Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy

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1 doi: /brain/awl071 Brain (2006), 129, Characterization of the muscle involvement in dynamin 2-related centronuclear myopathy Dirk Fischer, 1,5 Muriel Herasse, 1,2 Marc Bitoun, 1,2 Héctor M. Barragán-Campos, 3,4 Jacques Chiras, 3,4 Pascal Laforêt, 1,2,4 Michel Fardeau, 1,2,4 Bruno Eymard, 1,2,4 Pascale Guicheney 1,2 and Norma B. Romero 1,2,4 1 Institut National de la Santé et de la Recherche Médicale U582, Institut de Myologie, IFR14, Groupe Hospitalier Pitié-Salpêtrière, 2 Université Pierre et Marie Curie, 3 Department of Neuroradiology, Groupe Hospitalier Pitié-Salpêtrière and 4 Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France and 5 Muskellabor, Department of Neurology, University of Bonn, Germany Correspondence to: Dr Norma Beatriz Romero, Inserm U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France nb.romero@myologie.chups.jussieu.fr Centronuclear myopathy (CNM) is a slowly progressive congenital myopathy characterized by abnormal centrally located nuclei in a large number of muscle fibres. Recently, different missense mutations affecting the middle domain of the dynamin 2 (DNM2) have been shown to cause autosomal dominant CNM. In order to better define the phenotype of DNM2-related CNM, we report here on the clinical and muscle imaging findings of 10 patients harbouring DNM2 mutations. DNM2-CNM is characterized by slowly progressive muscular weakness usually beginning in adolescence or early adulthood. In addition to bilateral ptosis, our data show that distal muscle weakness often exceeds proximal involvement. Furthermore, electrophysiological investigations frequently demonstrated signs of mild axonal peripheral nerve involvement, and electromyographical examination may show neuropathic changes in addition to the predominant myopathic changes. These features overlap with findings seen in the phenotype of DNM2-related autosomal dominant Charcot Marie Tooth disease type 2B. In all 10 DNM2-CNM patients, muscle computer tomography assessment showed a consistent pattern of muscular involvement and a characteristic temporal course with early and predominant distal muscle involvement, and later affection of the posterior thigh compartment and gluteus minimus muscles. The recognition of this specific imaging pattern of muscle involvement distinct to the reported patterns in other congenital myopathies may enable a better selection for direct genetic testing. Keywords: dynamin 2; centronuclear myopathy; CMT-2B; muscle CT; distal muscle weakness Abbreviations: CK = creatine kinase; CMAP = compound motor action potentials; CNM = centronuclear myopathy; DTRs = deep tendon reflexes; GED = GTPase effector domain; MNCR = median nerve conduction velocities; NCS = nerve conduction studies; NEE = needle electrode examination; PH = Pleckstrin Homology Received December 3, Revised February 7, Accepted March 3, Advance Access publication April 3, 2006 Introduction Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by slowly progressive generalized muscular weakness and atrophy usually beginning in childhood or early adolescence (Fardeau and Tomé 1994; Jeannet et al., 2004). Proximal limb girdle and paraspinal muscles have been described as the most severely affected muscles in several patients (McLeod et al., 1972; Pepin et al., 1976; Felice et al., 1997), but distal muscular weakness has also been reported (Goulon et al., 1976; Ferrer et al., 1992). Furthermore, ptosis and involvement of the extraocular eye muscles are frequent findings (Spiro et al., 1966; Fardeau and Tomé, 1994; Jeannet et al., 2004). CNM is morphologically characterized by chains of centrally located nuclei in a large number of (extrafusal) muscle fibres, a predominance and hypotrophy of type I fibres and a radial arrangement of sarcoplasmic strands around the central nuclei seen on nicotinamide adenosine dinucleotide-tetrazolium reductase staining (NADH-TR) and on immunostaining of desmin (Spiro et al., 1966; Goulon et al., 1976; Fardeau and Tomé, 1994; Mora et al., 1994; Jeannet et al., 2004). # The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 1464 Brain (2006), 129, D. Fischer et al. CNM was first reported in 1966 and was named myotubular myopathy because of morphological similarities with fetal myotubes (Spiro et al., 1966). Since everybody did not accept that the muscle was arrested in development at the myotubular stage in this congenital myopathy, the term centronuclear myopathy was proposed (Banker, 1967; Sher et al., 1967a, b). Currently, the term myotubular myopathy is restricted to the severe neonatal X-linked form (X-MTM), which is caused by MTM1 gene mutations, while the term centronuclear myopathy was preferred for the autosomal forms of the disorder (Engel et al., 1968; Campbell et al., 1969). Recently, different missense mutations affecting the middle domain of the dynamin 2 (DNM2, 19p13.2) were shown to cause autosomal dominant CNM (Bitoun et al., 2005). DNM2 encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The DNM2 protein comprises an N-terminal tripartite GTPase domain, a middle domain, a Pleckstrin Homology (PH) domain, a GTPase effector domain (GED) and a C-terminal proline rich domain (PRD). Interestingly, DNM2 mutations, restricted to the PH domain, were identified in dominant Charcot Marie Tooth disease type B (DNM2-CMT2B) (Zuchner et al., 2005). The aim of the present study is to define better the clinical characteristics with special emphasis on the muscular imaging findings of DNM2-related autosomal dominant CNM (DNM2-CNM). Methods Patients Ten patients aged years from three different autosomal dominant CNM families and one sporadic case with confirmed heterozygous DNM2 mutations were included in this study. Genetic analysis of the patients has been described previously (Bitoun et al., 2005). Eight patients were carriers of the R369Q missense mutation, one patient harboured a de novo R369W mutation and another the R465W mutation. Muscle CT imaging All patients were fully cooperative and had given written consent prior to the investigations. Computer tomography studies included standard scans at hip, thigh and lower leg level. The scans were examined for normal and abnormal muscle bulk (atrophy/ hypertrophy), and for abnormal signal density. Each muscle group was staged according to the degree of degeneration using a modified 5-point scale as described (Lamminen, 1990; Mercuri et al., 2002a; Fischer et al., 2005): Stage 0: normal appearance, Stage 1: mild with only traces of decreased signal density, Stage 2: moderate with decreased signal density in <50% of the examined muscle, Stage 3: severe with decreased signal density in >50% of the examined muscle, Stage 4: end-stage appearance, entire muscle replaced by lower density. The following muscles were evaluated: pelvis: gluteus maximus, gluteus medius, gluteus minimus; thigh: vastus medialis, vastus intermedius and lateralis, sartorius, gracilis, adductor muscles, semimembranosus, semitendinosus, biceps femoris; lower legs: tibialis anterior, peroneal group, soleus, medial and lateral gastrocnemius. Results The clinical phenotype in DNM2-CNM patients Detailed information on the clinical involvement and complementary neurophysiological, respiratory and cardiac investigations of each patient is provided in Table 1. The clinical and pathological findings in DNM2-CNM patients are illustrated in Fig. 1. Onset and progression Early motor milestone achievement was normal in all patients. Disease onset occurred in adolescence in six individuals and in adulthood for the remaining four. First symptoms included exercise-related muscle pain (seven patients), walking difficulties and/or frequent falls (four), difficulties at school sports (two) and climbing stairs (three). Muscle weakness was slowly progressive in all patients, and severe involvement with loss of independent ambulation was observed in one individual occurring in the fifth decade (Patient 10). Clinical examination On examination, nine patients presented with bilateral ptosis, two individuals had different types of extraocular eye muscle involvement (upgaze limitation, abduction restriction and mild ophthalmoparesis). Four individuals displayed mild facial weakness. Axial muscle weakness (neck flexion, lumbar extension and abdominal muscle weakness) and/or hyperlordosis were reported in three patients. In the upper limbs, moderate to severe weakness was present in six patients, which was more pronounced in distal (hand and finger extensor) than in proximal muscles in all six patients. In the lower limbs, mild, moderate or severe limb muscle weakness was present in eight individuals, four of them with distal (foot and toe extensors) greater than proximal weakness, two with proximal exceeding distal weakness and two with equal proximal and distal weakness (Table 1). Achilles tendon contractors were seen in nine patients, while finger flexor contractors and a mild rigidity of the spine were present in three patients. Deep tendon reflexes (DTRs) were reported in six individuals, four of them showing reduced to absent DTRs. Cognitive impairment was observed in one patient. Neurophysiological and laboratory examination Electrophysiological studies were performed on seven patients. On needle electrode examination (NEE), all seven individuals showed myopathic changes. Four patients showed additional signs of neuropathic changes on NEE or had pathological nerve conduction studies (NCS). Three patients presented pathological spontaneous activity (fibrillation potentials and pseudomyotonic discharges). NCS gave normal results in four patients, but three showed a reduction

3 Phenotype of DNM2-CNM Brain (2006), 129, Table 1 Patient data, clinical and complementary findings in DNM2-CNM Patient data First symptoms Weakness Additional findings Electrophysiology CK Resp. Cardiac Muscle biopsy Patient Sex Mutation A/E Onset EM SS CS W Face AX UL LL Contract. DTR s Other NEE CMAP MNCV (U/l) (VC) (%) P EOM Fa Prox. Distal Prox. Distal (ECG, Echo) CN ID IA RS A/B 1 M R369Q 15 Adol A N M,F red. N nd. nd. nd. nd. nd. nd. 2 F R369Q 12 Adol A nr. M red. N nd. nd. nd. nd. nd. nd. 3 (1 4)* M R465W 31 Adol A, FF, S red. Cogn. imp. nd. nd. N N (3 18)* M R369Q 21 Adol A, FF, S nr. M N N nd. nd. nd. nd. nd. nd. 5 (3 17)* F R369Q 46 Adult A, S nr. M N N 215 nd. N. nd. nd. nd. nd. nd. 6 (2 10)* F R369Q 52 Adult A M,F N N N (3 14)* F R369Q 46 Adult A, FF, S red. Hyperld, M.hypert. nd. nd. N nd (3 13)* M R369Q 52 Adol A LL: - - M,F red. N nd (S) M R369W 38 Adult A, FF N Hyperld, nd. nd. N N (3 12)* M R369Q 74 Adult nr. M N N nr. nd. nd Weakness is described according to the Medical Research Council (MRC) grade. A/E = age at last examination, +=present, = absent, red. = reduced, N = normal, n.d. = not done, n.r. = not reported, Adol. = Adolescence, Adult. = Adulthood, EM = exercise-related myalgia, SS = school sports difficulties, CS = climbing stairs difficulties, W = walking difficulties, P = ptosis, EOM = extraocular eye muscles, Fa. = facial muscles, Ax = axial muscles, UL = upper limb muscles, LL = lower limb muscles, prox. = proximal, dist. = distal, Contract. = contractures, DTRs = deep tendon reflexes, cogn. imp.= cognitive impairment, Hyperld. = hyperlordosis, M.hypert. = muscular hypertrophy, A = Achilles tendon, FF = finger flexors, S = (rigid) spine, CMAP = compound motor action potential, NEE = needle electrode examination, M = myopathic changes, F = fibrillations, MNCV = median nerve conduction velocity, CK = creatine kinase (normal to 170 U/l), Resp. = respiratory examination, VC = vital capacity, CN = increased number of central nuclei, ID = fibre type I predominance, IA = fibre type I atrophy or hypotrophy, RS = radial sarcomeric strands. A/B = age at muscle biopsy. * Patient number in Jeannet et al

4 1466 Brain (2006), 129, D. Fischer et al. seen in various other conditions (Jeannet et al., 2004), the presence of all of these features in all available muscle biopsies suggests that they are, together, highly characteristic for DNM2-CNM. Fig. 1 The clinical and pathological findings observed in DYN2-CNM. Clinically, patients present with mild facial weakness and bilateral ptosis (A and B). Characteristic histopathological findings with myotube-like fibres that show an increased number of centralized nuclei (C; HE, original magnification 20), presence of fibre type 1 predominance and atrophy (D; ATP 9.4), as well as radial distribution of sarcoplasmic strands seen on NADH (E) and electron microscopy (F). of 15 30% of the compound motor action potentials (CMAP). Median nerve conduction velocities (MNCVs) were normal in all patients, but two had very mildly (95% of the normal value) reduced motor and/or sensory NCVs in the lower leg nerves. Serum creatine kinase (CK) was normal (<170 U/I) in three patients and mildly to moderately elevated in six patients (one and a half to five times the normal value). Respiratory and cardiac function None of the ten patients reported symptoms of respiratory dysfunction or showed signs of nocturnal hypoventilation. Respiratory function was studied in eight patients, all showing normal results. Two patients mentioned exercise-related shortness of breath, but no other cardiological symptoms. Complete cardiac investigations, including electrocardiogram and echocardiogram, were performed and were normal in four patients. Muscle biopsy Diagnostic muscle biopsies taken from the deltoid muscles had been performed in six patients (at least one patient in each family) before the DNM2 genetic diagnosis was available. All six biopsies displayed an increased number of central nuclei, a predominance with an atrophy or an hypotrophy of type I fibres and a radial distribution of sarcomeric strands seen with staining for oxidative enzymes (Fig. 1). On electron microscopy, the central nucleus is surrounded by a zone devoid of organelles and discloses radial distribution of the intermyofibrillar sarcoplasmic strands (Fig. 1). Although when taken separately each of these findings can also be Muscle imaging showing a characteristic muscular involvement pattern Muscular CT images were obtained from all ten patients and detailed information on muscle imaging scores for each patient is given in Table 2. Muscular imaging findings of several patients ranging from a mild to a very severe clinical phenotype are illustrated in Fig. 2. The medial gastrocnemius was in general the most affected muscle and showed moderate to severe changes (mean score: 2.7) in nine patients. The remaining posterior compartment muscles [soleus (2.1), lateral gastrocnemius (1.7)] displayed more involvement compared with the anterior compartment muscles [anterior tibial muscle (0.9) and muscles of the peroneal group (1.1)]. Two patients showed no changes in the thigh muscles but in all other patients the posterior compartment [semitendinosus (1.4), biceps femoris (2.1), semimembranosus (2.1)] was the most affected compartment. In the medial compartment, the adductor magnus muscle (1.7) was the most affected, while the sartorius (0.7) and gracilis (0.4) muscles were relatively spared and only involved in severely affected patients. The anterior compartment muscles displayed moderate to severe involvement in more severely affected patients [vastus intermedius (1.3), vastus lateralis (0.8), vastus medialis (0.9), rectus femoris (0.5)]. At the pelvic level, eight patients showed moderate to severe abnormalities in the gluteus minimus muscles (1.8). The gluteus medius (0.8) and maximus muscles (1.1) displayed less involvement and occurred only in the more severely affected patients. The present imaging data in patients with a different clinical disease severity point towards a specific temporal pattern of muscular involvement in DNM2-CNM. The earliest and most severe changes were always observed in the distal posterior lower leg muscles sooner than in proximal muscles. The first changes were observed in the medial head of the gastrocnemius (Fig. 2A), as well as the soleus and the lateral gastrocnemius muscles (Fig. 2B), while involvement of the anterior compartment muscles [peroneal group muscles (Fig. 2D) and tibialis anterior (Fig. 2E)] was only present in the more severely affected patients. With further disease progression, degenerative changes were also seen in the posterior thigh compartment muscles beginning in the biceps femoris (Fig. 2B) and semimembranosus muscles (Fig. 2C), followed by involvement of the semitendinosus muscle (Fig. 2D). Affection of the medial thigh compartment muscles (adductor muscles, Fig. 2C), generally, occurred later followed by the relatively late involvement of the sartorius and gracilis muscles (Fig. 2F). At the pelvis, changes always begin in the gluteus minimus (Fig. 2B), followed by affection of the gluteus maximus (Fig. 2C) and gluteus medius (Fig. 2D).

5 Phenotype of DNM2-CNM Brain (2006), 129, Table 2 Details of muscular imaging scores in the reported DNM2-CNM patients Patient Pelvis Thigh Lower legs GMI GME GMA VL VIM RF VM S G AM SM ST BF GM GL SOL TP TA PG Mean GMI = gluteus minimus, GMA = gluteus maximus, GME = gluteus medius, VL = vastus lateralis, VIM = vastus intermedialis, RF = rectus femoris, VM = vastus medialis, S = sartorius, G = gracilis, AM = adductor magnus, SM = semimembranosus, ST = semitendinosus, BF = biceps femoris, GM = medial gastrocnemius, GL = lateral gastrocnemius, SOL = Soleus, TP = tibialis posterior, TA = tibialis anterior, PG = peroneal group muscles. Fig. 2 Muscular imaging in six DNM2-CNM patients ranging from a mild (A, patient 2, 12 years old) to a very severe clinical phenotype (F, patient 10, 74 years old,) showing a characteristic temporal pattern of early and predominant distal muscle involvement. The first changes appear in the distal lower leg muscles (medial gastrocnemius, arrowheads, A), followed by involvement of soleus, lateral gastrocnemius, and in the thigh biceps, femoris and gluteus minimus muscles (B, Patient 6). Later, affection of the remaining posterior thigh compartment muscles, mild quadriceps changes and gluteus maximus muscle involvement are observed (C, Patient 7), which precede degenerative changes in the anterior lower leg and the gluteus medius muscles (D, Patient 8). Sartorius, gracilis and rectus femoris are relatively preserved for a long period of time (D, Patient 8), and are the latest affected muscles (E, Patient 9). Discussion In the present report, we performed a systematic clinical and muscular CT assessment in ten patients with a genetically confirmed diagnosis of DNM2-CNM. Clinically, achievement of early motor milestones was normal in all patients, and disease onset occurred only in adolescence or early adulthood commonly beginning with exercise-related muscle pain and walking difficulties. On examination, bilateral ptosis was an almost invariable clinical sign, while mild facial weakness and extraocular eye muscle involvement were less often present. Previous reports on CNM have described proximal limb girdle and paraspinal muscles to be the most affected muscles in CNM (Spiro et al., 1966; Fardeau and Tomé, 1994; Jeannet et al., 2004). In contrast, in our series of patients with a genetically confirmed diagnosis of DNM2-CNM, distal limb muscles were generally weaker than proximal and axial muscles. In accordance, distal contractures of Achilles tendons were frequent findings and finger flexor muscle contractures also developed in some patients. In addition, in the majority of patients DTRs were diminished or absent. Seven patients were investigated electrophysiologically, all of them showing characteristic myopathic changes on NEE. However, four patients presented additional neuropathic signs such as pathological spontaneous activity (fibrillations) on NEE and/or a 15 30% reduction of the CMAP in some lower leg nerves on NCS. These results are consistent with features of the axonal CMT forms (CMT type 2; Harding and Thomas, 1980). Similarly, neuropathic changes were also reported in some earlier pre-genetic studies on CNM (van Wijngaarden et al., 1969; Meyers et al., 1974; Pavone et al., 1980). These findings are of special interest as mutations in the PH domain of DNM2 have also been identified in the dominant form of Charcot Marie Tooth disease 2B (DNM2-CMT2B), suggesting some overlapping features between the DNM2-CNM and DNM2-CMT2B phenotypes.

6 1468 Brain (2006), 129, D. Fischer et al. The pattern of muscular weakness with distal muscle involvement was also mirrored in our muscle imaging analysis. In all DNM2-CNM patients, muscle CT assessment showed a consistent pattern with early and predominant distal lower leg muscle affection, and milder involvement of the posterior thigh compartment and the gluteus minimus muscle. This selective pattern seems to be highly characteristic for DNM2-CNM as the muscular involvement in other congenital myopathies caused by mutations in the SEPN1, RYR1, NEB or collagen VI encoding (COL6A1, COL6A2, and COL6A3) genes is different (Mercuri et al., 2005a). Congenital myopathies related to NEB gene mutations show predominant anterior lower leg and mild anterior thigh compartment involvement as opposed to the predominant posterior thigh and posterior lower leg involvement in DNM2-CNM (Jungbluth et al., 2004b). Patients harbouring RYR1 gene mutations have a more significant and earlier involvement of the anterior thigh compartment muscles and relative selective changes in the soleus muscle (Jungbluth et al., 2004a). SEPN1 patients typically show an affection of sartorius and normal appearance of the gracilis (Mercuri et al., 2002b), while both are relatively spared in patients with DNM2-CNM. Patients with Ullrich CMD or Bethlem myopathy related to collagen VI encoding genes show an early and peculiar involvement of the vastus lateralis with relative sparing of the centre of the muscle, a pattern we have not observed in DNM2-CNM (Mercuri et al., 2003; Bitoun et al., 2005; Mercuri et al., 2005b). In conclusion, our clinical and muscle imaging studies in DNM2-CNM showed that muscular imaging is a powerful tool for differentiating DNM2-CNM from other forms of congenital myopathies. 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