MOLECULAR MEDICINE REPORTS 13: 4273-4278, 2016

Clinical, pathological and genetic characteristics of autosomal dominant inherited dynamin 2

XINHONG LIU1,2, HUAMIN WU3, JIAN GONG4, TAO WANG2 and CHUANZHU YAN1

1Department of Neurology, Qilu Hospital of Shandong University, Jinan, Shandong 250012; Departments of 2Neurology, 3Radiology and 4Digestive System, Tai'an Central Hospital, Tai'an, Shandong 271000, P.R. China

Received February 21, 2015; Accepted December 18, 2015

DOI: 10.3892/mmr.2016.5047

Abstract. The aim of the present study was to report on a the 1 (MTM1) (2). A third gene, associ- family with pathologically and genetically diagnosed auto- ated with autosomal recessive inherited CNM, is bridging somal dominant inherited centronuclear myopathy (CNM). In integrator 1 (3). addition, this study aimed to investigate the clinical, patho- Previous studies on DNM2‑associated CNM logical and molecular genetic characteristics of the disease. (DNM2 ‑CNM) cases have demonstrated that it can range from This pedigree was traced back three generations, four patients severe neonatal onset to mild adult onset, and the severity of underwent neurological examination, two patients underwent the clinical manifestations vary (4‑7). The majority of patients muscle biopsy, and eight family members were subjected to exhibit distal or proximal muscle weakness as a first symptom, dynamin 2 (DNM2) gene mutation analysis. DNM2 mutations presenting as general muscle weakness, eyelid drooping, were detected in seven family members, of which four patients extraocular muscle paralysis, high arch palate, contracture of exhibited DNM2 mutation‑specific clinical and pathological the Achilles tendon, trismus, and reduction or lack of tendon features. Lower extremity weakness was the predominant reflexes, among which the weakness of the distal or lower limbs symptom of these patients, however, proximal and distal lower is most notable (4,8). Disease progression is predominantly extremity involvement was inconsistent. All patients exhibited slow and few patients develop independent‑walking difficulties marked systematic muscle atrophy and various degrees of in middle age or restrictive ventilatory disorders (9). Typical facial muscle involvement. The patients presented the typical pathological features of DNM2‑CNM are type I fiber predom- pathological changes of CNM, and their muscle tissues were inance and type I atrophy, increased proportions of radial heavily replaced by adipose tissue, with clustered distribution fibers and central nuclei in the sarcoplasmic reticulum (1). of muscle fibers as another notable feature. DNM2‑CNM Approximately 100 DNM2‑CNM families have exhibited patients of this pedigree exhibited heterogeneous clinical and 18 different DNM2 mutations (10). Patients with mutations pathological features, providing a basis for further molecular affecting the intermediate domains of DNM2 usually present genetic analysis. with relatively mild clinical features (5,11), while mutations impacting the pleckstrin family homology (PH) Introduction domain and GED structures result in more serious clinical manifestations (4). Centronuclear myopathies (CNMs) are a group of rare slowly To the best of our knowledge, this study is the first to progressive congenital myopathies, which are character- report on a Chinese family with pathologically and genetically ized by centronuclear dysplasia in muscle fibers. Autosomal confirmed DNM2‑associated autosomal dominant inherited dominant inherited mutations of the dynamin 2 (DNM2) CNM. This study aimed to investigate the clinical, patholog- gene are the cause of 50% of CNM cases (1). Clinical symp- ical and genetic characteristics of this disease, and contribute toms of DNM2‑associated CNM are milder than those of to further molecular genetic studies of autosomal dominant X ‑linked recessive inheritedRETRACTED CNM caused by mutations in inherited CNM.

Materials and methods

Subjects. Four patients, two males and two females, belonging Correspondence to: Professor Chuanzhu Yan, Department of Neurology, Qilu Hospital of Shandong University, 107 Culture West to a family with three generations of autosomal dominant Road, Jinan, Shandong 250012, P.R. China inherited CNM (pedigree presented in Fig. 1), were investi- E ‑mail: [email protected] gated. The patients were recruited from the Qilu Hospital of Shandong University (Jinan, China) and presented muscle Key words: autosomal dominant inheritance, dynamin 2, centronuclear weakness. All patients underwent physical examination, myopathy genetic testing, and two of the patients further provided muscle biopsies. Detailed case history enquiries and clinical examina- tion were conducted by two neurologists. The present study 4274 LIU et al: CHARACTERISTICS OF DYNAMIN 2‑CENTRONUCLEAR MYOPATHY

Table I. Clinical patient data from d=four cases of dynamin 2‑centronuclear myopathy.

Variable I1 II2 II4 II5

Gender/age Female Male Female Male Age (years) 59 38 33 30 Onset Adolescence Adolescence Adolescence Adolescence Developmental delay Normal Normal Could walk at 2‑years‑old Unknown First symptom Lower extremity Lower extremity Lower extremity Lower extremity weakness weakness weakness weakness Muscle involvement Neck + ‑ ‑ ‑ Upper limb Proximal 3 5 3‑4 5 Distal 4 5 5 5 Lower limb Proximal 3 4‑5 4 5 Distal 4 3 3 5 Limb‑girdle muscular Upper limb 3‑4 4 4 5 Lower limb 3‑4 4 4 4 Facial muscle involvement + + + + Eyelid drooping + ‑ ‑ ‑ Ophthalmoplegia - - - - High‑vaulted arch ‑ + ‑ + Joint contractures ‑ ‑ ‑ + Arched feet ‑ ‑ ‑ ‑ Curvature of spine ‑ ‑ ‑ ‑ Muscle atrophy + + + + Tendon reflexes + ‑ + ‑ + ‑ + ‑ Serum CK 126 Not tested Not tested Not tested EMG Myogenic damage Myogenic damage Not tested Not tested Dysphagia - - - - Breathing difficulty ‑ ‑ ‑ ‑

CK, creatine kinase; EMG, electromyography. ‑, negative; +, positive; + ‑, likely positive. Muscle strength grade: level 0, muscle paralysis, no contraction; level 1, slight contraction of the muscles, but no action; level 2, muscles only function when not subjected to excessive weight; level 3, muscles can carry out actions against gravity but not with added resistance; level 4, able to counteract some resistance against the muscle; level 5, normal muscle strength.

was conducted in accordance with the declaration of Helsinki and with approval from the Ethics Committee of Shandong University (Jinan, China). Written informed consent was obtained from all participants.RETRACTED

Pathological specimens. Muscle specimens of two patients were obtained from the left biceps by open biopsy. Fresh muscle samples were snap‑frozen in liquid nitrogen‑cooled isopentane (Sinopharm Chemical Reagent Co., Ltd., Beijing, China), and 8‑µm tissue sections were cut using a Figure 1. Dynamin 2‑associated autosomal dominant central nucleus myopathy cryo ‑ultramicrotome (Leica 1900; Leica Microsystems GmbH, family pedigree. Circle, female; square, male; black, affected; white, unaffected. Wetzlar, Germany) at ‑20 to ‑25˚C. Tissues were then stained with hematoxylin‑eosin (H&E), modified Gomori's trichrome, NADH ‑tetrazolium reductase, cytochrome c oxidase, succinate routine use of dynamin‑N, R, and C monoclonal antibody dehydrogenase, lactate dehydrogenase, periodic acid‑Schiff, immunohistochemical staining in order to analyze dynamin and oil red O. Dystrophin staining was carried out with the protein expression levels in the sarcolemma using an optical MOLECULAR MEDICINE REPORTS 13: 4273-4278, 2016 4275

A B C

D E F

G H

Figure 2. (A and B) I1, H&E staining, visible adipose tissue, muscle fibers distributed in clusters, fiber size is different in muscle tissue, the fibers are homo- geneously small, round and polygonal, with no obvious hyperplasia of the endomysium, >90% of the muscle fibers contain a central nucleus. (C) I1, NADH was used to distinguish between two types of fiber. (D‑I) II2, eldest son of I1 muscle pathology, (D and E) H&E staining, >90% of muscle fibers contain a central nucleus and exhibit visible adipose infiltration between the fibers. (F) NADH staining, typical appearance of fibrin observed. (G) Trophin staining demonstrates the membrane integrity with fat infiltration between the muscle fibers. (H) ATP staining demonstrated type I fiber predominated, however, a number of type II fibers were observed with normal ATP staining. microscope (Olympus BH‑2; Olympus Corporation, Tokyo, involvement and various degrees of systematic muscle Japan). Remaining samples were stored at ‑80˚C until further atrophy. Symptoms are first identified at ~20 years of age, use. All specimens were reviewed and confirmed by two experi- while they were capable of taking care of themselves and enced clinical neurologists. living normal lives. The grandchildren of proband I1, III1 (13 years old), III2 (4 years old), III3 (4 years old) and III4 Gene sequencing analysis. Based on the DNM2 genome (5 years old), did not exhibit symptoms of muscle weakness, sequence, primers were designed to cover 22 exons, including and their sports activities were the same as healthy children alternate exons, exon 10b and exon 13b. DNM2 sequences of of the same age. However, III3 exhibited general features of eight family members were determined and compared with congenital muscular disease, including emaciation, narrow the human gene mutation database (http://www.hgmd.cf.ac. face and high‑vaulted arch. Judging from the combined uk/ac/index.php) by Beijing ACCB Biotech, Ltd. (Beijing, inheritance mode and clinical symptoms, this family met the China). criteria of late‑onset autosomal dominant inheritance.

Results Pathology of muscle biopsies. Following muscle biopsy (Fig. 2), it was demonstrated that muscle tissues of I1 were largely Clinical data. Table I presentsRETRACTED the clinical data of four patients. replaced by fat tissues. H&E staining demonstrated that there Proband I1 experienced onset of the disease in adolescence, was a large amount of adipose tissue distributed within the continuing for >30 years. Lower extremity weakness was the first muscle fibers (Fig. 2). The size of the muscle fibers varied. The and predominant symptom, which slowly developed and resulted fibres appeared slightly round or polygonal without notable in marked muscle weakness by the age of 30. Systematic muscle muscular intimal hyperplasia and with >90% of muscle fibers atrophy was apparent, rendering the patient wheelchair‑bound, containing central nuclei (Fig. 2A‑C). Dystrophin staining and was accompanied by double‑eyelid drooping and facial indicated intact membrane structures of myofibrils. In addition, weakness. Creatine kinase levels were mildly elevated, electro- the muscles of II2 demonstrated typical CNM pathological myography (EMG) demonstrated the typical myogenic changes, changes, including: i) >90% of fibers containing a central nuclei and a high spontaneous potential was detected (12,13). The (Fig. 2D); ii) inconsistent size and rounding of muscle fibers; children of I1 (II2, II4 and II5) all experienced onset of the iii) selective type I fiber predominance and type I and atrophy disease in adolescence, and also predominantly presented with as demonstrated by ATPase staining (Fig. 2H); and iv) radially lower extremity weakness accompanied by light facial muscle arranged, wheel‑like sarcoplasm with central nuclei (Fig. 2F). 4276 LIU et al: CHARACTERISTICS OF DYNAMIN 2‑CENTRONUCLEAR MYOPATHY

Discussion

CNM was first reported by Spiro et al (14) in 1966 and, as the pathological characteristics were similar to those of myotubes in the fetal period, it was designated myotubular myopathy. However, as no arrest of muscle development at the stages of myotube formation was demonstrated as the cause of the disease, the name centronuclear myopathy was regarded to be more appropriate (15). It was later observed that 50% of CNM cases were the result of autosomal dominant inherited DNM2 mutations (1). To the best of our knowledge, this is the first study of a Chinese family with pathologically and genetically confirmed DNM2 ‑associated autosomal dominant inherited CNM. Among the three generations of this family, there were four patients (Il, II2, II4, II5) of which the oldest son (II2) of the proband (I1) and the disease‑free grandson (III3) demonstrated general characteristics of congenital muscle disease, such as emaciation, narrow face and high‑vaulted arch. All four patients experienced onset of disease in adolescence or youth, with lower extremity weakness as the first and predominant symptom, gradually involving the upper limbs. As the disease slowly progressed, muscles exhibited various degrees of atrophy, involving upper and lower extremities, while in proximal and distal muscles, the effects were inconsistent, in contrast to an earlier study (16). In other countries, DNM2‑CNM patients have a high incidence of eyelid drooping (9/10, 7/11) and ophthalmoplegia (2/10, 5/11) (16). Proband I1 exhibited characteristic eyelid drooping, which was not observed in the other family members, whereas 18 non‑DNM2‑CNM patients presented with eyelid drooping and ophthalmoplegia, indicating that eyelid drooping is not a unique characteristic of DNM2‑CNM patients (17). The four patients of this family exhibited facial muscle involvement, marked in proband I1 and milder in her children, indicating that the inci- Figure 3. Analysis of G‑A displacement mutation in exon 8 of the dyanamin 2 dence of facial muscle involvement may be higher in China and gene at position 1,106 in patients, I1, II2, II4, II5, III2, III3, III4. possibly a unique feature of Chinese CNM, however, more cases would be required to further elucidate this. None of the four patients of this family indicated joint contractures, scoliosis, arched feet, or other features that are regarded as characteristic of CNM (18). Mandibular muscle contracture was reported as an important feature of newborn or childhood DNM2‑CNM in an Italian study (19). In this pedigree, no breathing disorders were present, although emphasis has been placed on respiratory distress problems in DNM2‑CNM patients. Recently, Italian and German CNM studies demonstrated various degrees of Figure 4. Dynamin 2 gene structure. PH, pleckstrin protein family homology restrictive ventilatory disorders (7‑10,20). The four patients domain; GED, GTP enzyme effector domain; PRD, proline‑rich domain. in the present study demonstrated mental retardation but no RETRACTEDdysphagia or diplopia, no associated muscle pain or sensory disorders, however, all exhibited diminished tendon reflexes and While there was marked adipose tissue infiltration among the muscle tone. Proband I1 and her eldest son exhibited a normal myofibrils (Fig. 2E), dystrophin staining demonstrated intact muscle enzymogram, and their EMG exhibited myogenic myofibril membrane structures (Fig. 2G). changes, consistent with previous studies (17,19,21). As current clinical studies on myopathy are not systematic or common, it Mutation screening. Gene sequencing analysis demonstrated that was difficult to conduct a comprehensive comparative study on family members Il, II2, II4, II5, III2, III3 and III4 possess a G‑A a whole family, requiring in‑depth investigation and follow‑up substitution mutation at position 1,106 (1,106G>A) of DNM2 domestically and abroad. exon 8 (Fig. 3), resulting in an amino acid change from arginine The diagnosis of the disease depends on muscle pathology, to glutamine at position 369 (R369Q) of the DNM2 protein. As and typical patient manifestations include wide‑range nuclear this mutation was not detected in normal individuals (10), it is ingressions of a large number of muscle fibrous nuclei, a mark- assumed to be causatively associated with the disease. edly increased proportion of central nuclei, radial arrangement MOLECULAR MEDICINE REPORTS 13: 4273-4278, 2016 4277 of the perinuclear muscle mass, type I fiber predominance and While III2 (4 years old), III3 (4 years old), and III4 (5 years old) type I atrophy. The muscle tissues of proband I1 and her eldest carried this DNM2 gene mutation, due to their young age they son, II2 exhibited typical CNM pathological changes. did not exhibit notable signs of muscle weakness, consistent Central nucleus pathological manifestations can be found with the age of onset of the disease in their family. However, III3 in numerous diseases, including muscular dystrophy, recycled exhibited general characteristics of CMD, including emaciation, fiber, denervation, and metabolic and toxic myopathy, thereby narrow face and high‑vaulted arch. not defining a specific disease. Within these myopathies, In conclusion, a DNM2‑CNM pedigree was confirmed perinuclear sarcoplasmic radial arrangement and type I fiber pathologically and genetically, and was identified to be consis- predominance and type I atrophy would not appear, and these tent with the clinical and pathological changes in previously symptoms are characteristic of the pathology of the muscular reported cases. While four patients had facial muscle involve- biopsies of patients with CNM. Therefore, the reliability of ment, this was not accompanied by eyelid drooping and paralysis pathological diagnosis towards CNM was higher. However, of extraocular muscles, which is possibly a unique feature of congenital and X‑linked genetic myotu- Chinese CNM patients, but requires further investigation into bular myopathy exhibit similar clinical and pathological a large number of Chinese cases. Muscle pathologies predomi- characteristics and should therefore be differentially diagnosed nantly consisted of: Muscle fibers exhibiting central nuclei; by genetic analysis of the children and their mother's EMG. perinuclear muscle mass demonstrating radial arrangement; Proband I1 presented at a late stage, with muscle tissues type I fibers, and atrophy. In addition, two patients demonstrated heavily infiltrated by adipose tissues, while the dystrophin massive adipose tissue infiltration, which may be the result of staining indicated that this fatty infiltration occurred outside the development of the disease or other specific changes, this of the muscle fiber membrane. In a previous report on CNM requires verificationin a large numbers of cases. The sequencing patients with extensive pseudo‑muscular hypertrophy, comput- results of the present study demonstrated that seven members of erized tomography scanning, ultrasound and histochemical this pedigree carried the G‑A substitution mutation in exon 8 staining demonstrated that this muscular hypertrophy was position 1,106 of the DNM2 gene, resulting in an amino acid due to the marked infiltration of muscular bundles by adipose change from arginine to glutamine at position 369 (R369Q) of tissues (21). By contrast, patients in the present study did not the DNM2 protein, previously indicated as the disease‑causing exhibit muscular hypertrophy but muscular atrophy, pathologi- mutation (6). While family members, III2 (4 years old), III3 cally indicated by markedly reduced numbers of muscle fibers. (4 years old), and III4 (5 years old) also exhibited this DNM2 A previous study observed extensive muscular hypertrophy gene mutation, they were probably too young to exhibit notable in two patients from one family and divided CNM into two signs of muscle weakness, which would be consistent with the clinical subtypes accordingly, assuming that the subtype with age of onset of the disease in their family. the extensive muscular hypertrophy would rapidly progress. The results of the present study suggest that careful exami- However, their biopsy specimens, regardless of muscle nation of clinical and pathological features allow for improved hypertrophy, exhibited no increase in adipose and connective molecular genetics analyses in CNM. tissues (22), thereby not providing a pathological basis for the connection to muscle hypertrophy and fat infiltration. To References verify whether the muscular pathological features of patients in the present study were the result of disease progression or of 1. Romero NB: Centronuclear myopathies: A widening concept. Neuromuscul Disord 20: 223‑228, 2010. other specific changes requires further investigation. 2. Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, The DNM2 gene located at 19p13.2 contains 22 exons Klauck SM, Poustka A and Dahl N: A gene mutated in and five structural domains (Fig. 4), including a GTP enzyme X‑linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet 13: 175‑182, domain (GTPase), an intermediate domain, a PH domain 1996. (substrate of platelet leukocyte C kinase), a GTP enzyme 3. Nicot AS, Toussaint A, Tosch V, Kretz C, Wallgren‑Pettersson C, effector structural domain, and a structural proline‑rich Iwarsson E, Kingston H, Garnier JM, Biancalana V, Oldfors A, et al: Mutations in amphiphysin 2 (BIN1) disrupt interaction domain. The encoded protein is functionally involved in cellular with dynamin 2 and cause autosomal recessive centronuclear endocytosis, membrane anchoring, actin assembly and centro- myopathy. Nat Genet 39: 1134‑1139, 2007. some binding. Furthermore, it was observed that the exon 8, 4. Bitoun M, Bevilacqua JA, Prudhon B, Maugenre S, Taratuto AL, Monges S, Lubieniecki F, Cances C, Uro‑Coste E, Mayer M, et al: mutations 1,105C>T, 1,102G>A and 1,106G>A, in addition to Dynamin 2 mutations cause sporadic centronuclear myopathy the exon 11 mutation 1,393C>T,RETRACTED were high frequency muta- with neonatal onset. Ann Neurol 62: 666‑670, 2007. tions of this disease, resulting in amino acid changes R369W, 5. Bitoun M, Maugenre S, Jeannet PY, Lacène E, Ferrer X, Laforêt P, Martin JJ, Laporte J, Lochmüller H, Beggs AH, etl a : Mutations E368K, R369Q and R465W, respectively (10). Böhm et al (10) in dynamin 2 cause dominant centronuclear myopathy. Nat investigated 100 pedigrees in 2012 and identified 18 different Genet 37: 1207‑1209, 2005. mutations of dynamin 2 (DNM2, 19p13.2) with five domains 6. Bitoun M, Bevilacqua JA, Eymard B, Prudhon B, Fardeau M, Guicheney P and Romero NB: A new centronuclear myopathy involved. Sequencing results in the present study demonstrated phenotype due to a novel dynamin 2 mutation. Neurology 72: that seven family members (I1, II2, II4, II5, III2, III3 and III4) 93 ‑95, 2009. exhibited the G‑A substitution mutation at exon 8 position 1,106 7. Hanisch F, Müller T, Dietz A, Bitoun M, Kress W, Weis J, Stoltenburg G and Zierz S: Phenotype variability and histo- of the DNM2 gene, resulting in an amino acid change from pathological findings in centronuclear myopathy due to DNM2 arginine to glutamine at position 369 (R369Q) of the DNM2 mutations. J Neurol 258: 1085‑1090, 2011. protein. Bitoun et al (6) reported the 1,106G>A mutation in 8. Fischer D, Herasse M, Bitoun M, Barragán‑Campos HM, Chiras J, Laforêt P, Fardeau M, Eymard B, Guicheney P and Romero NB: a French pedigree, where it was not observed in normal indi- Characterization of the muscle involvement in dynamin 2‑related viduals, indicating that it was the disease‑causing mutation. centronuclear myopathy. Brain 129: 1463‑1469, 2006. 4278 LIU et al: CHARACTERISTICS OF DYNAMIN 2‑CENTRONUCLEAR MYOPATHY

9. Melberg A, Kretz C, Kalimo H, Wallgren‑Pettersson C, 17. Mori ‑Yoshimura M, Okumab A, Oyaa Y, Fujimura‑Kiyono C, Toussaint A, Böhm J, Stålberg E and Laporte J: Adult course Nakajima H, Matsuura K, Takemura A, Malicdan MC, in dynamin 2 dominant centronuclear myopathy with neonatal Hayashi YK, Nonaka I, et al: Clinicopathological features of onset. Neuromuscul Disord 20: 53‑56, 2010. centronuclear myopathy in Japanese populations harboring 10. Böhm J, Biancalana V, Dechene ET, Bitoun M, Pierson CR, mutations in dynamin 2. Clin Neurol Neurosurg 114: 678‑683, Schaefer E, Karasoy H, Dempsey MA, Klein F, Dondaine N, etl a : 2012. Mutation spectrum in the large GTPase dynamin 2, and 18. Jungbluth H, Wallgren‑Pettersson C and Laporte J: genotype ‑phenotype correlation in autosomal dominant centro- Centronuclear (myotubular) myopathy. Orphanet J Rare Dis 3: nuclear myopathy. Hum Mutat 33: 949‑959, 2012. 26, 2008. 11. Schessl J, Medne L, Hu Y, Zou Y, Brown MJ, Huse JT, 19. Catteruccia M, Fattori F, Codemo V, Ruggiero L, Maggi L, Torigian DA, Jungbluth H, Goebel HH and Bönnemann CG: MRI Tasca G, Fiorillo C, Pane M, Berardinelli A, Verardo M, et al: in DNM2‑related centronuclear myopathy: Evidence for highly Centronuclear myopathy related to dynamin 2 mutations: selective muscle involvement. Neuromuscul Disord 17: 28‑32, 2007. Clinical, morphological, muscle imaging and genetic features 12. Hørder M and Gerhardt W: The Scandinavian committee on of an Italian cohort. Neuromuscul Disord 23: 229‑238, 2013. enzymes. Scand J Clin Lab Invest Suppl 179: 13‑17, 1985. 20. Jungbluth H, Wallgren‑Pettersson C and Laporte JF; 13. Finsterer J and Fuglsang‑Frederiksen A: Concentric needle Centronuclear (Myotubular) Myopathy Consortium: 198th EMG versus macro EMG I. Relation in healthy subjects. Clin ENMC International workshop: 7th workshop on centronuclear Neurophysiol 111:1211‑1215, 2000. (myotubular) myopathies, 31st May‑2nd June 2013, Naarden, 14. Spiro AJ, Shy GM and Gonatas NK: Myotubular myopathy. The Netherlands. Neuromuscul Disord 23: 1033‑1043, 2013. Persistence of fetal muscle in an adolescent boy. Arch Neurol 14: 21. Kerst B, Mennerich D, Schuelke M, Stoltenburg‑Didinger G, 1 ‑14, 1966. von Moers A, Gossrau R, van Landeghem FK, Speer A, 15. Sher JH, Rimalovske AB, Athanassiades TJ and Aronson SM: Braun T and Hübner C: Heterozygous myogenic factor 6 Familial centronuclear myopathy: A clinical and pathological mutation associated with myopathy and severe course of study. Neurology 17: 727‑742, 1967. Becker muscular dystrophy. Neuromuscul Disord 10: 572‑577, 16. Susman RD, Quijano‑Roy S, Yang N, Webster R, Clarke NF, 2000. Dowling J, Kennerson M, Nicholson G, Biancalana V, Ilkovski B, 22. Jeannet PY, Bassez G, Eymard B, Laforêt P, Urtizberea JA, etl a : Expanding the clinical, pathological and MRI phenotype of Rouche A, Guicheney P, Fardeau M and Romero NB: Clinical DNM2 ‑related centronuclear myopathy. Neuromuscul Disord 20: and histologic findings in autosomal centronuclear myopathy. 229‑237, 2010. Neurology 62: 1484‑1490, 2004.

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