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Myofibrillar myopathy 2(MFM2)

MedGen UID:
324735
Concept ID:
C1837317
Disease or Syndrome
Synonyms: Alpha-B crystallinopathy; MYOPATHY, DESMIN-RELATED, ASSOCIATED WITH MUTATION IN THE CRYAB GENE; MYOPATHY, MYOFIBRILLAR, ALPHA-B CRYSTALLIN-RELATED; MYOPATHY, MYOFIBRILLAR, WITH OR WITHOUT CATARACT AND/OR CARDIOMYOPATHY
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): CRYAB (11q23.1)
 
Monarch Initiative: MONDO:0012130
OMIM®: 608810
Orphanet: ORPHA399058

Definition

Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003). A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869. 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
Shoulder girdle muscle weakness
MedGen UID:
96533
Concept ID:
C0427063
Finding
The shoulder, or pectoral, girdle is composed of the clavicles and the scapulae. Shoulder-girdle weakness refers to lack of strength of the muscles attaching to these bones, that is, lack of strength of the muscles around the shoulders.
Pelvic girdle muscle weakness
MedGen UID:
96534
Concept ID:
C0427064
Finding
Weakness of the muscles of the pelvic girdle (also known as the hip girdle), that is, lack of strength of the muscles around the pelvis.
Absent Achilles reflex
MedGen UID:
108240
Concept ID:
C0558845
Finding
Absence of the Achilles reflex (also known as the ankle jerk reflex), which can normally be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Decreased Achilles reflex
MedGen UID:
324765
Concept ID:
C1837323
Finding
Decreased intensity of the Achilles reflex (also known as the ankle jerk reflex), which can be elicited by tapping the tendon is tapped while the foot is dorsiflexed.
Limb-girdle muscle weakness
MedGen UID:
347625
Concept ID:
C1858127
Finding
Weakness of the limb-girdle muscles (also known as the pelvic and shoulder girdles), that is, lack of strength of the muscles around the shoulders and the pelvis.
Foot dorsiflexor weakness
MedGen UID:
356163
Concept ID:
C1866141
Finding
Weakness of the muscles responsible for dorsiflexion of the foot, that is, of the movement of the toes towards the shin. The foot dorsiflexors include the tibialis anterior, the extensor hallucis longus, the extensor digitorum longus, and the peroneus tertius muscles.
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.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Fasciculations
MedGen UID:
5124
Concept ID:
C0015644
Sign or Symptom
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
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.
Neck muscle weakness
MedGen UID:
66808
Concept ID:
C0240479
Finding
Decreased strength of the neck musculature.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Quadriceps muscle weakness
MedGen UID:
154367
Concept ID:
C0577655
Sign or Symptom
Weakness of the quadriceps muscle (that is, of the muscle fasciculus of quadriceps femoris).
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.
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.
Leg muscle stiffness
MedGen UID:
870176
Concept ID:
C4024610
Sign or Symptom
Late-onset proximal muscle weakness
MedGen UID:
871110
Concept ID:
C4025578
Finding
Lack of strength of the proximal musculature occurring late in the clinical course.
Skeletal muscle autophagosome accumulation
MedGen UID:
1814214
Concept ID:
C5676640
Finding
Abnormal accumulation of autophagosomes in skeletal muscle tissue.
Orthopnea
MedGen UID:
508348
Concept ID:
C0085619
Finding
A sensation of breathlessness in the recumbent position, relieved by sitting or standing.
Paradoxical respiration
MedGen UID:
534076
Concept ID:
C0231852
Sign or Symptom
Breathing movements in which the chest wall moves in on inspiration and out on expiration, in reverse of the normal movements. It may be seen in children with respiratory distress of any cause, which leads to indrawing of the intercostal spaces during inspiration. Patients with chronic airways obstruction also show indrawing of the lower ribs during inspiration, due to the distorted action of a depressed and flattened diaphragm. Crush injuries of the chest, with fractured ribs and sternum, can lead to a severe degree of paradoxical breathing.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Antinuclear antibody positivity
MedGen UID:
101792
Concept ID:
C0151480
Laboratory or Test Result
The presence of autoantibodies in the serum that react against nuclei or nuclear components.
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.
Scleroderma
MedGen UID:
3770
Concept ID:
C0011644
Disease or Syndrome
A chronic autoimmune phenomenon characterized by fibrosis (or hardening) and vascular alterations of the skin.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Myofibrillar myopathy 2 in Orphanet.

Professional guidelines

PubMed

Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL
Equine Vet J 2023 Mar;55(2):230-238. Epub 2022 Apr 1 doi: 10.1111/evj.13574. PMID: 35288976Free PMC Article
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
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
Liewluck T, Milone M
Muscle Nerve 2018 Aug;58(2):167-177. Epub 2018 Feb 7 doi: 10.1002/mus.26077. PMID: 29350766
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
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

Chrisman C, McKeever PE
J Clin Neuromuscul Dis 2020 Dec;22(2):90-96. doi: 10.1097/CND.0000000000000317. PMID: 33214394
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
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
Dowling P, Murphy S, Ohlendieck K
Expert Rev Proteomics 2016 Aug;13(8):783-99. Epub 2016 Jul 25 doi: 10.1080/14789450.2016.1209416. PMID: 27376776
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

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
Maerkens A, Kley RA, Olivé M, Theis V, van der Ven PF, Reimann J, Milting H, Schreiner A, Uszkoreit J, Eisenacher M, Barkovits K, Güttsches AK, Tonillo J, Kuhlmann K, Meyer HE, Schröder R, Tegenthoff M, Fürst DO, Müller T, Goldfarb LG, Vorgerd M, Marcus K
J Proteomics 2013 Sep 2;90:14-27. Epub 2013 Apr 30 doi: 10.1016/j.jprot.2013.04.026. PMID: 23639843Free PMC Article

Prognosis

Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL
Equine Vet J 2023 Mar;55(2):230-238. Epub 2022 Apr 1 doi: 10.1111/evj.13574. PMID: 35288976Free PMC Article
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
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
Andersen AG, Fornander F, Schrøder HD, Krag T, Straub V, Duno M, Vissing J
Neuromuscul Disord 2018 Sep;28(9):798-801. Epub 2018 Jul 5 doi: 10.1016/j.nmd.2018.06.019. PMID: 30061062
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

Clinical prediction guides

Valberg SJ, Henry ML, Herrick KL, Velez-Irizarry D, Finno CJ, Petersen JL
Equine Vet J 2023 Mar;55(2):230-238. Epub 2022 Apr 1 doi: 10.1111/evj.13574. PMID: 35288976Free PMC Article
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
Andersen AG, Fornander F, Schrøder HD, Krag T, Straub V, Duno M, Vissing J
Neuromuscul Disord 2018 Sep;28(9):798-801. Epub 2018 Jul 5 doi: 10.1016/j.nmd.2018.06.019. PMID: 30061062
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
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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