Myofibrillar Myopathy
Disease synonyms
Myofibrillar myopathy, MFM
Inheritance pattern
Autosomal recessive, autosomal dominant, X-linked
Clinical features
Myofibrillar myopathies (MFM) are group of neuromuscular diseases characterized by slowly progressive weakness that can involve both proximal and distal muscles. MFM primarily affects skeletal muscles and in some cases cardiac muscle. The signs and symptoms of MFM vary widely among affected individuals, typically depending on the genetic cause. Most people with this disorder begin to develop muscle weakness in mid-adulthood.
Myofibrillar myopathy includes following disorders:
- Alpha-B crystallinopathy, associated with pathogenic variants in the CRYAB gene, encoding α-crystallin B chain 2
- BAG3-related myofibrillar myopathy, associated with pathogenic variants in BAG3, encoding BAG family molecular chaperone regulator 3 3
- Desminopathy, caused by mutations in DES, encoding desmin 4
- DNAJB6-related myofibrillar myopathy caused by mutations in DNAJB6, encoding DnaJ homolog subfamily B member 6 (heat shock protein 40) 5
- FHL1-related myofibrillar myopathy caused by mutations in FLH1, encoding four and a half LIM containing protein 1 6
- Filaminopathy caused by mutations in FLCN, encoding filamin-C 7
- Myotilinopathy associated with pathogenic variants in MYOT, encoding myotilin 8
- Zaspopathy caused by mutations in LDB3 (ZASP) encoding LIM domain-binding protein 3 9
The diagnosis of myofibrillar myopathy is based on the following signs and symptoms:
- History of slowly progressive weakness accompanied by paresthesia, muscle atrophy, stiffness or aching, cramps, dyspnea, and dysphagia. The majority of affected individuals show proximal and distal weakness. Facial weakness is uncommon, while tendon reflexes are usually normal.
- Electromyography (EMG) shows abnormal electrical irritability, including fibrillation potentials, complex repetitive discharges, and myotonic discharges.
- Abnormal nerve conduction studies are detected in about 20% of individuals 1.
Histological analysis of muscle samples reveals characteristic changes in almost all myofibrillar myopathy-affected patients:
- Characteristic alterations in trichromatically stained frozen sections consisting of amorphous, hyaline, or granular material in a variable proportion of the muscle fibers
- Sharply circumscribed decreases of oxidative enzyme activity in many abnormal fiber regions
- Intense congophilia of many hyaline structures, best observed under rhodamine fluorescence optics
- Presence of small vacuoles in affected fibers
- Abnormal ectopic expression of myotilin (90% of abnormal fibers), desmin (75%), α-B crystallin (75%), dystrophin (70%), and β-amyloid precursor protein (70%)
- Progressive myofibrillar degeneration commencing at the Z-disk, disintegration of sarcomeres, high number of pleomorphic hyaline inclusions and autophagic vacuoles.
Peripheral nerve biopsies show accumulation of neurofilaments, neurotubules, and formation of axonal spheroids. Myocardial biopsies show desmin-immunoreactive cytoplasmic inclusions, especially near intercalated disks and interstitial fibrosis. Serum creatine kinase concentration can be normal or elevated to no greater than seven times the upper normal limit.
Because myofibrillar myopathy is caused by mutations in any of eight different genes (BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC, LDB3, MYOT; see table) and each disease-associated gene may have different types of mutations, the molecular pathogenesis may be highly variable. The initial pathologic change in myofibrillar myopathy involves disintegration of the Z-disk in muscle cells, and all disease proteins identified to date are involved in maintaining the structural integrity of the Z-disk. Because the Z-disks are sites of tension transmission between sarcomeres, the myofibrils fall apart when the Z-disks disintegrate.
Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
---|---|---|---|
AARS1 | 601065 | type 2N Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 29 | AD, AR |
ABHD5 | 604780 | Chanarin-Dorfman syndrome | AR |
ACAD9 | 611103 | Acyl-Coa Dehydrogenase Family, Member 9, Deficiency Of | AR |
ACADM | 607008 | medium chain acyl-CoA dehydrogenase deficiency | AR |
ACADVL | 609575 | very long chain acyl-CoA dehydrogenase deficiency | AR |
ACTA1 | 102610 | Myopathy, nemaline, 3; Myopathy, congenital, with fiber-type disproportion | AD, AR |
AGL | 610860 | glycogen storage disease type III | AR |
AGRN | 103320 | congenital myasthenic syndrome type 8, with pre- and postsynaptic defects | AR |
AHCY | 180960 | Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase | AR |
AIFM1 | 300169 | Deafness, X-linked 5; Combined oxidative phosphorylation deficiency 6; Cowchock syndrome | XLR |
ALDOA | 103850 | Glycogen storage disease XII | AR |
ALG14 | 612866 | AR | |
ALG2 | 607905 | congenital disorder of glycosylation type 1i | AR |
AMPD1 | 102770 | Myopathy due to myoadenylate deaminase deficiency | AR |
ANO5 | 608662 | gnathodiaphyseal dysplasia; limb-girdle muscular dystrophy type 2L | AD, AR |
ARHGEF10 | 608136 | slowed nerve conduction velocity | AD |
ARHGEF9 | 300429 | Epileptic encephalopathy, early infantile, 8 | XLR |
ASAH1 | 613468 | Spinal muscular atrophy with progressive myoclonic epilepsy; Farber lipogranulomatosis | AR |
ATL1 | 606439 | spastic paraplegia 3A | AD |
ATP2A1 | 108730 | Brody myopathy | AR |
ATP7A | 300011 | X-linked distal spinal muscular atrophy type 3; Occipital horn syndrome; Menkes disease | XLR |
B3GALNT2 | 610194 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A11 | AR |
B4GAT1 | 605517 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A13 | AR |
BAG3 | 603883 | Myopathy, myofibrillar, 6; dilated cardiomyopathy-1HH | AD |
BICD2 | 609797 | autosomal dominant lower extremity-predominant spinal muscular atrophy type 2 | AD |
BIN1 | 601248 | centronuclear myopathy | AR |
BSCL2 | 606158 | Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy | AD, AR |
CACNA1S | 114208 | hypokalemic periodic paralysis 1; Thyrotoxic periodic paralysis Type 1; Malignant hyperthermia susceptibility 5 | AD |
CAPN3 | 114240 | limb-girdle muscular dystrophy type 1; limb-girdle muscular dystrophy type 4 | AD, AR |
CASK | 300172 | Fg Syndrome 4; Mental retardation and microcephaly with pontine and cerebellar hypoplasia | XLD |
CAV1 | 601047 | AD, AR | |
CAV3 | 601253 | Creatine phosphokinase, elevated serum; familial hypertrophic cardiomyopathy 1; Rippling muscle disease; Rippling muscle disease 2; long QT syndrome 9 | AD, DiD |
CCDC78 | 614666 | Myopathy, centronuclear, 4 | AD |
CFL2 | 601443 | nemaline myopathy type 7 | AR |
CHAT | 118490 | Presynaptic congenital myasthenic syndrome type 6 | AR |
CHCHD10 | 615903 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 | AD |
CHKB | 612395 | Muscular dystrophy, congenital, megaconial type | AR |
CHRNA1 | 100690 | Multiple pterygium syndrome, lethal type; Myasthenic syndrome, slow-channel congenital; Myasthenic syndrome, fast-channel congenital | AD, AR |
CHRNB1 | 100710 | Myasthenic syndrome, congenital, 2A, slow-channel; Myasthenic syndrome, congenital, 2C, associated with acetylcholine receptor deficiency | AD, AR |
CHRND | 100720 | Multiple pterygium syndrome, lethal type; slow-channel congenital myasthenic syndrome type 3A; Congenital fast-channel myasthenic syndrome type 3B; ?Myasthenic syndrome, congenital, 3C, associated with acetylcholine receptor deficiency | AD, AR |
CHRNE | 100725 | slow-channel congenital myasthenic syndrome type 4A; congenital myasthenic syndrome type 4C, associated with acetylcholine receptor deficiency; fast-channel congenital myasthenic syndrome type 4B | AD, AR |
CHRNG | 100730 | Multiple pterygium syndrome, lethal type; Multiple Pterygium Syndrome, Escobar Variant | AR |
CHST14 | 608429 | Ehlers-Danlos syndrome musculocontractural type 1 | AR |
CLCN1 | 118425 | myotonia congenita (Thomsen myotonia); myotonia congenita (Becker myotonia) | AD, AR |
CNTN1 | 600016 | Myopathy, congenital, Compton-North | AR |
COL12A1 | 120320 | Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 | AD |
COL6A1 | 120220 | Bethlem myopathy type 1; Ullrich congenital muscular dystrophy | AD, AR |
COL6A2 | 120240 | Bethlem myopathy type 1; Ullrich congenital muscular dystrophy | AD, AR |
COL6A3 | 120250 | Bethlem myopathy type 1; Ullrich congenital muscular dystrophy; dystonia 27 | AD, AR |
COLQ | 603033 | congenital myasthenic syndrome type 5 | AR |
COQ2 | 609825 | Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 | AD, AR |
COX6A1 | 602072 | intermediate type D Charcot-Marie-Tooth | AR |
CPT2 | 600650 | stress-induced myopathic CPT II deficiency; infantile CPT deficiency; lethal neonatal CPT II deficiency; susceptibility to infection-induced acute encephalopathy type 4 | AD, AR |
CRPPA | 614631 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A7; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C7 | AR |
CRYAB | 123590 | Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, Myofibrillar, Fatal Infantile Hypertonic, Alpha-B Crystallin-Related; dilated cardiomyopathy-1II | AD, AR |
CSRP3 | 600824 | dilated cardiomyopathy-1M; Cardiomyopathy, familial hypertrophic, 12 | AD |
CTDP1 | 604927 | Congenital cataracts, facial dysmorphism, and neuropathy | AR |
DAG1 | 128239 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C9 | AR |
DCTN1 | 601143 | amyotrophic lateral sclerosis 1; Perry syndrome; Neuronopathy, Distal Hereditary Motor, Type Viib | AD, AR |
DES | 125660 | Scapuloperoneal syndrome, neurogenic, Kaeser type; Myopathy, myofibrillar, 1; dilated cardiomyopathy-1I | AD, AR |
DGUOK | 601465 | mitochondrial DNA depletion syndrome 3 | AR |
DHCR24 | 606418 | Desmosterolosis | AR |
DHTKD1 | 614984 | 2-aminoadipic 2-oxoadipic aciduria; type 2Q Charcot-Marie-Tooth disease | AD, AR |
DMD | 300377 | Becker muscular dystrophy; dilated cardiomyopathy type 3B; Duchenne muscular dystrophy | XL, XLR |
DMPK | 605377 | myotonic dystrophy type 1 | AD |
DNA2 | 601810 | Progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant, 6 | AD, AR |
DNAJB2 | 604139 | autosomal recessive distal spinal muscular atrophy type 5 | AR |
DNAJB6 | 611332 | limb-girdle muscular dystrophy type 1E | AD |
DNM2 | 602378 | Myopathy, centronuclear 1; CHARCOT-MARIE-TOOTH, DOMINANT INTERMEDIATE TYPE B; Lethal congenital contracture syndrome 5 | AD, AR |
DNMT1 | 126375 | cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE | AD |
DOK7 | 610285 | congenital myasthenic syndrome type 10 | AR |
DPAGT1 | 191350 | congenital disorder of glycosylation type 1j; Myasthenic syndrome, congenital, with tubular aggregates 13 | AR |
DPM1 | 603503 | Congenital disorder of glycosylation, type Ie | AR |
DPM2 | 603564 | Congenital disorder of glycosylation, type Iu | AR |
DPM3 | 605951 | congenital disorder of glycosylation, type Io | AR |
DYNC1H1 | 600112 | lower extremity-predominant spinal muscular atrophy type 1; type 2O Charcot-Marie-Tooth disease; mental retardation-13 | AD |
DYSF | 603009 | limb-girdle muscular dystrophy type 2B; Miyoshi muscular dystrophy type 1; distal myopathy with anterior tibial onset | AR |
ECEL1 | 605896 | distal arthrogryposis type 5D | AR |
EGR2 | 129010 | Dejerine-Sottas syndrom; congenital hypomyelinating neuropathy; type 1D Charcot-Marie-Tooth disease | AD, AR |
ELP1 | 603722 | hereditary sensory and autonomic neuropathy type III | AR |
EMD | 300384 | Emery-Dreifuss muscular dystrophy type 1 | XLR |
ENO3 | 131370 | Glycogen storage disease XIII | AR |
ERCC5 | 133530 | xeroderma pigmentosum complementation group G; cerebrooculofacioskeletal syndrome type 3 | AR |
ERCC6 | 609413 | Cockayne syndrome, type B; Lung Cancer; Cerebrooculofacioskeletal syndrome 1 | AD, AR |
ETFA | 608053 | multiple acyl-CoA dehydrogenase deficiency | AR |
ETFB | 130410 | multiple acyl-CoA dehydrogenase deficiency | AR |
ETFDH | 231675 | multiple acyl-CoA dehydrogenase deficiency | AR |
EXOSC3 | 606489 | pontocerebellar hypoplasia type 1B | AR |
EXOSC8 | 606019 | AR | |
FBLN5 | 604580 | Cutis laxa, autosomal recessive, type IA; hereditary neuropathy with or without age-related macular degeneration | AD, AR |
FBN2 | 612570 | congenital contractural arachnodactyly; early-onset macular degeneration | AD |
FBXO38 | 608533 | distal hereditary motor neuronopathy type IID | AD |
FGD4 | 611104 | type 4H Charcot-Marie-Tooth disease | AR |
FHL1 | 300163 | Scapuloperoneal myopathy, X-linked dominant; Myopathy, X-linked, with postural muscle atrophy; Emery-Dreifuss muscular dystrophy 6; Myopathy, Reducing Body, X-Linked, Early-Onset, Severe; Myopathy, reducing body, X-linked, childhood-onset | XL, XLD, XLR |
FIG4 | 609390 | Yunis-Varon syndrome; type 4J Charcot-Marie-Tooth disease; amyotrophic lateral sclerosis 11; Polymicrogyria, bilateral temporooccipital | AD, AR |
FKBP10 | 607063 | Bruck syndrome 1; osteogenesis imperfecta type 11 | AR |
FKRP | 606596 | Muscular dystrophy-dystroglycanopathy (congenital with or without mental retardation), type B5; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C5; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5 | AR |
FKTN | 607440 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A4; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C4; dilated cardiomyopathy type 1X; congenital muscular dystrophy-dystroglycanopathy without mental retardation type B4 | AR |
FLNC | 102565 | Myopathy, myofibrillar, 5; distal myopathy type 4; Cardiomyopathy, Familial Hypertrophic, 26 | AD |
GAA | 606800 | Pompe disease | AR |
GAN | 605379 | giant axonal neuropathy | AR |
GARS1 | 600287 | Neuropathy, distal hereditary motor, type V; type 2D Charcot-Marie-Tooth disease | AD |
GBA | 606463 | Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form | AD, AR |
GBE1 | 607839 | storage disease type 4; Polyglucosan body disease, adult form | AR |
GDAP1 | 606598 | type 4A Charcot-Marie-Tooth disease; type 2K Charcot-Marie-Tooth disease | AD, AR |
GFPT1 | 138292 | congenital myasthenic syndrome with tubular aggregates type 1 | AR |
GJB1 | 304040 | Charcot-Marie-Tooth disease type 1 | XLD |
GLE1 | 603371 | Lethal congenital, contracture syndrome 1 | AR |
GLRA1 | 138491 | Hyperekplexia, hereditary 1, autosomal dominant or recessive | AD, AR |
GLRB | 138492 | Hyperekplexia 2, autosomal recessive | AR |
GMPPB | 615320 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14; Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 14; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 | AR |
GNB4 | 610863 | intermediate type F Charcot-Marie-Tooth | AD |
GNE | 603824 | Sialuria; Nonaka myopathy | AD, AR |
GPHN | 603930 | Molybdenum cofactor deficiency, complementation group c | AR |
GYG1 | 603942 | Glycogen storage disease XV; Polyglucosan body myopathy 2 | AR |
GYS1 | 138570 | Glycogen storage disease 0, muscle | AR |
HADHA | 600890 | mitochondrial trifunctional protein deficiency; long-chain 3-hydroxyl-CoA dehydrogenase deficiency | AR |
HADHB | 143450 | mitochondrial trifunctional protein deficiency | AR |
HINT1 | 601314 | Neuromyotonia and axonal neuropathy, autosomal recessive | AR |
HK1 | 142600 | Hemolytic anemia due to hexokinase deficiency; Neuropathy, hereditary motor and sensory, Russe type; Retinitis pigmentosa 79; Neurodevelopmental disorder with visual defects and brain anomalies | AD, AR |
HNRNPDL | 607137 | limb-girdle muscular dystrophy type 1G | AD |
HOXD10 | 142984 | AD | |
HRAS | 190020 | Bladder Cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Costello syndrome | AD |
HSPB1 | 602195 | type 2F Charcot-Marie-Tooth disease; Neuropathy, distal hereditary motor, type IIB | AD |
HSPB3 | 604624 | Neuronopathy, distal hereditary motor, type iic | AD |
HSPB8 | 608014 | Neuropathy, distal hereditary motor, type IIA; type 2L Charcot-Marie-Tooth disease | AD |
HSPG2 | 142461 | Silverman-Handmaker type of dyssegmental dysplasia; Schwartz-Jampel syndrome | AR |
IGHMBP2 | 600502 | distal hereditary motor neuronopathy type VI; type 2S Charcot-Marie-Tooth disease | AR |
INF2 | 610982 | Focal Segmental Glomerulosclerosis 5; intermediate type E Charcot-Marie-Tooth | AD |
ISCU | 611911 | AR | |
ITGA7 | 600536 | Muscular dystrophy, congenital, due to ITGA7 deficiency | AR |
KARS1 | 601421 | CHARCOT-MARIE-TOOTH, RECESSIVE INTERMEDIATE TYPE B; Deafness, autosomal recessive 89 | AR |
KAT6B | 605880 | Ohdo syndrome, SBBYS variant; Genitopatellar syndrome | AD |
KBTBD13 | 613727 | Nemaline Myopathy 6 | AD |
KCNA1 | 176260 | Episodic ataxia/myokymia syndrome | AD |
KCNE3 | 604433 | Brugada syndrome 6 | |
KIF1A | 601255 | spastic paraplegia 30; Neuropathy, hereditary sensory, type IIC; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 | AD, AR |
KIF1B | 605995 | type 2A1 Charcot-Marie-Tooth disease; pheochromocytoma | AD |
KIF5A | 602821 | spastic paraplegia 10; Neonatal intractable myoclonus | AD |
KLHL40 | 615340 | Nemaline myopathy 8, autosomal recessive | AR |
KLHL41 | 607701 | Nemaline myopathy 9 | AR |
LAMA2 | 156225 | congenital muscular dystrophy type 1A; limb-girdle Muscular dystrophy type 23 | AR |
LAMB2 | 150325 | Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalities | AR |
LAMP2 | 309060 | Danon disease | XLD |
LARGE1 | 603590 | congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A6 | AR |
LDB3 | 605906 | dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 | AD |
LDHA | 150000 | Glycogen storage disease XI | AR |
LIMS2 | 607908 | limb-girdle muscular dystrophy type 2W | AR |
LITAF | 603795 | type 1C Charcot-Marie-Tooth disease | AD |
LMNA | 150330 | dilated cardiomyopathy-1A; Lipodystrophy, familial partial, 2; Hutchinson-Gilford progeria; limb-girdle muscular dystrophy type 1B; Emery-Dreifuss muscular dystrophy 2; Malouf syndrome; Mandibuloacral dysplasia; Restrictive dermopathy, lethal; type 2B1 Charcot-Marie-Tooth disease; Heart-hand syndrome, Slovenian type; Muscular dystrophy, congenital; Emery-Dreifuss muscular dystrophy 3, AR | AD, AR |
LMOD3 | 616112 | Nemaline myopathy 10 | AR |
LPIN1 | 605518 | Myoglobinuria, acute recurrent, autosomal recessive | AR |
LRSAM1 | 610933 | type 2P Charcot-Marie-Tooth disease | AD, AR |
MAGEL2 | 605283 | Schaaf-Yang syndrome | AD |
MAMLD1 | 300120 | Hypospadias 2, X-linked | XLR |
MARS1 | 156560 | Interstitial lung and liver disease; type 2U Charcot-Marie-Tooth disease | AD, AR |
MATR3 | 164015 | Myopathy, Distal, 2 | AD |
MED25 | 610197 | Basel-Vanagait-Smirin-Yosef syndrome | AR |
MEGF10 | 612453 | Myopathy, areflexia, respiratory distress, and dysphagia, early-onset | AR |
MFN2 | 608507 | hereditary motor and sensory neuropathy type VIA with optic atrophy; axonal Charcot-Marie-Tooth disease type 2A2A; axonal Charcot-Marie-Tooth disease type 2A2B | AD, AR |
MICU1 | 605084 | Myopathy with extrapyramidal signs | AR |
MPV17 | 137960 | mitochondrial DNA depletion syndrome type 6 | AR |
MPZ | 159440 | type 1B Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; type 2I Charcot-Marie-Tooth disease; type 2J Charcot-Marie-Tooth disease | AD, AR |
MTM1 | 300415 | X-linked myotubular myopathy | XLR |
MTMR14 | 611089 | Myopathy, centronuclear 1 | AD |
MTMR2 | 603557 | type 4B1 Charcot-Marie-Tooth disease | AR |
MUSK | 601296 | Fetal akinesia deformation sequence; myasthenic syndrome, congenital type 9, associated with acetylcholine receptor deficiency | AR |
MYBPC1 | 160794 | Arthrogryposis, distal, type 1B; Lethal congenital contracture syndrome 4 | AD, AR |
MYBPC3 | 600958 | familial hypertrophic cardiomyopathy 4; dilated cardiomyopathy-1MM | AD, AR |
MYH2 | 160740 | Inclusion body myopathy 3, autosomal dominant | AD, AR |
MYH3 | 160720 | distal arthrogryposis type 2A; Distal arthrogryposis type 2B3 (Sheldon-Hall) | AD, AR |
MYH7 | 160760 | Liang distal myopathy; Scapuloperoneal syndrome, myopathic type; familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myopathy, myosin storage, autosomal dominant; dilated cardiomyopathy-1S | AD, AR, DiD |
MYH8 | 160741 | distal arthrogryposis type 7; Carney complex variant | AD |
MYO18B | 607295 | Klippel-Feil syndrome 4, autosomal recessive, with myopathy and facial dysmorphism | AR |
MYOT | 604103 | Myopathy, spheroid body; Myopathy, myofibrillar, 3; limb-girdle muscular dystrophy type 1A | AD |
MYPN | 608517 | dilated cardiomyopathy-1KK; Autosomal recessive Nemaline myopathy type 11 | AD, AR |
NALCN | 611549 | Hypotonia, infantile, with psychomotor retardation and characteristic facies; Congenital contractures of the limbs and face, hypotonia, and developmental delay | AD, AR |
NDRG1 | 605262 | type 4D Charcot-Marie-Tooth disease | AR |
NEB | 161650 | nemaline myopathy type 2 | AR |
NTRK1 | 191315 | hereditary sensory and autonomic neuropathy type 4 | AR |
OPA1 | 605290 | Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 | AD, AR |
OPA3 | 606580 | Optic atrophy type 3 with cataract; 3-methylglutaconic aciduria type III | AD, AR |
PDK3 | 300906 | type X6 Charcot-Marie-Tooth | XLD |
PFKM | 610681 | Glycogen storage disease type VII | AR |
PGAM2 | 612931 | Glycogen storage disease X | AR |
PGK1 | 311800 | Phosphoglycerate kinase 1 deficiency | XLR |
PGM1 | 171900 | congenital disorder of glycosylation type 1t | AR |
PHKA1 | 311870 | Muscle glycogenosis | XLR |
PIEZO2 | 613629 | Arthrogryposis, distal, type 5; Marden-Walker syndrome; Arthrogryposis, distal, with impaired proprioception and touch | AD, AR |
PLEC | 601282 | epidermolysis bullosa simplex, Ogna type; epidermolysis bullosa simplex with muscular dystrophy; epidermolysis bullosa simplex with pyloric atresia; limb-girdle muscular dystrophy type 2Q | AD, AR |
PLEKHG5 | 611101 | autosomal recessive distal spinal muscular atrophy type 4; recessive intermediate Charcot-Marie-Tooth disease type C | AR |
PLOD2 | 601865 | Bruck syndrome 2 | AR |
PMM2 | 601785 | congenital disorder of glycosylation type 1a | AR |
PMP22 | 601097 | type 1A Charcot-Marie-Tooth disease; Dejerine-Sottas syndrom; Neuropathy, recurrent, with pressure palsies | ?AD, AD, AR |
PNPLA2 | 609059 | Neutral lipid storage disease with myopathy | AR |
POLG | 174763 | progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B | AD, AR |
POLG2 | 604983 | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 | AD, AR |
POMGNT1 | 606822 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A3; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B3; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C3; retinitis pigmentosa type 76 | AR |
POMGNT2 | 614828 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A8 | AR |
POMK | 615247 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A12; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type C12 | AR |
POMT1 | 607423 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A1; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C1; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B1 | AR |
POMT2 | 607439 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A2; congenital muscular dystrophy-dystroglycanopathy with mental retardation type B2; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C2 | AR |
PREPL | 609557 | congenital myasthenic syndrome type 22 | AR |
PRKAG2 | 602743 | Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 | AD |
PRPS1 | 311850 | Phosphoribosylpyrophosphate synthetase superactivity; Arts syndrome; deafness type 1; type X5 Charcot-Marie-Tooth | XL, XLR |
PRX | 605725 | Dejerine-Sottas syndrom; type 4F Charcot-Marie-Tooth disease | AD, AR |
PYGM | 608455 | glycogen storage disease type 5 | AR |
QARS1 | 603727 | Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy | AR |
RAB7A | 602298 | type 2B Charcot-Marie-Tooth disease | AD |
RAPSN | 601592 | congenital myasthenic syndrome, type 11, associated with acetylcholine receptor deficiency | AR |
RBCK1 | 610924 | Polyglucosan body myopathy 1 with or without immunodeficiency | AR |
REEP1 | 609139 | spastic paraplegia 31; Neuronopathy, distal hereditary motor, type VB | AD |
RETREG1 | 613114 | hereditary sensory and autonomic neuropathy type IIB | AR |
RRM2B | 604712 | mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 | AD, AR |
RXYLT1 | 605862 | congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies A10 | AR |
RYR1 | 180901 | central core disease; malignant hyperthermia; minicore myopathy with external ophthalmoplegia | AD, AR |
SBF1 | 603560 | type 4B3 Charcot-Marie-Tooth disease | AR |
SBF2 | 607697 | type 4B2 Charcot-Marie-Tooth disease | AR |
SCN4A | 603967 | Paramyotonia congenita; Hyperkalemic periodic paralysis, type 2; Atypical myotonia congenita, acetazolamide-responsive; Hypokalemic periodic paralysis, type 2; Myasthenic syndrome, acetazolamide-responsive | AD, AR |
SELENON | 606210 | Myopathy, congenital, with fiber-type disproportion; rigid spine syndrome | AD, AR |
SGCA | 600119 | limb-girdle Muscular dystrophy type 3 | AR |
SGCB | 600900 | limb-girdle muscular dystrophy type 2E | AR |
SGCD | 601411 | limb-girdle muscular dystrophy type 2F; dilated cardiomyopathy-1L | AR |
SGCE | 604149 | myoclonus-dystonia | AD |
SGCG | 608896 | limb-girdle muscular dystrophy type 2C | AR |
SH3TC2 | 608206 | type 4C Charcot-Marie-Tooth disease; Mononeuropathy of the median nerve, mild | AD, AR |
SIL1 | 608005 | Marinesco-Sjogren syndrome | AR |
SLC12A6 | 604878 | Agenesis of the corpus callosum with peripheral neuropathy | AR |
SLC16A1 | 600682 | Monocarboxylate transporter 1 deficiency | AD, AR |
SLC22A5 | 603377 | systemic primary carnitine deficiency | AR |
SLC25A1 | 190315 | Combined D-2- and L-2-hydroxyglutaric aciduria | AR |
SLC25A20 | 613698 | Carnitine-acylcarnitine translocase deficiency | AR |
SLC25A46 | 610826 | Neuropathy, hereditary motor and sensory, type VIB | AR |
SLC5A7 | 608761 | Neuronopathy, distal hereditary motor, type VIIA; Myasthenic syndrome, congenital, 20, presynaptic | AD, AR |
SLC6A5 | 604159 | Hyperekplexia 3 | AD, AR |
SMCHD1 | 614982 | Fascioscapulohumeral muscular dystrophy 2, digenic | AD |
SMN1 | 600354 | spinal muscular atrophy type 1; spinal muscular atrophy type 3; spinal muscular atrophy type 2; spinal muscular atrophy type 4 | AR |
SMN2 | 601627 | spinal muscular atrophy type 3 | AR |
SPEG | 615950 | centronuclear myopathy type 5 | AR |
SPG11 | 610844 | Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X | AR |
SPTLC1 | 605712 | Neuropathy, hereditary sensory and autonomic, type IA | AD |
SPTLC2 | 605713 | Neuropathy, hereditary sensory and autonomic, type ic | AD |
SUCLA2 | 603921 | mitochondrial DNA depletion syndrome 5 | AR |
SYNE1 | 608441 | autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4 | AD, AR |
SYNE2 | 608442 | Emery-Dreifuss muscular dystrophy 5 | AD |
TAZ | 300394 | Barth syndrome | XLR |
TCAP | 604488 | limb-girdle muscular dystrophy type 2G; cardiomyopathy, familial hypertrophic, 25 | AD, AR |
TFG | 602498 | Hereditary motor and sensory neuropathy, Okinawa type; spastic paraplegia 57 | AD, AR |
TGFB3 | 190230 | Arrhythmogenic right ventricular dysplasia 1; Loeys-Dietz syndrome 5 | AD |
TK2 | 188250 | mitochondrial DNA depletion syndrome 2 | AR |
TMEM43 | 612048 | arrhythmogenic right ventricular dysplasia 5 | AD |
TNNI2 | 191043 | distal arthrogryposis type 2B | AD |
TNNT1 | 191041 | Nemaline myopathy 5, Amish type | AR |
TNNT3 | 600692 | AD | |
TNPO3 | 610032 | limb-girdle muscular dystrophy type 1F | AD |
TOR1A | 605204 | dystonia 1 | AD |
TPM2 | 190990 | Nemaline myopathy type 4, autosomal dominant | AD |
TPM3 | 191030 | Myopathy, congenital, with fiber-type disproportion; Nemaline myopathy 1, autosomal dominant or recessive | AD, AR |
TRAPPC11 | 614138 | limb-girdle muscular dystrophy type 2S | AR |
TRIM2 | 614141 | type 2R Charcot-Marie-Tooth disease | AR |
TRIM32 | 602290 | limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 | AR |
TRPV4 | 605427 | Brachyolmia type 3; Metatropic dysplasia; Spondylometaphyseal dysplasia, Kozlowski type; Hereditary motor and sensory neuropathy, type IIc | AD |
TSEN2 | 608753 | pontocerebellar hypoplasia type 2B | AR |
TSFM | 604723 | Combined oxidative phosphorylation deficiency 3 | AR |
TTN | 188840 | Tibial muscular dystrophy, tardive; Hereditary myopathy with early respiratory failure; dilated cardiomyopathy type 1G; limb-girdle muscular dystrophy type 2J; early-onset myopathy with fatal cardiomyopathy; familial hypertrophic cardiomyopathy type 9 | AD, AR |
TWNK | 606075 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 | AD, AR |
TYMP | 131222 | mitochondrial DNA depletion syndrome 1 | AR |
UBA1 | 314370 | X-linked infantile spinal muscular atrophy type 2 | XLR |
VAMP1 | 185880 | Spastic ataxia 1, autosomal dominant; Myasthenic syndrome, congenital, 25 | AD, AR |
VAPB | 605704 | Finkel type late-onset spinal muscular atrophy; amyotrophic lateral sclerosis 8 | AD |
VCP | 601023 | inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; amyotrophic lateral sclerosis 14; Charcot-Marie-Tooth disease type 2Y | AD |
VIPAS39 | 613401 | Arthrogryposis, renal dysfunction, and cholestasis 2 | AR |
VRK1 | 602168 | pontocerebellar hypoplasia type 1A | AR |
WNK1 | 605232 | Neuropathy, hereditary sensory and autonomic, type II; Pseudohypoaldosteronism, type IIC | AD, AR |
XK | 314850 | Mcleod syndrome | XL |
YARS1 | 603623 | intermediate type C Charcot-Marie-Tooth | AD |
Treatment for patients affected with myofibrillar myopathy commonly includes supportive therapies, including pacemakers and implantable cardioverter defibrillators in individuals with arrhythmia and/or cardiac conduction defects. Cardiac transplantation could be considered in individuals with life-threatening cardiomyopathy, and respiratory support could be applied in individuals with respiratory failure.
CENTOGENE offers sequencing and deletion/duplication analysis for the Myofibrillar myopathy panel (genes: BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC, LDB3, MYOT).
Differential diagnosis
The differential diagnosis of myofibrillar myopathy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Myotonic dystrophy type 1 (DM1) caused by expansion of a CTG trinucleotide repeat in DMPK
- Myotonic dystrophy type 2 (DM2) caused by a complex repeat expansion (TG)n(TCTG)n(CCTG)n in ZNF9 (CNBP)
- Inclusion body myopathy type 2 (IBM2) caused by mutations in GNE
- Dysferlinopathy, caused by mutations in DYSF
- Other muscular dystrophies including tibial muscular dystrophy (Udd distal myopathy), telethoninopathy, Laing distal myopathy, facioscapulohumeral dystrophy and others.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for myofibrillar myopathy using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Myofibrillar myopathy panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the myofibrillar myopathy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for myofibrillar myopathy testing:
- Individuals with a family history of myofibrillar myopathy and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling myofibrillar myopathy
- Individuals with a negative but suspected family history of myofibrillar myopathy, in order to perform proper genetic counseling.
Test utility
Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having myofibrillar myopathy and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the myofibrillar myopathy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.