levodopa, 항콜린제, baclofen의경막내혹은경구투여, 근육긴장이상에보튤리늄독소주입을고려하며, 기타치료로는창백핵절단술, 시상절단술, 뇌심부자극술 (deep brain stimulation), 철킬레이팅제제의경구투여가있다. PANK2 enzyme 의기질로작용되는 pantothenate high dose투여, Omega-3-fats (fish oil) 의경구투여도치료방법으로고려된다. 6,11 본증례에서는광범위한망막색소변성소견이관찰되었고, 환아는야맹증을주소로내원하였다. 위소견을바탕으로고려할수있는전신질환으로는망막색소변성과함께청각장애, 함구증, 전정기능장애를동반하는 Usher s 증후군, 극세포증, 흡수장애 ( 지방 ), 신경근육질환을동반하는 Bassen-Kornzweig disease, 진행성신경병증, 난청, 간질환등을동반하는 Refsum s disease, 다지증, 선천성비만을특징으로하는 Bardet Biedl 증후군등을고려해볼수있다. 19 따라서소아에서발생하는야맹증과망막색소변성의경우위와같은전신질환에대한감별검사를시행하는것이필요하다고생각한다

4 - 대한안과학회지 2013 년제 54 권제 3 호 - PKAN은매우드문질환이지만, 신경학적퇴행소견과발달장애를동반한망막색소변성을감별진단할때에는 PKAN 을염두에두어야할것으로생각하며, 뇌자기공명영상촬영과유전자검사를통한정확한진단과치료가필요하다고생각한다. 참고문헌 1) Rock CO, Calder RB, Karim MA, Jackowski S. Pantothenate kinase regulation of the intracellular concentration of coenzyme A. J Biol Chem 2000;275: ) Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348: ) Koeppen AH, Dickson AC. Iron in the Hallervorden-Spatz syndrome. Pediatr Neurol 2001;25: ) Kuo YM, Duncan JL, Westaway SK, et al. Deficiency of pantothenate kinase 2 (Pank2) in mice leads to retinal degeneration and azoospermia. Hum Mol Genet 2005;14: ) Egan RA, Weleber RG, Hogarth P, et al. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol 2005;140: ) Gordon N. Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). Eur J Paediatr Neurol 2002;6: ) Valentino P, Annesi G, Cirò Candiano IC, et al. Genetic heterogeneity in patients with pantothenate kinase-associated neurodegeneration and classic magnetic resonance imaging eye-of-the-tiger pattern. Mov Disord 2006;21: ) Zhou B, Westaway SK, Levinson B, et al. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 2001;28: ) Johnson MA, Kuo YM, Westaway SK, et al. Mitochondrial localization of human PANK2 and hypotheses of secondary iron accumulation in pantothenate kinase-associated neurodegeneration. Ann N Y Acad Sci 2004;1012: ) Hayflick SJ, Penzien JM, Michl W, et al. Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome. Pediatr Neurol 2001;25: ) Hayflick SJ. Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-associated neurodegeneration is the name. Curr Opin Pediatr 2003;15: ) Feliciani M, Curatolo P. Early clinical and imaging (high-field MRI) diagnosis of Hallervorden-Spatz disease. Neuroradiology 1994;36: ) Ponka P. Hereditary causes of disturbed iron homeostasis in the central nervous system. Ann N Y Acad Sci 2004;1012: ) Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of neurodegeneration with brain iron accumulation. J Med Genet 2009;46: ) Tripathi RC, Tripathi BJ, Bauserman SC, Park JK. Clinicopathologic correlation and pathogenesis of ocular and central nervous system manifestations in Hallervorden-Spatz syndrome. Acta Neuropathol 1992;83: ) He X, Hahn P, Iacovelli J, et al. Iron homeostasis and toxicity in retinal degeneration. Prog Retin Eye Res 2007;26: ) Battistella PA, Midena E, Suppiej A, Carollo C. Optic atrophy as the first symptom in Hallervorden-Spatz syndrome. Childs Nerv Syst 1998;14: ) Newell FW, Johnson RO 2nd, Huttenlocher PR. Pigmentary degeneration of the retina in the Hallevorden-Spatz syndrome. Am J Ophthalmol 1979;88: ) Sharma YR, Reddy PRR, Singh DV. Retinitis pigmentosa and allied disorders. JK Sci 2004;6:

5 - 조성호외 : PKAN 에서발생한망막색소변성 1 예 - =ABSTRACT= A Case of Retinal Pigmentary Degeneration in PKAN Seong Ho Jo, MD 1, Chong Kun Cheon, MD, PhD 2, Yong U Kim, MD, PhD 3, Jae Ho Jung, MD, PhD 1 Department of Ophthalmology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine 1, Busan, Korea Department of Pediatrics, Division of Genetics and Metabolism, Pusan National University Children s Hospital, Pusan National University School of Medicine 2, Busan, Korea Department of Radiology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine 3, Busan, Korea Purpose: Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation is an extremely rare degenerative disease. The present study reports a case of retinal pigmentary changes in PKAN. Case summary: A 6-year-old girl presented with night blindness and developmental delay. Neurologic examination revealed toe gait and dystonia. Ocular examination showed retinal pigmentary change in the entire retina without optic atrophy. Brain magnetic resonance imaging showed iron deposits in the basal ganglia, the so-called eye of the tiger sign. Genetic tests confirmed a mutation in the gene encoding pantothenate kinase 2. Electroretinography demonstrated severe loss of rod and cone responses, prominently reduced in the rod response. The patient was diagnosed with PKAN and pharmacologic treatment started. Conclusions: In the case of systemic neurological abnormalities with pigmentary retinal change, PKAN should be considered as a differential diagnosis. J Korean Ophthalmol Soc 2013;54(3): Key Words: Iron, Pantothenate kinase-associated neurodegeneration, Retinal degeneration Address reprint requests to Jae Ho Jung, MD, PhD Department of Ophthalmology, Pusan National University Yangsan Hospital #20 Geumo-ro, Mulgeum-eup, Yangsan , Korea Tel: , Fax: , jaeho0130@naver.com 533

A 617

A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R