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Myopathy, centronuclear, 6, with fiber-type disproportion(CNM6)

MedGen UID:
1627492
Concept ID:
C4540345
Disease or Syndrome
Synonyms: CNM6; MYOPATHY, CENTRONUCLEAR, 6, WITH FIBER-TYPE DISPROPORTION
 
Gene (location): MAP3K20 (2q31.1)
 
Monarch Initiative: MONDO:0054695
OMIM®: 617760

Definition

Centronuclear myopathy-6 with fiber-type disproportion (CNM6) is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy (summary by Vasli et al., 2017). For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150). [from OMIM]

Clinical features

From HPO
Ankle flexion contracture
MedGen UID:
332440
Concept ID:
C1837407
Anatomical Abnormality
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Easy fatigability
MedGen UID:
373253
Concept ID:
C1837098
Finding
Increased susceptibility to fatigue.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Hyperlordosis
MedGen UID:
9805
Concept ID:
C0024003
Finding
Abnormally increased curvature (anterior concavity) of the lumbar or cervical spine.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Muscle spasm
MedGen UID:
52431
Concept ID:
C0037763
Sign or Symptom
Sudden and involuntary contractions of one or more muscles.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
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.
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).
Calf muscle hypertrophy
MedGen UID:
335868
Concept ID:
C1843057
Finding
Muscle hypertrophy affecting the calf muscles.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
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.
Rimmed vacuoles
MedGen UID:
340089
Concept ID:
C1853932
Finding
Presence of abnormal vacuoles (membrane-bound organelles) in the sarcolemma. On histological staining with hematoxylin and eosin, rimmed vacuoles are popcorn-like clear vacuoles with a densely blue rim. The vacuoles are often associated with cytoplasmic and occasionally intranuclear eosinophilic inclusions.
Type 1 muscle fiber predominance
MedGen UID:
344274
Concept ID:
C1854387
Finding
An abnormal predominance of type I muscle fibers (in general, this feature can only be observed on muscle biopsy).
Increased endomysial connective tissue
MedGen UID:
867771
Concept ID:
C4022161
Finding
An increased volume of the endomysium, which is a connective tissue sheath that surrounds each muscule fiber. Together, bundles of muscle fibers form a fasciculus, surrounded by another layer of connective tissue called the perimysium.
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.

Professional guidelines

PubMed

Ramos-Fransi A, Martínez-Piñeiro A, Almendrote M, Lucente G, Carrato C, Ballester-Lopez A, Lucia A, Pintos-Morell G, Nogales-Gadea G, Coll-Cantí J
Muscle Nerve 2018 Jun;57(6):E138-E140. Epub 2018 Feb 2 doi: 10.1002/mus.26078. PMID: 29350769
Rosenberg H, Rueffert H
Eur J Hum Genet 2011 Jun;19(6) Epub 2011 Jan 19 doi: 10.1038/ejhg.2010.248. PMID: 21248738Free PMC Article
Wallgren-Pettersson C, Bushby K, Mellies U, Simonds A; ENMC
Neuromuscul Disord 2004 Jan;14(1):56-69. doi: 10.1016/j.nmd.2003.09.003. PMID: 14659414

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
Butterfield RJ
Continuum (Minneap Minn) 2019 Dec;25(6):1640-1661. doi: 10.1212/CON.0000000000000792. PMID: 31794464
Janin A, N'Guyen K, Habib G, Dauphin C, Chanavat V, Bouvagnet P, Eschalier R, Streichenberger N, Chevalier P, Millat G
Clin Genet 2017 Dec;92(6):616-623. Epub 2017 May 18 doi: 10.1111/cge.13043. PMID: 28436997
Staiano L, De Leo MG, Persico M, De Matteis MA
Biochim Biophys Acta 2015 Jun;1851(6):867-81. Epub 2014 Dec 12 doi: 10.1016/j.bbalip.2014.12.001. PMID: 25510381
Bodensteiner J
Neurol Clin 1988 Aug;6(3):499-518. PMID: 3065597

Diagnosis

Wen Q, Chang X, Guo J
Acta Neurol Belg 2020 Dec;120(6):1351-1360. Epub 2019 Nov 6 doi: 10.1007/s13760-019-01230-3. PMID: 31696431
Butterfield RJ
Continuum (Minneap Minn) 2019 Dec;25(6):1640-1661. doi: 10.1212/CON.0000000000000792. PMID: 31794464
Krishnan M, Selvaraj C, Sivakumar S
J Assoc Physicians India 2016 Jun;64(6):81-82. PMID: 27739277
Madonia P, Wilson J, Bican O, Willis M, Bass P 3rd
J La State Med Soc 2012 Nov-Dec;164(6):320-3. PMID: 23431674
Bodensteiner J
Neurol Clin 1988 Aug;6(3):499-518. PMID: 3065597

Therapy

Shieh PB, Kuntz NL, Dowling JJ, Müller-Felber W, Bönnemann CG, Seferian AM, Servais L, Smith BK, Muntoni F, Blaschek A, Foley AR, Saade DN, Neuhaus S, Alfano LN, Beggs AH, Buj-Bello A, Childers MK, Duong T, Graham RJ, Jain M, Coats J, MacBean V, James ES, Lee J, Mavilio F, Miller W, Varfaj F, Murtagh M, Han C, Noursalehi M, Lawlor MW, Prasad S, Rico S
Lancet Neurol 2023 Dec;22(12):1125-1139. doi: 10.1016/S1474-4422(23)00313-7. PMID: 37977713
Ramos-Fransi A, Martínez-Piñeiro A, Almendrote M, Lucente G, Carrato C, Ballester-Lopez A, Lucia A, Pintos-Morell G, Nogales-Gadea G, Coll-Cantí J
Muscle Nerve 2018 Jun;57(6):E138-E140. Epub 2018 Feb 2 doi: 10.1002/mus.26078. PMID: 29350769
Madonia P, Wilson J, Bican O, Willis M, Bass P 3rd
J La State Med Soc 2012 Nov-Dec;164(6):320-3. PMID: 23431674
Gener B, Burns JM, Griffin S, Boyer EW
Pediatrics 2010 Jun;125(6):e1514-7. Epub 2010 May 3 doi: 10.1542/peds.2009-2795. PMID: 20439600
Wallgren-Pettersson C, Laing NG
Neuromuscul Disord 2003 Aug;13(6):501-7. doi: 10.1016/s0960-8966(03)00007-5. PMID: 12899878

Prognosis

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
Letournel F, Le Clec'h C, Croué A, Marcorelles P, Lavigne C, Pénisson-Besnier I
Clin Neuropathol 2010 Nov-Dec;29(6):357-60. doi: 10.5414/npp29357. PMID: 21073838
Gener B, Burns JM, Griffin S, Boyer EW
Pediatrics 2010 Jun;125(6):e1514-7. Epub 2010 May 3 doi: 10.1542/peds.2009-2795. PMID: 20439600
Wallgren-Pettersson C, Bushby K, Mellies U, Simonds A; ENMC
Neuromuscul Disord 2004 Jan;14(1):56-69. doi: 10.1016/j.nmd.2003.09.003. PMID: 14659414
Begley MJ, Taylor GS, Kim SA, Veine DM, Dixon JE, Stuckey JA
Mol Cell 2003 Dec;12(6):1391-402. doi: 10.1016/s1097-2765(03)00486-6. PMID: 14690594

Clinical prediction guides

Shieh PB, Kuntz NL, Dowling JJ, Müller-Felber W, Bönnemann CG, Seferian AM, Servais L, Smith BK, Muntoni F, Blaschek A, Foley AR, Saade DN, Neuhaus S, Alfano LN, Beggs AH, Buj-Bello A, Childers MK, Duong T, Graham RJ, Jain M, Coats J, MacBean V, James ES, Lee J, Mavilio F, Miller W, Varfaj F, Murtagh M, Han C, Noursalehi M, Lawlor MW, Prasad S, Rico S
Lancet Neurol 2023 Dec;22(12):1125-1139. doi: 10.1016/S1474-4422(23)00313-7. PMID: 37977713
Brady S, Healy EG, Gang Q, Parton M, Quinlivan R, Jacob S, Curtis E, Al-Sarraj S, Sewry CA, Hanna MG, Houlden H, Beeson D, Holton JL
J Neuropathol Exp Neurol 2016 Dec;75(12):1171-1178. doi: 10.1093/jnen/nlw096. PMID: 27941137
Begley MJ, Taylor GS, Kim SA, Veine DM, Dixon JE, Stuckey JA
Mol Cell 2003 Dec;12(6):1391-402. doi: 10.1016/s1097-2765(03)00486-6. PMID: 14690594
De Luca A, Tosolini A, Russo P, Severino A, Baldi A, De Luca L, Cavallotti I, Baldi F, Giordano A, Testa JR, Paggi MG
J Histochem Cytochem 2001 Jun;49(6):693-8. doi: 10.1177/002215540104900603. PMID: 11373316
Wallgren-Pettersson C, Avela K, Marchand S, Kolehmainen J, Tahvanainen E, Hansen FJ, Muntoni F, Dubowitz V, De Visser M, Van Langen IM
Neuromuscul Disord 1995 Nov;5(6):441-3. doi: 10.1016/0960-8966(95)00022-f. PMID: 8580725

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