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Congenital myopathy 18(DHPRM; CMYO18)

MedGen UID:
1840919
Concept ID:
C5830283
Disease or Syndrome
Synonyms: DHPR CONGENITAL MYOPATHY; DIHYDROPYRIDINE RECEPTOR CONGENITAL MYOPATHY; Myopathy, congenital, due to dihydropyridine receptor defect
 
Gene (location): CACNA1S (1q32.1)
 
Monarch Initiative: MONDO:0859514
OMIM®: 620246

Definition

Congenital myopathy-18 (CMYO18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood. Most affected individuals show delayed motor development with generalized hypotonia and progressive axial and limb muscle weakness beginning soon after birth or in infancy. Additional features may include swallowing difficulties, external ophthalmoplegia, ptosis, high-arched palate, and respiratory insufficiency, which can lead to death in severe cases. Muscle biopsy shows variable morphologic abnormalities, including alveolar changes in the intermyofibrillar network, fiber size variability, focal disorganization, internal nuclei, and dilated sarcoplasmic reticulum and T-tubules. The disorder results from a defect in excitation-contraction coupling in skeletal muscle (Schartner et al., 2017; Ravenscroft et al., 2021; Mauri et al., 2021; Yis et al., 2019). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000). [from OMIM]

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
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.
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).
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).
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.
Fatty replacement of skeletal muscle
MedGen UID:
866735
Concept ID:
C4021082
Finding
Muscle fibers degeneration resulting in fatty replacement of skeletal muscle fibers
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.
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.
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).
Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.

Professional guidelines

PubMed

Vanbelleghem E, Van Damme T, Beyens A, Symoens S, Claes K, De Backer J, Meerschaut I, Vanommeslaeghe F, Delanghe SE, van den Ende J, Beyltjens T, Scimone ER, Lindsay ME, Schimmenti LA, Hinze AM, Dunn E, Gomez-Ospina N, Vandernoot I, Delguste T, Coppens S, Cormier-Daire V, Tartaglia M, Garavelli L, Shieh J, Demir Ş, Arslan Ateş E, Zenker M, Rohanizadegan M, Rivera-Cruz G, Douzgou S; Myhre Syndrome Foundation, Lin AE, Callewaert B
Eur J Hum Genet 2024 Sep;32(9):1086-1094. Epub 2024 Jul 12 doi: 10.1038/s41431-024-01664-1. PMID: 38997468Free PMC Article
Meola G
Acta Myol 2013 Dec;32(3):154-65. PMID: 24803843Free PMC Article
Do TT
Curr Opin Pediatr 2006 Feb;18(1):26-9. doi: 10.1097/01.mop.0000192520.48411.fa. PMID: 16470158

Recent clinical studies

Etiology

Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators
Neurology 2023 Jul 18;101(3):e238-e252. Epub 2023 Jun 2 doi: 10.1212/WNL.0000000000207402. PMID: 37268435Free PMC Article
Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H
Autophagy 2022 Mar;18(3):496-517. Epub 2021 Aug 19 doi: 10.1080/15548627.2021.1943177. PMID: 34130600Free PMC Article
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L
Cochrane Database Syst Rev 2020 Oct 28;10(10):CD013400. doi: 10.1002/14651858.CD013400.pub2. PMID: 33112424Free PMC Article
Kennedy RA, Carroll K, McGinley JL, Paterson KL
J Foot Ankle Res 2020 Mar 2;13(1):10. doi: 10.1186/s13047-020-0378-2. PMID: 32122377Free PMC Article
Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, Minetti C, Astrea G, Bruno C, Santorelli FM; Italian Network on Congenital Myopathies
Ital J Pediatr 2017 Nov 15;43(1):101. doi: 10.1186/s13052-017-0419-z. PMID: 29141652Free PMC Article

Diagnosis

Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H
Autophagy 2022 Mar;18(3):496-517. Epub 2021 Aug 19 doi: 10.1080/15548627.2021.1943177. PMID: 34130600Free PMC Article
Kennedy RA, Carroll K, McGinley JL, Paterson KL
J Foot Ankle Res 2020 Mar 2;13(1):10. doi: 10.1186/s13047-020-0378-2. PMID: 32122377Free PMC Article
Clarke NF
Semin Pediatr Neurol 2011 Dec;18(4):264-71. doi: 10.1016/j.spen.2011.10.008. PMID: 22172422
Jungbluth H, Sewry CA, Muntoni F
Semin Pediatr Neurol 2011 Dec;18(4):239-49. doi: 10.1016/j.spen.2011.10.005. PMID: 22172419
Do TT
Curr Opin Pediatr 2006 Feb;18(1):26-9. doi: 10.1097/01.mop.0000192520.48411.fa. PMID: 16470158

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
Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators
Neurology 2023 Jul 18;101(3):e238-e252. Epub 2023 Jun 2 doi: 10.1212/WNL.0000000000207402. PMID: 37268435Free PMC Article
Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L
Cochrane Database Syst Rev 2020 Oct 28;10(10):CD013400. doi: 10.1002/14651858.CD013400.pub2. PMID: 33112424Free PMC Article
Do TT
Curr Opin Pediatr 2006 Feb;18(1):26-9. doi: 10.1097/01.mop.0000192520.48411.fa. PMID: 16470158

Prognosis

Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
Deneubourg C, Ramm M, Smith LJ, Baron O, Singh K, Byrne SC, Duchen MR, Gautel M, Eskelinen EL, Fanto M, Jungbluth H
Autophagy 2022 Mar;18(3):496-517. Epub 2021 Aug 19 doi: 10.1080/15548627.2021.1943177. PMID: 34130600Free PMC Article
Amburgey K, Acker M, Saeed S, Amin R, Beggs AH, Bönnemann CG, Brudno M, Constantinescu A, Dastgir J, Diallo M, Genetti CA, Glueck M, Hewson S, Hum C, Jain MS, Lawlor MW, Meyer OH, Nelson L, Sultanum N, Syed F, Tran T, Wang CH, Dowling JJ
Neurology 2021 Mar 9;96(10):e1425-e1436. Epub 2021 Jan 4 doi: 10.1212/WNL.0000000000011458. PMID: 33397769Free PMC Article
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L
Cochrane Database Syst Rev 2020 Oct 28;10(10):CD013400. doi: 10.1002/14651858.CD013400.pub2. PMID: 33112424Free PMC Article
Cassandrini D, Trovato R, Rubegni A, Lenzi S, Fiorillo C, Baldacci J, Minetti C, Astrea G, Bruno C, Santorelli FM; Italian Network on Congenital Myopathies
Ital J Pediatr 2017 Nov 15;43(1):101. doi: 10.1186/s13052-017-0419-z. PMID: 29141652Free PMC Article

Clinical prediction guides

Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, Mancuso M; MMPOWER-3 Trial Investigators
Neurology 2023 Jul 18;101(3):e238-e252. Epub 2023 Jun 2 doi: 10.1212/WNL.0000000000207402. PMID: 37268435Free PMC Article
Thornton CA, Moxley RT 3rd, Eichinger K, Heatwole C, Mignon L, Arnold WD, Ashizawa T, Day JW, Dent G, Tanner MK, Duong T, Greene EP, Herbelin L, Johnson NE, King W, Kissel JT, Leung DG, Lott DJ, Norris DA, Pucillo EM, Schell W, Statland JM, Stinson N, Subramony SH, Xia S, Bishop KM, Bennett CF
Lancet Neurol 2023 Mar;22(3):218-228. doi: 10.1016/S1474-4422(23)00001-7. PMID: 36804094
Amburgey K, Acker M, Saeed S, Amin R, Beggs AH, Bönnemann CG, Brudno M, Constantinescu A, Dastgir J, Diallo M, Genetti CA, Glueck M, Hewson S, Hum C, Jain MS, Lawlor MW, Meyer OH, Nelson L, Sultanum N, Syed F, Tran T, Wang CH, Dowling JJ
Neurology 2021 Mar 9;96(10):e1425-e1436. Epub 2021 Jan 4 doi: 10.1212/WNL.0000000000011458. PMID: 33397769Free PMC Article
Piché J, Van Vliet PP, Pucéat M, Andelfinger G
Cell Cycle 2019 Nov;18(21):2828-2848. Epub 2019 Sep 13 doi: 10.1080/15384101.2019.1658476. PMID: 31516082Free PMC Article
Do TT
Curr Opin Pediatr 2006 Feb;18(1):26-9. doi: 10.1097/01.mop.0000192520.48411.fa. PMID: 16470158

Recent systematic reviews

Rice SM, Varotsis DF, Wodoslawsky S, Critchlow E, Liu R, McLaren RA Jr, Makhamreh MM, Firman B, Berger SI, Al-Kouatly HB
Prenat Diagn 2024 Oct;44(11):1381-1397. Epub 2024 Sep 3 doi: 10.1002/pd.6637. PMID: 39228063
Buchignani B, Marinella G, Pasquariello R, Sgherri G, Frosini S, Santorelli FM, Orsini A, Battini R, Astrea G
Genes (Basel) 2024 Feb 5;15(2) doi: 10.3390/genes15020208. PMID: 38397198Free PMC Article
Jeffery TC, Chang AB, Conwell LS
Cochrane Database Syst Rev 2023 Jan 10;1(1):CD002010. doi: 10.1002/14651858.CD002010.pub5. PMID: 36625789Free PMC Article
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L
Cochrane Database Syst Rev 2020 Oct 28;10(10):CD013400. doi: 10.1002/14651858.CD013400.pub2. PMID: 33112424Free PMC Article
Lawal TA, Wires ES, Terry NL, Dowling JJ, Todd JJ
Orphanet J Rare Dis 2020 May 7;15(1):113. doi: 10.1186/s13023-020-01384-x. PMID: 32381029Free PMC Article

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