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Myofibrillar myopathy 6(MFM6)

MedGen UID:
414119
Concept ID:
C2751831
Disease or Syndrome
Synonym: Myofibrillar myopathy, BAG3-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): BAG3 (10q26.11)
 
Monarch Initiative: MONDO:0013061
OMIM®: 612954
Orphanet: ORPHA199340

Definition

Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), 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
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Knee flexion contracture
MedGen UID:
98042
Concept ID:
C0409355
Finding
A type of knee joint contracture in which the knee is in a fixed bent (flexed) configuration such that it cannot be straightened actively or passively.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Pes valgus
MedGen UID:
299028
Concept ID:
C1578482
Anatomical Abnormality
An outward deviation of the foot at the talocalcaneal or subtalar joint.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Restrictive cardiomyopathy
MedGen UID:
40111
Concept ID:
C0007196
Disease or Syndrome
Restrictive left ventricular physiology is characterized by a pattern of ventricular filling in which increased stiffness of the myocardium causes ventricular pressure to rise precipitously with only small increases in volume, defined as restrictive ventricular physiology in the presence of normal or reduced diastolic volumes (of one or both ventricles), normal or reduced systolic volumes, and normal ventricular wall thickness.
Mitral regurgitation
MedGen UID:
7670
Concept ID:
C0026266
Disease or Syndrome
An abnormality of the mitral valve characterized by insufficiency or incompetence of the mitral valve resulting in retrograde leaking of blood through the mitral valve upon ventricular contraction.
Demyelinating peripheral neuropathy
MedGen UID:
82859
Concept ID:
C0270922
Disease or Syndrome
Demyelinating neuropathy is characterized by slow nerve conduction velocities with reduced amplitudes of sensory/motor nerve conduction and prolonged distal latencies.
Tip-toe gait
MedGen UID:
98104
Concept ID:
C0427144
Finding
An abnormal gait pattern characterized by the failure of the heel to contact the floor at the onset of stance during gait.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Axonal loss
MedGen UID:
316962
Concept ID:
C1832338
Finding
A reduction in the number of axons in the peripheral nervous system.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Facial palsy
MedGen UID:
87660
Concept ID:
C0376175
Disease or Syndrome
Facial nerve palsy is a dysfunction of cranial nerve VII (the facial nerve) that results in inability to control facial muscles on the affected side with weakness of the muscles of facial expression and eye closure. This can either be present in unilateral or bilateral form.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Generalized muscle weakness
MedGen UID:
155433
Concept ID:
C0746674
Sign or Symptom
Generalized weakness or decreased strength of the muscles, affecting both distal and proximal musculature.
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Axial muscle weakness
MedGen UID:
334472
Concept ID:
C1843697
Finding
Reduced strength of the axial musculature (i.e., of the muscles of the head and neck, spine, and ribs).
Thoracic scoliosis
MedGen UID:
387910
Concept ID:
C1857790
Anatomical Abnormality
Spinal rigidity
MedGen UID:
346721
Concept ID:
C1858025
Finding
Reduced ability to move the vertebral column with a resulting limitation of neck and trunk flexion.
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.
Diaphragmatic paralysis
MedGen UID:
1632032
Concept ID:
C4551685
Finding
The presence of a paralyzed diaphragm.
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.
Reduced forced vital capacity
MedGen UID:
337630
Concept ID:
C1846678
Finding
An abnormal reduction in the amount of air a person can expel following maximal inspiration.
Restrictive ventilatory defect
MedGen UID:
478856
Concept ID:
C3277226
Finding
A functional defect characterized by reduced total lung capacity (TLC) not associated with abnormalities of expiratory airflow or airway resistance. Spirometrically, a restrictive defect is defined as FEV1 (forced expiratory volume in 1 second) and FVC (forced vital capacity) less than 80 per cent. Restrictive lung disease may be caused by alterations in lung parenchyma or because of a disease of the pleura, chest wall, or neuromuscular apparatus.
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.
Hypernasal speech
MedGen UID:
107884
Concept ID:
C0566620
Finding
A type of speech characterized by the presence of an abnormally increased nasal airflow during speech associated with structural abnormality of the nasal passages.

Recent clinical studies

Etiology

Verdonschot JAJ, Vanhoutte EK, Claes GRF, Helderman-van den Enden ATJM, Hoeijmakers JGJ, Hellebrekers DMEI, de Haan A, Christiaans I, Lekanne Deprez RH, Boen HM, van Craenenbroeck EM, Loeys BL, Hoedemaekers YM, Marcelis C, Kempers M, Brusse E, van Waning JI, Baas AF, Dooijes D, Asselbergs FW, Barge-Schaapveld DQCM, Koopman P, van den Wijngaard A, Heymans SRB, Krapels IPC, Brunner HG
Hum Mutat 2020 Jun;41(6):1091-1111. Epub 2020 Mar 20 doi: 10.1002/humu.24004. PMID: 32112656Free PMC Article
Vincent AE, Grady JP, Rocha MC, Alston CL, Rygiel KA, Barresi R, Taylor RW, Turnbull DM
Neuromuscul Disord 2016 Oct;26(10):691-701. Epub 2016 Aug 10 doi: 10.1016/j.nmd.2016.08.004. PMID: 27618136Free PMC Article
Chanson JB, Lannes B, Echaniz-Laguna A
Eur J Neurol 2016 Jun;23(6):1086-92. Epub 2016 Mar 10 doi: 10.1111/ene.12989. PMID: 26969127
Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O'Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF
JAMA Neurol 2015 Dec;72(12):1424-32. doi: 10.1001/jamaneurol.2015.2274. PMID: 26436962
Taylor MR, Slavov D, Ku L, Di Lenarda A, Sinagra G, Carniel E, Haubold K, Boucek MM, Ferguson D, Graw SL, Zhu X, Cavanaugh J, Sucharov CC, Long CS, Bristow MR, Lavori P, Mestroni L; Familial Cardiomyopathy Registry; BEST (Beta-Blocker Evaluation of Survival Trial) DNA Bank
Circulation 2007 Mar 13;115(10):1244-51. Epub 2007 Feb 26 doi: 10.1161/CIRCULATIONAHA.106.646778. PMID: 17325244

Diagnosis

Jiang K, Zheng Y, Lin J, Wu X, Yu Y, Zhu M, Fang X, Zhou M, Li X, Hong D
Brain Behav 2022 Feb;12(2):e2469. Epub 2022 Jan 3 doi: 10.1002/brb3.2469. PMID: 34978387Free PMC Article
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
Yogev Y, Perez Y, Noyman I, Madegem AA, Flusser H, Shorer Z, Cohen E, Kachko L, Michaelovsky A, Birk R, Koifman A, Drabkin M, Wormser O, Halperin D, Kadir R, Birk OS
Eur J Hum Genet 2017 Aug;25(8):966-972. Epub 2017 May 10 doi: 10.1038/ejhg.2017.85. PMID: 28488683Free PMC Article
Chanson JB, Lannes B, Echaniz-Laguna A
Eur J Neurol 2016 Jun;23(6):1086-92. Epub 2016 Mar 10 doi: 10.1111/ene.12989. PMID: 26969127
Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, Needham M, Liang C, Waddell LB, Nicholson G, O'Grady G, Kaur S, Ong R, Davis M, Sue CM, Laing NG, North KN, MacArthur DG, Clarke NF
JAMA Neurol 2015 Dec;72(12):1424-32. doi: 10.1001/jamaneurol.2015.2274. PMID: 26436962

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

Jiang K, Zheng Y, Lin J, Wu X, Yu Y, Zhu M, Fang X, Zhou M, Li X, Hong D
Brain Behav 2022 Feb;12(2):e2469. Epub 2022 Jan 3 doi: 10.1002/brb3.2469. PMID: 34978387Free PMC Article
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
Verdonschot JAJ, Vanhoutte EK, Claes GRF, Helderman-van den Enden ATJM, Hoeijmakers JGJ, Hellebrekers DMEI, de Haan A, Christiaans I, Lekanne Deprez RH, Boen HM, van Craenenbroeck EM, Loeys BL, Hoedemaekers YM, Marcelis C, Kempers M, Brusse E, van Waning JI, Baas AF, Dooijes D, Asselbergs FW, Barge-Schaapveld DQCM, Koopman P, van den Wijngaard A, Heymans SRB, Krapels IPC, Brunner HG
Hum Mutat 2020 Jun;41(6):1091-1111. Epub 2020 Mar 20 doi: 10.1002/humu.24004. PMID: 32112656Free PMC Article
Piñol-Ripoll G, Shatunov A, Cabello A, Larrodé P, de la Puerta I, Pelegrín J, Ramos FJ, Olivé M, Goldfarb LG
Neuromuscul Disord 2009 Jun;19(6):418-22. Epub 2009 May 9 doi: 10.1016/j.nmd.2009.04.004. PMID: 19433360Free PMC Article
Kley RA, Hellenbroich Y, van der Ven PF, Fürst DO, Huebner A, Bruchertseifer V, Peters SA, Heyer CM, Kirschner J, Schröder R, Fischer D, Müller K, Tolksdorf K, Eger K, Germing A, Brodherr T, Reum C, Walter MC, Lochmüller H, Ketelsen UP, Vorgerd M
Brain 2007 Dec;130(Pt 12):3250-64. doi: 10.1093/brain/awm271. PMID: 18055494

Clinical prediction guides

Jiang K, Zheng Y, Lin J, Wu X, Yu Y, Zhu M, Fang X, Zhou M, Li X, Hong D
Brain Behav 2022 Feb;12(2):e2469. Epub 2022 Jan 3 doi: 10.1002/brb3.2469. PMID: 34978387Free PMC Article
Fattori F, Fiorillo C, Rodolico C, Tasca G, Verardo M, Bellacchio E, Pizzi S, Ciolfi A, Fagiolari G, Lupica A, Broda P, Pedemonte M, Moggio M, Bruno C, Tartaglia M, Bertini E, D'Amico A
Clin Genet 2018 Jun;93(6):1234-1239. Epub 2018 Mar 25 doi: 10.1111/cge.13240. PMID: 29457652
Yogev Y, Perez Y, Noyman I, Madegem AA, Flusser H, Shorer Z, Cohen E, Kachko L, Michaelovsky A, Birk R, Koifman A, Drabkin M, Wormser O, Halperin D, Kadir R, Birk OS
Eur J Hum Genet 2017 Aug;25(8):966-972. Epub 2017 May 10 doi: 10.1038/ejhg.2017.85. PMID: 28488683Free PMC Article
Guglielmi V, Marini M, Masson ÉF, Malatesta M, Forget D, Tomelleri G, Coulombe B, Vattemi G
Histopathology 2015 Dec;67(6):859-65. Epub 2015 May 25 doi: 10.1111/his.12715. PMID: 25891782
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

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