Background: Filamin C-related myofibrillar myopathies (MFM) are progressive skeletal myopathies with an autosomal dominant inheritance pattern. The conditions are caused by mutations of the filamin C gene (FLNC) located in the chromosome 7q32-q35 region. Genetic variations in the FLNC gene result in various clinical phenotypes. Case presentation: We describe a 43-year-old woman who suffered filamin C-related MFM, with symptoms first presenting in the proximal muscles of the lower limbs and eventually spreading to the upper limbs and distal muscles. The patient’s serum level of creatine kinase was mildly increased. Mildy myopathic changes in the electromyographic exam and moderate lipomatous alterations in lower limb MRI were found. Histopathological examination revealed increased muscle fiber size variability, disturbances in oxidative enzyme activity, and the presence of abnormal protein aggregates and vacuoles in some muscle fibers. Ultrastructural analysis showed inclusions composed of thin filaments and interspersed granular densities. DNA sequencing analysis detected a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the FLNC gene. The patient’s father, sister, brother, three paternal aunts, one paternal uncle, and the uncle’s son also had slowly progressive muscle weakness, and thus, we detected an autosomal dominant inheritance pattern of the disorder. Conclusions: A novel heterogeneous 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 of the FLNC gene was found to cause filamin C-related MFM. This deletion in the FLNC gene causes protein aggregation, abnormalities in muscle structure, and impairment in muscle fiber function, which leads to muscle weakness. Keywords: Deletion, Filamin C gene, Dominant, Myofibrillar myopathy, Case report Background these mutations, codon 2710 is a mutational hotspot . Filamin C-related myofibrillar myopathies (MFM) caused Mutations in different functional domains of filamins can by mutations in the filamin C gene (FLNC) are autosomal cause various clinical phenotypes [2, 3]. Most patients dominant inherited and characterized by progressive my- with mutations in FLNC-Ig-like domains 7, 22, and 24 opathies that eventually result in wheelchair dependence. present with weakness in limb-girdle muscles, cardiomy- The FLNC gene is located in the 7q32-q35 chromosome opathy, and typical protein aggregation [1, 2, 4, 5], while band and includes 48 coding exons. To date, a continually those with mutations in the actin-binding domains or increasing number of mutations in the FLNC gene have Ig-like domain 15 mostly present with weakness in the been reported in various populations worldwide. Among distal muscles and no cardiomyopathy or typical path- ology [6, 7]. Here, we report a Chinese family suffering * Correspondence: firstname.lastname@example.org from filamin-C-related MFM caused by a novel 15-bp Jing Miao and Fei-fei Su contributed equally to this work. deletion in exon 18 of the FLNC gene. Department of Neurology and Neuroscience Center First Affiliated Hospital of Jilin University, Changchun, 130021 Jilin, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Miao et al. BMC Neurology (2018) 18:79 Page 2 of 5 Fig. 1 Pedigree of the patient’s family. The affected members are indicated with shading. Squares and circles represent males and females, respectively. Arrow indicates the case of the report Case presentation not detect any cardiac abnormalities. Fatty degeneration A 43-year-old woman suffered progressively worsening was detected in a few lower limb muscles by magnetic proximal muscle weakness for 10 years resulting in diffi- resonance imaging (MRI), including the vastus interme- culties with fast walking, climbing stairs, and rising from dius, vastus lateralis, semimembranosus, adductor mag- a chair. She had experienced normal growth and devel- nus and the long head of the biceps femoris muscles. opment. She reported lumbar back pain. Now, the symp- The rectus femoris was slightly involved. No abnormal- tom of proximal lower limb weakness had spread to her ities were detected in the gracilis, sartorius, or semiten- arms, causing her difficulty in washing clothes. Her dinosus muscles. At the distal leg level, the soleus, father, sister, brother, three paternal aunts, one paternal gastrocnemius medialis, and gastrocnemius lateralis uncle, and the uncle’s son also had slowly progressive showed degeneration with fatty infiltration (Fig. 2). proximal muscle weakness, but not as severe as hers. After the patient provided written consent, a skeletal The pedigree of her family revealed an autosomal dom- muscle biopsy was taken from the tibial anterior inant inheritance pattern (Fig. 1). Muscle weakness was muscle, precooled with isopentane, and frozen in li- detected in the biceps and triceps muscles (MRC4+/5), quid nitrogen. Frozen sections of 8 μmwere prepared wrist flexor extensor muscles (MRC 4/5), iliopsoas mus- and histopathological examination showed increased cles (MRC 3/5), and quadriceps muscles (MRC 4−/5). fiber size variability with atrophic and hypertrophic fi- Her distal arm strength was 4. She had a waddling gait bers. Muscle fiber necrosis and phagocytosis were ob- and muscle atrophy in the quadriceps and distal lower served. There was a mild increase in connective legs. In her most recent examination, she could not walk tissue. Non-rimmed vacuoles were commonly present. on her toes. Deep tendon reflexes were absent. Gower’s Some fibers showed structural changes with abnormal ma- sign was present. No cranial nerve dysfunction or sen- terial deposits after staining with hematoxylin-eosin (HE), sory disturbance was noted. Her serum level of creatine modified Gomori’s trichrome (MGT) (Fig. 3a and b). kinase was 2-fold higher than the upper normal value. Oxidative enzyme activities were reduced focally in some fi- An electromyogram revealed mild myogenic changes. bers, occasionally resulting in core-like lesions after staining Echocardiography and electrocardiogram evaluations did with succinate dehydrogenase (SDH), NADH-tetrazolium Fig. 2 Image and transverse T1-weighted muscle MR image from the patient. MR images demonstrated a typical pattern of muscle involvement (hyperintensities reflect lipomatous alterations). On the thigh level a the vastus intermedius, vastus lateralis, semimembranosus, adductor magnus and long head of the biceps femoris muscles showed moderate lipomatous alterations. On the lower leg level b the soleus, gastrocnemius medialis, and gastrocnemius lateralis muscles show pronounced fatty changes Miao et al. BMC Neurology (2018) 18:79 Page 3 of 5 Fig. 3 Histopathological examination of the skeletal muscles. a HE staining showed muscle fibers of variable sizes, vacuoles (black arrow), and abnormal material deposits (white arrow). b MGT staining showed abnormal material deposits in a muscle fiber (black arrow).c NADH-TR and (d) COX staining showed reduced oxidative enzyme activities in some fibers, like core-like lesions (white arrow) reductase (NADH-TR), and cytochrome c oxidase (COX) vitamins for about 1 year, but their symptoms were not (Fig. 3c and d). Electron microscopy showed myofibrillar relieved. deposits of thin filaments interspersed with dense granular material between myofibrils, frequently in spheroid shape. Discussions and conclusions Thesestructuresweresurroundedbyradiallyarranged thin In the current case, a novel 15-bp deletion in the FLNC filaments (Fig. 4). Next generation sequencing identified a gene showed an autosomal dominant inheritance pattern 15-nucleotide deletion (c.2791_2805del, p.931_935del) in and caused muscle weakness in all limbs, a mildly ele- the immunoglobulin (Ig)-like domain 7 of the FLNC gene vated serum level of creatine kinase, slight myogenic (Fig. 5). Genetic testing revealed that this deletion had been changes on EMG, variations in muscle fiber size, and the passed to the patient from her father and carried by her presence of abnormal protein aggregates and vacuoles in other symptomatic relatives. The patient and her relatives some muscle fibers. These phenotypic manifestations were administered 10 mg per day coenzyme Q10 and some were also observed in the previously identified FLNC gene mutation-mediated MFM cases [1, 2, 4, 5]. The FLNC gene is located in the 7q32-q35 chromo- some band and contains 48 coding exons. In general, three different domains harbored in the filamin-C pro- tein may have different filaminS C-related myopathy phenotypes: N-terminal acting-binding domain and the frameshift deletion c.5161delG mutation in the rod do- main involved with distal muscle weakness [6, 8], 24 Ig-like repeat domains, and a C-terminal dimerization domain associated with limb-girdle proximal muscle weakness . In 2016, a 15-bp (c.2786_2800del) muta- tion in the Ig-like domain 7 of the FLNC gene was re- ported to cause limb-girdle muscular dystrophy (LGMD) , whereas the novel 15-bp (c.2791_2805del) mutation in the same domain in our case obviously caused the clinical phenotypes of filamin C–related MFM and dis- Fig. 4 Ultrastructural examination of the skeletal muscle fibers showed played a typical autosomal dominant inheritance pattern. deposits of dense granular material and thin filaments The two deletions in the same domain are very likely to Miao et al. BMC Neurology (2018) 18:79 Page 4 of 5 Fig. 5 DNA sequencing analysis showed an internal 15-nucleotide deletion in exon 18 of the FLNC gene (red arrows) result in protein aggregation in muscle fibers, causing 20160520164JH) and the 7th Youth Foundation of the First Hospital of Jilin University (No, JDYY72016028). similar clinical phenotypes [4, 5, 10]. The variation in fiber size and the presence of necrosis and fatty degener- Availability of data and materials ation in muscle tissues in our case, which were also ob- All data are presented in the manuscript. There are no additional data. served in cases harboring different mutations in the Consent to publish same Ig-like domain [4, 5], indicate that mutations in Written informed consent for publication of this Case Report was obtained the Ig-like domain 7 of the FLNC gene lead to structural from the patient and her relatives. A copy of each written consent form is changes in skeletal muscles. The presence of phagocyt- available for review to the Editor of this journal. osis, non-rimmed vacuoles, and abnormal material de- Authors’ contributions posits in the muscles in our case, which is in agreement JM drafted the manuscript and figures; FS designed and analyzed the study; with the observations in other Ig-like domain 7 XL and XW analyzed and interpreted histological data; YY analyzed and interpreted the electron microscopy imaging; XY revised the manuscript and mutation-mediated filamin C–related MFM cases [4, 5] gave the final approval of the version to be published. All authors read and and in cultured cells transfected with expression vectors approved the contents of the case report. for the FLNC gene with a mutation in Ig-like domain 7 , indicates that the 15-bp deletion in the Ig-like do- Authors’ information All of authors are from the Department of Neurology and the Neuroscience main 7 of the FLNC gene in our case may lead to pro- Center of the First Affiliated Hospital of Jilin University. tein misfolding, trigger aggregation of the mutant filamin C protein, and decrease the efficiency of both Competing interests the ubiquitin–proteasome system and autophagy system The authors declare that they have no competing interests. to degrade protein aggregates [10–13]. These events ul- timately result in disruption of myofibrils [10, 14] and Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in muscle weakness. published maps and institutional affiliations. In conclusion, a novel 15-nucleotide deletion (c.2791_2805del, p.931_935del) in the Ig-like domain 7 Author details Department of Neurology and Neuroscience Center, First Affiliated Hospital of the FLNC gene was found to cause filamin C–related of Jilin University, Changchun, 130021 Jilin, People’s Republic of China. MFM. This deletion in the FLNC gene causes protein Department of Neurology, Peking University First Hospital, #8 Xishiku St, aggregation, abnormalities in muscle structure, and im- Xicheng District, Beijing 100034, China. Department of Neurology and Neuroscience Center First Affiliated Hospital of Jilin University, Changchun, pairment in muscle fiber function, which leads to muscle 130021 Jilin, People’s Republic of China. weakness. Received: 19 October 2017 Accepted: 22 May 2018 Abbreviations COX: Cytochrome c oxidase (COX; HE: Hematoxylin-eosin; LGMD: Limb-girdle muscular dystrophy; MFM: Myofibrillar myopathies; MGT: Modified Gomori- References trichrome; MRI: Magnetic resonance imaging;; NADH-TR: NADH-tetrazolium 1. Vorgerd M, van der Ven PF, Bruchertseifer V, Löwe T, Kley RA, Schröder R, reductase; PAS: Periodic acid-schiff; SDH: Succinate dehydrogenase et al. A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy. Am J Hum Genet. Acknowledgements 2005;77:297–304. The authors thank Medjaden Bioscience Limited for proofreading the 2. Tasca G, Odgerel Z, Monforte M, Aurino S, Clarke NF, Waddell LB, et al. manuscript. Novel FLNC mutation in a patient with myofibrillar myopathy in combination with late-onset cerebellar ataxia. Muscle Nerve. 2012;46: Funding 275–82. This work was supported by the National Natural Science Foundation of 3. Avila-Smirnow D, Gueneau L, Batonnet-Pichon S, Delort F, Bécane HM, China (No, 81601088), Natural Science Foundation of Jilin Province (No, Claeys K, et al. Cardiac arrhythmia and late-onset muscle weakness caused Miao et al. BMC Neurology (2018) 18:79 Page 5 of 5 by a myofibrillar myopathy with unusual histopathological features due to a novel missense mutation in FLNC. Rev Neurol (Paris). 2016;172:594–606. 4. Luan X, Hong D, Zhang W, Wang Z, Yuan Y. A novel heterozygous deletion- insertion mutation (2695-2712 del/GTTTGT ins) in exon 18 of the filamin C gene causes filaminopathy in a large Chinese family. Neuromuscul Disord. 2010;20:390–6. 5. Shatunov A, Olivé M, Odgerel Z, Stadelmann-Nessler C, Irlbacher K, van Landeghem F, et al. In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy. Eur J Hum Genet. 2009;17:656–63. 6. Duff RM, Tay V, Hackman P, Ravenscroft G, McLean C, Kennedy P, et al. Mutations in the N-terminal actin-binding domain of filamin C cause a distal myopathy. Am J Hum Genet. 2011;88:729–40. 7. Guergueltcheva V, Peeters K, Baets J, Ceuterick-de Groote C, Martin JJ, Suls A, et al. Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency. Neurology. 2011;77:2105–14. 8. Rossi D, Palmio J, Evilä A, Galli L, Barone V, Caldwell TA, et al. A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy. PLoS One. 2017;12:e0186642. 9. Evilä A, Arumilli M, Udd B, Hackman P. Targeted next-generation sequencing assay for detection of mutations in primary myopathies. Neuromuscul Disord. 2016;26:7–15. 10. Kley RA, Serdaroglu-Oflazer P, Leber Y, Odgerel Z, van der Ven PF, Olivé M, et al. Pathophysiology of protein aggregation and extended phenotyping in filaminopathy. Brain. 2012;135:2642–60. 11. Kley RA, van der Ven PF, Olivé M, Höhfeld J, Goldfarb LG, Fürst DO, et al. Impairment of protein degradation in myofibrillar myopathy caused by FLNC/filamin C mutations. Autophagy. 2013;9:422–3. 12. Chevessier F, Schuld J, Orfanos Z, Plank AC, Wolf L, Maerkens A, et al. Myofibrillar instability exacerbated by acute exercise in filaminopathy. Hum Mol Genet. 2015;24:7207–20. 13. Fürst DO, Goldfarb LG, Kley RA, Vorgerd M, Olivé M, van der Ven PF. Filamin C-related myopathies: pathology and mechanisms. Acta Neuropathol. 2013; 125:33–46. 14. Löwe T, Kley RA, van der Ven PF, Himmel M, Huebner A, Vorgerd M, et al. The pathomechanism of filaminopathy: altered biochemical properties explain the cellular phenotype of a protein aggregation myopathy. Hum Mol Genet. 2007;16:1351–8.
BMC Neurology – Springer Journals
Published: Jun 4, 2018
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