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Myofibrillar myopathy 4(MFM4)

MedGen UID:
1648314
Concept ID:
C4721886
Disease or Syndrome
Synonyms: Myofibrillar myopathy, ZASP-related; Zaspopathy; Zaspopathy (type)
 
Gene (location): LDB3 (10q23.2)
 
Monarch Initiative: MONDO:0012277
OMIM®: 609452
Orphanet: ORPHA98912

Definition

Myofibrillar myopathy-4 (MFM4) is an autosomal dominant disorder characterized by adult-onset distal muscle weakness primarily affecting the lower limbs at onset. Affected individuals usually present with gait difficulties in their forties, followed by slow progression with eventual involvement of the hands and proximal muscles of the lower limbs. Rare patients may develop cardiomyopathy. Skeletal muscle biopsy shows myopathic changes with myofibrillar changes (Selcen and Engel, 2005; Griggs et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419). [from OMIM]

Additional description

From MedlinePlus Genetics
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.

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).  https://medlineplus.gov/genetics/condition/myofibrillar-myopathy

Clinical features

From HPO
Hyporeflexia of lower limbs
MedGen UID:
371881
Concept ID:
C1834696
Finding
Reduced intensity of muscle tendon reflexes in the lower limbs. Reflexes are elicited by stretching the tendon of a muscle, e.g., by tapping.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Polyneuropathy
MedGen UID:
57502
Concept ID:
C0152025
Disease or Syndrome
A generalized disorder of peripheral nerves.
Progressive muscle weakness
MedGen UID:
68704
Concept ID:
C0240421
Finding
Autophagic vacuoles
MedGen UID:
107466
Concept ID:
C0544966
Finding
The lysosomal-vacuolar pathway has a role in the controlled intracellular digestion of macromolecules such as protein complexes and organelles. This feature refers to the presence of an abnormally increased number of autophagic vacuoles in muscle tissue.
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.
Progressive proximal muscle weakness
MedGen UID:
322841
Concept ID:
C1836156
Finding
Lack of strength of the proximal muscles that becomes progressively more severe.
Progressive distal muscle weakness
MedGen UID:
324556
Concept ID:
C1836609
Finding
Progressively reduced strength of the distal musculature.
Myofibrillar myopathy
MedGen UID:
395532
Concept ID:
C2678065
Finding
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.
EMG: myopathic abnormalities
MedGen UID:
867362
Concept ID:
C4021726
Pathologic Function
The presence of abnormal electromyographic patterns indicative of myopathy, such as small-short polyphasic motor unit potentials.
EMG: neuropathic changes
MedGen UID:
867363
Concept ID:
C4021727
Finding
The presence of characteristic findings of denervation on electromyography (fibrillations, positive sharp waves, and giant motor unit potentials).
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.

Term Hierarchy

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
Carvalho AAS, Lacene E, Brochier G, Labasse C, Madelaine A, Silva VGD, Corazzini R, Papadopoulos K, Behin A, Laforêt P, Stojkovic T, Eymard B, Fardeau M, Romero N
Genet Test Mol Biomarkers 2018 Jun;22(6):374-383. doi: 10.1089/gtmb.2018.0004. PMID: 29924655
Winter L, Goldmann WH
Cell Biol Int 2015 Apr;39(4):361-3. Epub 2014 Dec 3 doi: 10.1002/cbin.10384. PMID: 25264173
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

Xu Y, Liu SX, Xu WB, Luo JM, Niu JW, Liu Z, Gao JM, Wang JL, Dai Y, Wang MZ
Chin Med Sci J 2021 Dec 31;36(4):265-278. doi: 10.24920/003883. PMID: 34986963
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
Savarese M, Sarparanta J, Vihola A, Jonson PH, Johari M, Rusanen S, Hackman P, Udd B
Acta Myol 2020 Dec;39(4):245-265. Epub 2020 Dec 1 doi: 10.36185/2532-1900-028. PMID: 33458580Free PMC Article
Lim KY, Kim HH, Sung JJ, Oh BM, Kim K, Park SH
Neuropathology 2020 Apr;40(2):185-190. Epub 2019 Dec 5 doi: 10.1111/neup.12619. PMID: 31803991
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

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

Prognosis

Xu Y, Liu SX, Xu WB, Luo JM, Niu JW, Liu Z, Gao JM, Wang JL, Dai Y, Wang MZ
Chin Med Sci J 2021 Dec 31;36(4):265-278. doi: 10.24920/003883. PMID: 34986963
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
Jain P, Rajeshwari SM, Singh J, Kumar T, Agarwal SP, Das P
Fetal Pediatr Pathol 2016;35(2):124-8. Epub 2016 Jan 30 doi: 10.3109/15513815.2015.1131783. PMID: 26828629
Lee HC, Cherk SW, Chan SK, Wong S, Tong TW, Ho WS, Chan AY, Lee KC, Mak CM
Clin Genet 2012 Apr;81(4):394-8. Epub 2011 Apr 4 doi: 10.1111/j.1399-0004.2011.01659.x. PMID: 21361913

Clinical prediction guides

Scarpini G, Valentino ML, Giannotta M, Ragni L, Torella A, Columbaro M, Nigro V, Pini A
Acta Myol 2021 Dec;40(4):177-183. Epub 2021 Dec 31 doi: 10.36185/2532-1900-061. PMID: 35047758Free PMC Article
Xu Y, Liu SX, Xu WB, Luo JM, Niu JW, Liu Z, Gao JM, Wang JL, Dai Y, Wang MZ
Chin Med Sci J 2021 Dec 31;36(4):265-278. doi: 10.24920/003883. PMID: 34986963
Keduka E, Hayashi YK, Shalaby S, Mitsuhashi H, Noguchi S, Nonaka I, Nishino I
Am J Pathol 2012 Apr;180(4):1570-80. Epub 2012 Feb 18 doi: 10.1016/j.ajpath.2011.12.040. PMID: 22349301
Bär H, Goudeau B, Wälde S, Casteras-Simon M, Mücke N, Shatunov A, Goldberg YP, Clarke C, Holton JL, Eymard B, Katus HA, Fardeau M, Goldfarb L, Vicart P, Herrmann H
Hum Mutat 2007 Apr;28(4):374-86. doi: 10.1002/humu.20459. PMID: 17221859
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

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