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Myofibrillar myopathy, filamin C-related(MFM5)

MedGen UID:
372186
Concept ID:
C1836050
Disease or Syndrome
Synonyms: Filaminopathy; Filaminopathy (type); FILAMINOPATHY, AUTOSOMAL DOMINANT; MFM5; MYOPATHY, MYOFIBRILLAR, 5
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM
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

Muscle filaminopathy is a rare myofibrillar myopathy characterized by slowly progressive, proximal skeletal muscle weakness, which is initially more prominent in lower extremities and involves upper extremities with disease progression. Patients present with difficulty climbing stairs, a waddling gait, marked winging of scapula, lower back pain, paresis of limb girdle musculature, hypo-/areflexia and/or mild facial muscle weakness in rare cases. Respiratory muscle weakness is common and cardiac anomalies (conduction blocks, tachycardia, diastolic dysfunction, left ventricular hypertrophy) have been reported in some cases. [from ORDO]

Additional descriptions

From MedlinePlus Genetics
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).\n\nThe 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\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.  https://medlineplus.gov/genetics/condition/myofibrillar-myopathy
From MedlinePlus Genetics
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.  https://medlineplus.gov/genetics/condition/myofibrillar-myopathy

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
Myofibrillar myopathy (MFM) describes a group of skeletal and cardiac muscle disorders, defined by the disintegration of myofibrils and aggregation of degradation products into intracellular inclusions, and is typically clinically characterized by slowly-progressive muscle weakness, which initially involves the distal muscles, but is highly variable and that can affect the proximal muscles as well as the cardiac and respiratory muscles in some patients.
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, CPK; EC 2.7.3.2) in the blood. CPK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Myofibrillar myopathy, filamin C-related in Orphanet.

Recent clinical studies

Etiology

Nicolau S, Liewluck T, Milone M
Muscle Nerve 2020 Oct;62(4):445-454. Epub 2020 Jun 1 doi: 10.1002/mus.26914. PMID: 32478919
Chen J, Wu J, Han C, Li Y, Guo Y, Tong X
BMC Neurol 2019 Aug 17;19(1):198. doi: 10.1186/s12883-019-1410-7. PMID: 31421687Free PMC Article
Ruparelia AA, Zhao M, Currie PD, Bryson-Richardson RJ
Hum Mol Genet 2012 Sep 15;21(18):4073-83. Epub 2012 Jun 16 doi: 10.1093/hmg/dds231. PMID: 22706277
Hedberg C, Melberg A, Kuhl A, Jenne D, Oldfors A
Eur J Hum Genet 2012 Sep;20(9):984-5. Epub 2012 Mar 7 doi: 10.1038/ejhg.2012.39. PMID: 22395865Free PMC Article
Vattemi G, Neri M, Piffer S, Vicart P, Gualandi F, Marini M, Guglielmi V, Filosto M, Tonin P, Ferlini A, Tomelleri G
Acta Myol 2011 Oct;30(2):121-6. PMID: 22106715Free PMC Article

Diagnosis

Nicolau S, Liewluck T, Milone M
Muscle Nerve 2020 Oct;62(4):445-454. Epub 2020 Jun 1 doi: 10.1002/mus.26914. PMID: 32478919
Chen J, Wu J, Han C, Li Y, Guo Y, Tong X
BMC Neurol 2019 Aug 17;19(1):198. doi: 10.1186/s12883-019-1410-7. PMID: 31421687Free PMC Article
Hanisch F, Kraya T, Kornhuber M, Zierz S
Muscle Nerve 2013 Jun;47(6):845-8. Epub 2013 Apr 21 doi: 10.1002/mus.23716. PMID: 23605961
Kley RA, Serdaroglu-Oflazer P, Leber Y, Odgerel Z, van der Ven PF, Olivé M, Ferrer I, Onipe A, Mihaylov M, Bilbao JM, Lee HS, Höhfeld J, Djinović-Carugo K, Kong K, Tegenthoff M, Peters SA, Stenzel W, Vorgerd M, Goldfarb LG, Fürst DO
Brain 2012 Sep;135(Pt 9):2642-60. doi: 10.1093/brain/aws200. PMID: 22961544Free PMC Article
Hedberg C, Melberg A, Kuhl A, Jenne D, Oldfors A
Eur J Hum Genet 2012 Sep;20(9):984-5. Epub 2012 Mar 7 doi: 10.1038/ejhg.2012.39. PMID: 22395865Free PMC Article

Clinical prediction guides

Nicolau S, Liewluck T, Milone M
Muscle Nerve 2020 Oct;62(4):445-454. Epub 2020 Jun 1 doi: 10.1002/mus.26914. PMID: 32478919
Chen J, Wu J, Han C, Li Y, Guo Y, Tong X
BMC Neurol 2019 Aug 17;19(1):198. doi: 10.1186/s12883-019-1410-7. PMID: 31421687Free PMC Article
Kley RA, Serdaroglu-Oflazer P, Leber Y, Odgerel Z, van der Ven PF, Olivé M, Ferrer I, Onipe A, Mihaylov M, Bilbao JM, Lee HS, Höhfeld J, Djinović-Carugo K, Kong K, Tegenthoff M, Peters SA, Stenzel W, Vorgerd M, Goldfarb LG, Fürst DO
Brain 2012 Sep;135(Pt 9):2642-60. doi: 10.1093/brain/aws200. PMID: 22961544Free PMC Article
Ruparelia AA, Zhao M, Currie PD, Bryson-Richardson RJ
Hum Mol Genet 2012 Sep 15;21(18):4073-83. Epub 2012 Jun 16 doi: 10.1093/hmg/dds231. PMID: 22706277

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