13-14-류일선

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1 대한근전도 전기진단의학회지 7(2):153~157, 울산대학교의과대학서울아산병원재활의학교실, 병리학교실, 고려대학교의과대학재활의학교실, 연세대학교의과대학영동세브란스신경과교실 류일선 박은하 편성범 강신광 최영철 Abstract Miyoshi myopathy: A Case Report Il-Sun Lew, M.D., Eun-Ha Park, M.D., Sung-Bom Pyun, M.D.**, Ph.D., Sin- Kwang Kang, M.D.*, Young-Chul Choi, M.D.*** Department of Rehabilitation Medicine, and Pathology*, Asan Medical Center, University of Ulsan College of Medicine, Department of Rehabilitation Medicine, Korea University College of Medicine**, Department of Neurology, Youngdong Severance Hospital, Yonsei University College of Medicine*** We report a 25-year-old man who manifested typical symptoms of Miyoshi myopathy with brief review of literatures. Miyoshi myopathy is a rare distal myopathy which develops between 15 and 30 years of age and starts from the distal muscles, especially posterior compartment of the legs. Creatine kinase (CK) level is characteristically elevated to 10~100 fold above normal range. Electromyographic findings are compatible with myopathy and muscle biopsy shows myopathic changes with non-rimmed vacuoles and absence of dysferlin protein on immunostaining. Key Words: Miyoshi myopathy, Dysferlin, Dysferlinopathy, Distal myopathy 서 론 일반적으로근육병증은상하지근위부근력약화가주증상인반면원위부근육병증은원위부근육에서먼저증상이발현되는매우드문질환이다. 원위부근육병증은유전방식과임상양상에따라 Welander 형, Markesbery 형, Nonaka 형, Miyoshi 형, Laing 형등으로분류되는데, 본저자들은특징적인 Miyoshi 형의원위부근육병증 1 예를경험하였기에보고하는바이다. 증 례 증례 : 25 세남자환자로수년전부터시작된양측하 지위약과비복근근위축을주소로본원재활의학과외래에내원하였다 (Fig. 1). 환자의과거력에서특이한병력은없었으며, 가족력에서도특이사항은없었다. 내원당시이학적검사에서양측상지근력은근위부와원위부에서모두정상이었으며, 하지근력은양측고관절과슬관절에서는 5/5 로정상소견을보였다. 양측발목관절에서족배굴곡의근력은 5/5 로정상소견이었으나, 족저굴곡의근력은 4/5 로약화되어있었고양측비복근의위축이관찰되었으며까치발보행이불가능하였다. 감각은정상이었으며, 양측슬관절반사는정상이었지만양측발목반사는나타나지않았고, 병적반사는관찰되지않았다. 외래에서시행한요추부단순방사선촬영에서특이소견은없었으며, 요추부자기공 Address reprint requests to Sung-Bom Pyun, Ph.D. Department of Rehabilitation Medicine, Korea University Anam Hospital 126-1, 5-ga, Anam-dong, Sungbuk-gu, , Seoul Korea Tel: , Fax: , rmpyun@korea.ac.kr 153

류일선 박은하 편성범 강신광 최영철 명영상에서도제 5 요추와제 1 천추사이의후관절에경도의퇴행성변화소견외에는모두정상이었다. 혈액화학적검사에서 CK 5,329 IU/L( 참고치 50~250 IU/L), LD 401 IU/L( 참고치 120~250 IU/L) 로 CK 수치가매우상승되어있었다.

정량적침근전도검사에서도진폭대반전비 (ampl:tude/ turn ratio) 가낮아근육병증을시사하는소견을보였다 (Table 1). 좌측대퇴이두근과비복근에서근생검 을시행하였으며, 면역형광염색에서좌측대퇴이두근에서 Dysferlin 이관찰되지않았고, 테두리없는액포가관찰되었으며, 다양한크기의근섬유와함께근섬유의괴사가관찰되는등근육병증에합당한소견을보였다.

2 류일선 박은하 편성범 강신광 최영철 명영상에서도제 5 요추와제 1 천추사이의후관절에경도의퇴행성변화소견외에는모두정상이었다. 혈액화학적검사에서 CK 5,329 IU/L( 참고치 50~250 IU/L), LD 401 IU/L( 참고치 120~250 IU/L) 로 CK 수치가매우상승되어있었다. 전기진단검사에서상하지의운동과감각신경전도검사는정상소견을보였고, F- 반사는상하지에서정상소견을보였지만, H- 반사는양측에서유발되지않았다. 침근전도검사에서우측비복근, 전경골근, 장비골근, 대퇴이두근에서비정상자발전위와함께작은진폭과짧은지속기간의다상성활동전위가관찰되었으며, 조기점증양상을보였고, 특히우측비복근에서는삽입전위가심하게감소되어있는소견을보였다. 정량적침근전도검사에서도진폭대반전비 (ampl:tude/ turn ratio) 가낮아근육병증을시사하는소견을보였다 (Table 1). 좌측대퇴이두근과비복근에서근생검 을시행하였으며, 면역형광염색에서좌측대퇴이두근에서 Dysferlin 이관찰되지않았고, 테두리없는액포가관찰되었으며, 다양한크기의근섬유와함께근섬유의괴사가관찰되는등근육병증에합당한소견을보였다. 좌측비복근에서는근섬유는관찰되지않은채심한섬유화소견만이관찰되는등근위부보다원위부에서심하게침범된소견을보여 Miyoshi 형근육병증에합당한소견을보였다 (Fig. 2). 고 찰 Miyoshi 형근육병증은 1977 년 Miyoshi 등에의해처음보고되었으며, 1 상염색체열성으로유전되거나산재성으로발현되어, 15~30 세사이의비교적젊은성인기에증상이시작된다. 근력약화는일반적인근육병과 Fig. 1. Anterior view (A) and posterior view (B) of the patient which shows atrophy of distal leg muscles. A B Fig. 2. Pathologic findings of muscle biopsy in biceps femoris long head. (A) Mild size variation of myofibers and scattered necrotic fibers. Rimmed vacuole is not observed (H&E, 200 magnification). (B) Absence of Dysferlin (immunofluorescence, 200 magnification). 154

3 는달리원위부근육부터약화가나타나며특히비복근에서가장심한근력약화를보이며, CK 수치는정상의 10~100배정도로매우높게증가되는것으로알려져있다. 2,3 원위부근육병증은현재까지밝혀진바로는 Welander형, Markesbery형, Nonaka형, Miyoshi 형, Laing형등이있으며, 현재도계속그표현형과유전형이밝혀지고있다 (Table 2). 4 Miyoshi형근육병증이일반적으로성인초기에발병하는것과는달리 Welander형과 Markesbery-Griggs/Udds형은성인후기에증상이발현된다. 3 또한 Welander형은주로상지를먼저침범하며, Nonaka형과 Laing형의경우에는 Miyoshi형근육병증과유사하게성인초기에발병하지만, Miyoshi형근육병증과는달리주로무릎이하의하지근육중앞쪽근육 (anterior compartment) 에서근위축이발생하며근생검에서공포가발견될수있고, 4 CK 수치가정상의 3~5 배이하로상승하는점에서 Miyoshi형근육병증과구별할수있다. 원위부근육병증의아형외에도감별이필요한근육질환으로는먼저봉입체근염 (inclusion body myositis) 을들수있는데, 근생검에서염증세포와테두리있는액포를관찰할수있어 Miyoshi형근육병증과는다르며, 호발부위가상지에서는주로손목이나손가락의굴곡과관계된장모지굴곡근 (flexor pollicis longus), 하지에서는주로대퇴직근 (restus femoris) 이나전경골근 (anterior tibialis) 으로원위부뿐만아니라근위부에서도근위축이발생할수있다는점에서도 Miyoshi형근육병증과감별된다. 5 그외에도신경질환중 Charcot-Marie-Tooth II 형과의감별이필요한데, 20대초반부터원위부의근육의약화를보이며, 감각신경은 Table1. Needle Electromyographic Findings Muscle Insertional activity Spontaneous activity MUAP 4 Recruitment pattern Rt. Deltoid Normal - Small amplitude, short duration Polys Increased Biceps Brachii IIA 1 F&P 3 (+) Small amplitude, short duration Polys Increased Flexor Carpi Radialis IIA - Normal Full First Dorsal Interosseous Normal - Small amplitude, short duration Polys Increased Vastus Laterlais IIA F&P (++) Small amplitude, short duration Polys Increased Tibialis Anterior IIA F&P (++) Small amplitude, short duration Polys Increased Gastrocnemius DIA 2 F&P (+-++) Small amplitude, short duration Polys Increased Lt. Tibialis Anterior IIA F&P (++) Small amplitude, short duration Polys Increased 1. IIA: increased insertional activity 2. DIA: decreased insertional activity 3. F & P: fibrillation potential & positive sharp wave 4. MUAP: motor unit action potential Table 2. Subtypes of Distal Myopathies4 Type Inheritance Gene location Initial weakness Creatine Kinase Muscle Biopsy Welander type Hands: finger/wrist Normal or slightly Myopathic with rimmed AD 1 2p13 Late adult onset I extensors increased vacuoles Markesberry-Griggs type Legs: anterior Normal orslightly Myopathic with rimmed AD 2q31-33 Late adult onset II compartment increased vacuoles Nonaka type Early adult onset I AR 2 2p1-q1 Legs: anterior slightly increased, Myopathic with compartment usually <5 normal rimmed vacuoles Miyoshi type Legs: posterior compartment Myopathic with Increased Early adult onset II AR 2p12-13 ; occasionally the anterior non-rimmed vacuoles and 10~150 normal (Dysferlin) compartment or hip girdle vessicles Laing type 14q11 Legs: anterior compartment, slightly increased, Myopathic Early adult onset III AD neck flexor usually <3 normal 1. AD: Autosomal dominant 2. AR: Autosomal recessive 155

4 류일선 박은하 편성범 강신광 최영철 비교적유지되어있고, 신경전도검사에서도거의정상소견을보일수있다는점에서 Miyoshi형근육병증과유사하나 CK 수치의증가가없고신경병성침근전도소견을보이며, 근생검에서근육병증소견이없다는점에서 Miyoshi형근육병증과감별할수있다. 그외에도하지의원위부에근력약화가나타나는다양한신경근육질환과의감별이필요하다 (Table 3). 3 Miyoshi형근육병증의원인에대해서는최근유전자연구에서 sarcolemma에서 dysferlin 이라는단백이없거나감소되어 dysferlinopathy 가그원인으로생각되고있다. 7 Dysferlinopathy는염색체 2p13.3에위치하면서 dysferlin 단백을 encoding하는유전자 (DYSF gene) 의돌연변이로인해발생하는데돌연변이의유형은결손돌연변이 (deletion), 삽입돌연변이 (insertion) 뿐아니라, 과오돌연변이 (missense) 혹은무의미돌연변이 (nonsense) 등매우다양해서돌연변이방식의특정한패턴이존재하지않는다. 또한유전자형 (genotype) 과표현형 (phenotype) 사이에중증도에따른연관성이없고, 임상적표현형에있어서도가족내 (intra-familial), 가족간 (inter-familial) 의변이도상당히다양한것으로알려져있다. 8 Dysferlinopathy의임상표현형 (clinical phenotype) 은 Miyoshi형근육병증뿐아니라지대형근이영양증 2B(limb girdle muscular dystrophy 2B, LGMD 2B) 가있으며동일한 DYSF 유전자의돌연변이가관찰된다. 이는 Miyoshi형근육병증과 LGMD 2B가서로 DYSF 유전자의대립유전자의변형 (allelic variation) 이라는사실을나타내며, 4 dysferlinopathy 가 LGMD 2B로나타날수도있고, Miyoshi형근육 Table 3. Differential Diagnoses of the Distal Myopathies Presenting with Leg Weakness 3 Charcot-Marie-Tooth disease (neuronal form) Myotonic dystrophy Distal chronic muscular atrophy Inflammatory myopathies (esp. inclusion body myositis) Motor neuropathies (e.g., lead toxicity, porphyria) Facioscapulohumeral muscular dystrophy Scapuloperoneal syndromes Nonspecific histology Nemaline myopathy Central core disease Centronuclear myopathy Debranching enzyme deficiency myopathy Phosphorylase b kinase deficiency Lipid storage myopathy 병증으로발현될수도있다. 더우기 DYSF 의동일한변이가한가족내에서 Miyoshi형근육병증과 LGMD 2B의두가지표현형으로나타날수도있으며, 9 또한한사람에게서두가지표현형이모두나타날수도있는것으로알려져있다 년 Miyoshi 등에의해처음보고된이후이러한돌연변이는대부분일본인에서확인되었지만, 최근보고에따르면 Miyoshi형근육병증과 LGMD 2B 모두전세계어디에서도발견될수있다. 11 Miyoshi 형근육병증의예후는비교적양호한것으로알려져있으나, 일상생활동작이나기능저하에대한장기적인예후에관한논문은거의없는상태로 Miyoshi형근육병증등원위부근육병증에대한효과적인치료법은아직까지알려져있지않으며 corticosteroid나 azathioprine 같은약제가투여되기도하였으나임상적효과를나타내지는못하였고, 12 발목관절의고정을위한단하지보조기가보행이나계단오르기등에유용하게사용될수있다. 3 참고문헌 11. Miyoshi K, Iwasa M, Kawai H, Sasaki N, Kusaka K, Yagita M, et al: Autosomal recessive distal muscular dystrophy-a new type of distal muscular dystrophy observed characteristically in Japan. Nippon Rinsho 1977: 35: Flachenecker P, Kiefer R, Naumann M, Handwerker M, Reichmann H: Distal muscular dystrophy of Miyoshi type. Report of two cases and review of the literature. J Neurol 1997: 244: Griggs RC, Markesbery WR: Distal myopathies. In: Engel AG, Franzini-Armstrong C, editors. Myology. New York: McGraw-Hill, 1994, pp Dumitru D, Amato AA, Zwarts M: Hereditary Myopathies in Dumitru D, Amato AA, Zwarts M, editors. Electrodiagontic Medicine 2nd ed, Philadelphia: Hanley & Belfus, 2002, pp Nonaka I, Sunohara N, Satoyoshi E, Terasawa K, Yonemoto K: Autosomal recessive distal muscular dystrophy: a comparative study with myopathy with rimmed vacuole formation. Ann Neurol 1985: 17: Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ: Inclusion body myositis. Observations in 40 patients. Brain 1989:112: Dyck PJ: Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In Dyck PJ, Thomas PK, Lambert EH, editors. 156

5 Peripheral Neuropathy. Philadelphia: Saunders, 1975, pp Liu J, Aoki M, Illa I, Wu C, Fardeau M, Angelini C, et al : Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998: 20: Takahashi T, Aoki M, Tateyama M, Kondo E, Mizuno T, Onodera Y, et al: Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype. Neurology 2003: 60: Weiler T, Bashir R, Anderson LV, Davison K, Moss JA, Britton S, et al: Identical mutation in patients with limb girdle muscular dystrophy type 2B or Miyoshi myopathy suggests a role for modifier gene(s). Hum Mol Genet 1999: 8: Nguyen K, Bassez G, Bernard R, Krahn M, Labelle V, Figarella-Branger D, et al: Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies. Hum Mutat 2005: 26: Argov Z, Sadeh M, Mazor K, Soffer D, Kahana E, Eisenberg I, et al: Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features. Brain 2000: 123: Miller RG, Blank NK, Layzer RB: Sporadic distal myopathy with early adult onset. Ann Neurol 1979: 5:

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<30342EC1F5B7CA2DB1E8B3B2C8F D E687770> 대한임상신경생리학회지 11(2):59~63, 2009 ISSN 1229-6414 Case Report 미요시근육병환자에서밝혀진 Dysferlin 유전자돌연변이 동국대학교의과대학신경과학교실 1, 부산대학교의과대학신경과학교실 2, 연세대학교의과대학신경과학교실 3 지명구 1 김남희 1 김대성 2 최영철 3 Identification of a Dysferlin Gene