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Myofibrillar myopathy 5(MFM5)

MedGen UID:
372186
Concept ID:
C1836050
Disease or Syndrome
Synonyms: Filaminopathy; Filaminopathy (type); FILAMINOPATHY, AUTOSOMAL DOMINANT; Myofibrillar myopathy, filamin C-related
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): FLNC (7q32.1)
 
Monarch Initiative: MONDO:0012289
OMIM®: 609524
Orphanet: ORPHA171445

Definition

The signs and symptoms of myofibrillar myopathy vary widely among affected individuals, typically depending on the condition's genetic cause. Most people with this disorder begin to develop muscle weakness (myopathy) in mid-adulthood. However, features of this condition can appear anytime between infancy and late adulthood. Muscle weakness most often begins in the hands and feet (distal muscles), but some people first experience weakness in the muscles near the center of the body (proximal muscles). Other affected individuals develop muscle weakness throughout their body. Facial muscle weakness can cause swallowing and speech difficulties. Muscle weakness worsens over time.

Other signs and symptoms of myofibrillar myopathy can include a weakened heart muscle (cardiomyopathy), muscle pain (myalgia), loss of sensation and weakness in the limbs (peripheral neuropathy), and respiratory failure. Individuals with this condition may have skeletal problems including joint stiffness (contractures) and abnormal side-to-side curvature of the spine (scoliosis). Rarely, people with this condition develop clouding of the lens of the eyes (cataracts).

Myofibrillar myopathy is part of a group of disorders called muscular dystrophies that affect muscle function and cause weakness. Myofibrillar myopathy primarily affects skeletal muscles, which are muscles that the body uses for movement. In some cases, the heart (cardiac) muscle is also affected. [from MedlinePlus Genetics]

Clinical features

From HPO
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Abnormal peripheral nervous system morphology
MedGen UID:
892389
Concept ID:
C4025831
Anatomical Abnormality
A structural abnormality of the peripheral nervous system, which is composed of the nerves that lead to or branch off from the central nervous system. This includes the cranial nerves (olfactory and optic nerves are technically part of the central nervous system).
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Muscle fiber splitting
MedGen UID:
322813
Concept ID:
C1836057
Finding
Fiber splitting or branching is a common finding in human and rat skeletal muscle pathology. Fiber splitting refers to longitudinal halving of the complete fiber, while branching originates from a regenerating end of a necrotic fiber as invaginations of the sarcolemma. In fiber branching, one end of the fiber remains intact as a single entity, while the other end has several branches.
Myofibrillar myopathy
MedGen UID:
395532
Concept ID:
C2678065
Finding
The signs and symptoms of myofibrillar myopathy vary widely among affected individuals, typically depending on the condition's genetic cause. Most people with this disorder begin to develop muscle weakness (myopathy) in mid-adulthood. However, features of this condition can appear anytime between infancy and late adulthood. Muscle weakness most often begins in the hands and feet (distal muscles), but some people first experience weakness in the muscles near the center of the body (proximal muscles). Other affected individuals develop muscle weakness throughout their body. Facial muscle weakness can cause swallowing and speech difficulties. Muscle weakness worsens over time.\n\nOther signs and symptoms of myofibrillar myopathy can include a weakened heart muscle (cardiomyopathy), muscle pain (myalgia), loss of sensation and weakness in the limbs (peripheral neuropathy), and respiratory failure. Individuals with this condition may have skeletal problems including joint stiffness (contractures) and abnormal side-to-side curvature of the spine (scoliosis). Rarely, people with this condition develop clouding of the lens of the eyes (cataracts).\n\nMyofibrillar myopathy is part of a group of disorders called muscular dystrophies that affect muscle function and cause weakness. Myofibrillar myopathy primarily affects skeletal muscles, which are muscles that the body uses for movement. In some cases, the heart (cardiac) muscle is also affected.
Muscle fiber cytoplasmatic inclusion bodies
MedGen UID:
867767
Concept ID:
C4022157
Finding
The presence of inclusion bodies within the cytoplasm of muscle cells. Inclusion bodies are aggregates (deposits) or stainable material, usually misfolded proteins.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.

Professional guidelines

PubMed

Mair D, Biskup S, Kress W, Abicht A, Brück W, Zechel S, Knop KC, Koenig FB, Tey S, Nikolin S, Eggermann K, Kurth I, Ferbert A, Weis J
Brain Pathol 2020 Sep;30(5):877-896. Epub 2020 Jun 15 doi: 10.1111/bpa.12864. PMID: 32419263Free PMC Article

Recent clinical studies

Etiology

Loarce-Martos J, Lilleker JB, Parker M, McHugh N, Chinoy H
Rheumatology (Oxford) 2021 Jul 1;60(7):3398-3403. doi: 10.1093/rheumatology/keaa801. PMID: 33367878
Fichna JP, Maruszak A, Żekanowski C
J Appl Genet 2018 Nov;59(4):431-439. Epub 2018 Sep 10 doi: 10.1007/s13353-018-0463-4. PMID: 30203143
Kley RA, Olivé M, Schröder R
Curr Opin Neurol 2016 Oct;29(5):628-34. doi: 10.1097/WCO.0000000000000357. PMID: 27389816
Olivé M, Kley RA, Goldfarb LG
Curr Opin Neurol 2013 Oct;26(5):527-35. doi: 10.1097/WCO.0b013e328364d6b1. PMID: 23995273Free PMC Article
Selcen D, Bromberg MB, Chin SS, Engel AG
Neurology 2011 Nov 29;77(22):1951-9. Epub 2011 Nov 16 doi: 10.1212/WNL.0b013e31823a0ebe. PMID: 22094483Free PMC Article

Diagnosis

Fichna JP, Maruszak A, Żekanowski C
J Appl Genet 2018 Nov;59(4):431-439. Epub 2018 Sep 10 doi: 10.1007/s13353-018-0463-4. PMID: 30203143
Kley RA, Olivé M, Schröder R
Curr Opin Neurol 2016 Oct;29(5):628-34. doi: 10.1097/WCO.0000000000000357. PMID: 27389816
Pfeffer G, Povitz M, Gibson GJ, Chinnery PF
J Neurol 2015 May;262(5):1101-14. Epub 2014 Nov 7 doi: 10.1007/s00415-014-7526-1. PMID: 25377282
Olivé M, Kley RA, Goldfarb LG
Curr Opin Neurol 2013 Oct;26(5):527-35. doi: 10.1097/WCO.0b013e328364d6b1. PMID: 23995273Free PMC Article
Selcen D, Bromberg MB, Chin SS, Engel AG
Neurology 2011 Nov 29;77(22):1951-9. Epub 2011 Nov 16 doi: 10.1212/WNL.0b013e31823a0ebe. PMID: 22094483Free PMC Article

Therapy

Loarce-Martos J, Lilleker JB, Parker M, McHugh N, Chinoy H
Rheumatology (Oxford) 2021 Jul 1;60(7):3398-3403. doi: 10.1093/rheumatology/keaa801. PMID: 33367878
Finsterer J, Stöllberger C, Höftberger R
Heart Lung 2011 Sep-Oct;40(5):e123-7. Epub 2011 Apr 9 doi: 10.1016/j.hrtlng.2010.07.016. PMID: 21481933

Prognosis

Bortolani S, Savarese M, Vattemi G, Bonanno S, Falzone YM, Pugliese A, Primiano G, Sancricca C, Lopergolo D, Greco G, Gemelli C, Ravaglia S, Bencivenga RP, Velardo D, Magri F, Valentino ML, Cheli M, Torchia E, Lucchini M, Petrucci A, Ricci G, Garibaldi M, Astrea G, Rubegni A, Angelini CI, Ariatti A, Santorelli FM, Ruggieri A, Antonini G, Siciliano G, Filosto M, Mirabella M, Liguori R, Comi GP, Ruggiero L, Grandis M, Massa R, Malandrini A, Servidei S, Mongini TE, Rodolico C, Toscano A, Previtali SC, Tonin P, Diaz-Manera J, Monforte M, Ricci E, Maggi L, Tasca G
Neurology 2024 Aug 27;103(4):e209697. Epub 2024 Aug 5 doi: 10.1212/WNL.0000000000209697. PMID: 39102614
Nicolau S, Milone M, Tracy JA, Mills JR, Triplett JD, Liewluck T
Muscle Nerve 2021 Dec;64(6):734-739. Epub 2021 Oct 15 doi: 10.1002/mus.27435. PMID: 34617293
Lee HH, Wong S, Sheng B, Pan NK, Leung YF, Lau KD, Cheng YS, Ho LC, Li R, Lee CN, Tsoi TH, Cheung YN, Fu YM, Kan NA, Chu YP, Au WL, Yeung HJ, Li SH, Cheung CM, Tong HF, Hung LE, Chan TY, Li CT, Tong TT, Tong TC, Leung HC, Lee KH, Yeung SS, Lee SB, Lau TG, Lam CW, Mak CM, Chan AY
Clin Genet 2020 May;97(5):747-757. Epub 2020 Feb 23 doi: 10.1111/cge.13715. PMID: 32022900
Alhammad RM, Naddaf E
Neuromuscul Disord 2020 Feb;30(2):128-136. Epub 2019 Dec 12 doi: 10.1016/j.nmd.2019.12.001. PMID: 32005492
Fichna JP, Maruszak A, Żekanowski C
J Appl Genet 2018 Nov;59(4):431-439. Epub 2018 Sep 10 doi: 10.1007/s13353-018-0463-4. PMID: 30203143

Clinical prediction guides

Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN, Selcen D
Ann Neurol 2011 May;69(5):866-71. Epub 2011 Feb 18 doi: 10.1002/ana.22331. PMID: 21337604Free PMC Article
Gontier Y, Taivainen A, Fontao L, Sonnenberg A, van der Flier A, Carpen O, Faulkner G, Borradori L
J Cell Sci 2005 Aug 15;118(Pt 16):3739-49. Epub 2005 Aug 2 doi: 10.1242/jcs.02484. PMID: 16076904
Olivé M, Goldfarb L, Dagvadorj A, Sambuughin N, Paulin D, Li Z, Goudeau B, Vicart P, Ferrer I
Acta Neuropathol 2003 Jul;106(1):1-7. Epub 2003 Apr 1 doi: 10.1007/s00401-003-0695-0. PMID: 12669240
Melberg A, Oldfors A, Blomström-Lundqvist C, Stålberg E, Carlsson B, Larrson E, Lidell C, Eeg-Olofsson KE, Wikström G, Henriksson G, Dahl N
Ann Neurol 1999 Nov;46(5):684-92. doi: 10.1002/1531-8249(199911)46:5<684::aid-ana2>3.0.co;2-#. PMID: 10970245
Nakano S, Engel AG, Waclawik AJ, Emslie-Smith AM, Busis NA
J Neuropathol Exp Neurol 1996 May;55(5):549-62. doi: 10.1097/00005072-199605000-00008. PMID: 8627346

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