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Myofibrillar myopathy 8(MFM8)

MedGen UID:
934612
Concept ID:
C4310645
Disease or Syndrome
Synonyms: MFM8; MYOPATHY, MYOFIBRILLAR, 8
 
Gene (location): PYROXD1 (12p12.1)
 
Monarch Initiative: MONDO:0014993
OMIM®: 617258

Definition

Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (O'Grady et al., 2016; Daimaguler et al., 2021). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (Woods et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419). [from OMIM]

Clinical features

From HPO
Pes planus
MedGen UID:
42034
Concept ID:
C0016202
Anatomical Abnormality
A foot where the longitudinal arch of the foot is in contact with the ground or floor when the individual is standing; or, in a patient lying supine, a foot where the arch is in contact with the surface of a flat board pressed against the sole of the foot by the examiner with a pressure similar to that expected from weight bearing; or, the height of the arch is reduced.
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Limb muscle weakness
MedGen UID:
107956
Concept ID:
C0587246
Finding
Reduced strength and weakness of the muscles of the arms and legs.
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).
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.
Tall stature
MedGen UID:
69137
Concept ID:
C0241240
Finding
A height above that which is expected according to age and gender norms.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Micrognathia
MedGen UID:
44428
Concept ID:
C0025990
Congenital Abnormality
Developmental hypoplasia of the mandible.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Neck muscle weakness
MedGen UID:
66808
Concept ID:
C0240479
Finding
Decreased strength of the neck musculature.
Achilles tendon contracture
MedGen UID:
98052
Concept ID:
C0410264
Anatomical Abnormality
A contracture of the Achilles tendon.
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
Frequent falls
MedGen UID:
163408
Concept ID:
C0850703
Finding
Generalized amyotrophy
MedGen UID:
234650
Concept ID:
C1389113
Disease or Syndrome
Generalized (diffuse, unlocalized) amyotrophy (muscle atrophy) affecting multiple muscles.
Centrally nucleated skeletal muscle fibers
MedGen UID:
330782
Concept ID:
C1842170
Finding
An abnormality in which the nuclei of sarcomeres take on an abnormally central localization (or in which this feature is found in an increased proportion of muscle cells).
Joint hypermobility
MedGen UID:
336793
Concept ID:
C1844820
Finding
The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.
Distal joint laxity
MedGen UID:
376894
Concept ID:
C1850851
Finding
Lack of stability of a distal joint (e.g., finger).
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.
Joint contracture of the 5th finger
MedGen UID:
356345
Concept ID:
C1865702
Anatomical Abnormality
Chronic loss of joint motion in the 5th finger due to structural changes in non-bony tissue. The term camptodactyly of the 5th finger is used if the distal and/or proximal interphalangeal joints are affected.
Pectus excavatum
MedGen UID:
781174
Concept ID:
C2051831
Finding
A defect of the chest wall characterized by a depression of the sternum, giving the chest ("pectus") a caved-in ("excavatum") appearance.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Nemaline bodies
MedGen UID:
814369
Concept ID:
C3808039
Finding
Nemaline rods are abnormal bodies that can occur in skeletal muscle fibers. The rods can be observed on histological analysis of muscle biopsy tissue or upon electron microscopy, where they appear either as extensions of sarcomeric Z-lines, in random array without obvious attachment to Z-lines (often in areas devoid of sarcomeres) or in large clusters localized at the sarcolemma or intermyofibrillar spaces.
Central core regions in muscle fibers
MedGen UID:
868176
Concept ID:
C4022568
Finding
The presence of disorganized areas called cores in the center of muscle fibers. There is a typical appearance of the biopsy on light microscopy, where the muscle cells have cores that are devoid of mitochondria and specific enzymes. Cores are typically well demarcated and centrally located, but may occasionally be multiple and of eccentric.
Reduced vital capacity
MedGen UID:
141657
Concept ID:
C0476408
Finding
An abnormal reduction on the vital capacity, which is defined as the total lung capacity (volume of air in the lungs at maximal inflation) less the residual volume (i.e., volume of air in the lungs following maximal exhalation) of the lung.
Recurrent lower respiratory tract infections
MedGen UID:
756211
Concept ID:
C3163798
Disease or Syndrome
An increased susceptibility to lower respiratory tract infections as manifested by a history of recurrent lower respiratory tract infections.
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.
Dental malocclusion
MedGen UID:
9869
Concept ID:
C0024636
Anatomical Abnormality
Dental malocclusion refers to an abnormality of the occlusion, or alignment, of the teeth and the way the upper and lower teeth fit together, resulting in overcrowding of teeth or in abnormal bite patterns.
Impaired mastication
MedGen UID:
66779
Concept ID:
C0239043
Finding
An abnormal reduction in the ability to masticate (chew), i.e., in the ability to crush and ground food in preparation for swallowing.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of strabismus with one or both eyes deviated outward.

Recent clinical studies

Etiology

Joel MM, Pontifex C, Martens K, Chhibber S, de Koning J, Pfeffer G
Neuromuscul Disord 2022 Aug;32(8):643-653. Epub 2022 Apr 29 doi: 10.1016/j.nmd.2022.04.009. PMID: 35850946
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
Olivé M, Odgerel Z, Martínez A, Poza JJ, Bragado FG, Zabalza RJ, Jericó I, Gonzalez-Mera L, Shatunov A, Lee HS, Armstrong J, Maraví E, Arroyo MR, Pascual-Calvet J, Navarro C, Paradas C, Huerta M, Marquez F, Rivas EG, Pou A, Ferrer I, Goldfarb LG
Neuromuscul Disord 2011 Aug;21(8):533-42. Epub 2011 Jun 14 doi: 10.1016/j.nmd.2011.05.002. PMID: 21676617Free PMC Article

Diagnosis

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
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
Panicucci C, Traverso M, Baratto S, Romeo C, Iacomino M, Gemelli C, Tagliafico A, Broda P, Zara F, Bruno C, Minetti C, Fiorillo C
Acta Myol 2019 Mar;38(1):8-12. Epub 2019 Mar 1 PMID: 31309175Free 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
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

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

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
Ma K, Luo D, Tian T, Li N, He X, Rao C, Zhong B, Lu X
Mol Genet Genomic Med 2019 Aug;7(8):e825. Epub 2019 Jun 18 doi: 10.1002/mgg3.825. PMID: 31215171Free PMC Article
Riley LG, Waddell LB, Ghaoui R, Evesson FJ, Cummings BB, Bryen SJ, Joshi H, Wang MX, Brammah S, Kritharides L, Corbett A, MacArthur DG, Cooper ST
Eur J Hum Genet 2019 Aug;27(8):1267-1273. Epub 2019 Apr 25 doi: 10.1038/s41431-019-0393-6. PMID: 31024060Free PMC Article
Del Bigio MR, Chudley AE, Sarnat HB, Campbell C, Goobie S, Chodirker BN, Selcen D
Ann Neurol 2011 May;69(5):866-71. Epub 2011 Feb 18 doi: 10.1002/ana.22331. PMID: 21337604Free PMC Article

Clinical prediction guides

Joel MM, Pontifex C, Martens K, Chhibber S, de Koning J, Pfeffer G
Neuromuscul Disord 2022 Aug;32(8):643-653. Epub 2022 Apr 29 doi: 10.1016/j.nmd.2022.04.009. PMID: 35850946
Ruparelia AA, McKaige EA, Williams C, Schulze KE, Fuchs M, Oorschot V, Lacene E, Meregalli M, Lee C, Serrano RJ, Baxter EC, Monro K, Torrente Y, Ramm G, Stojkovic T, Lavoie JN, Bryson-Richardson RJ
Autophagy 2021 Sep;17(9):2494-2510. Epub 2020 Oct 19 doi: 10.1080/15548627.2020.1833500. PMID: 33030392Free PMC Article
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
Vasu VT, Ott S, Hobson B, Rashidi V, Oommen S, Cross CE, Gohil K
Free Radic Res 2009 Feb;43(2):106-16. doi: 10.1080/10715760802616676. PMID: 19204867Free PMC Article
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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