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Bethlem myopathy 2(BTHLM2)

MedGen UID:
907426
Concept ID:
C4225313
Disease or Syndrome
Synonym: BTHLM2
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
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): COL12A1 (6q13-14.1)
 
Monarch Initiative: MONDO:0034022
OMIM®: 616471
Orphanet: ORPHA536516

Definition

Bethlem myopathy-2 (BTHLM2) is characterized by congenital hypotonia and myopathy. Motor development is delayed, but muscle strength improves with age, and patients are able to achieve ambulation. Proximal joint contractures that improve over time, as well as joint hyperlaxity, are also present. Muscle biopsy shows mild variability in fiber diameter, without degeneration or regeneration (Zou et al., 2014; Hicks et al., 2014). For a discussion of genetic heterogeneity of Bethlem myopathy, see BTHLM1 (158810). [from OMIM]

Clinical features

From HPO
Scapular winging
MedGen UID:
66822
Concept ID:
C0240953
Anatomical Abnormality
Abnormal protrusion of the scapula away from the surface of the back.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Stooped posture
MedGen UID:
1393424
Concept ID:
C4476759
Finding
A habitual positioning of the body with the head and upper back bent forward.
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
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.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
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.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
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.
Distal joint hypermobility
MedGen UID:
376894
Concept ID:
C1850851
Finding
Lack of stability of a distal joint (e.g., finger).
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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.
Atrophic scars
MedGen UID:
57875
Concept ID:
C0162154
Pathologic Function
Scars that form a depression compared to the level of the surrounding skin because of damage to the collagen, fat or other tissues below the skin.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies

Etiology

Silverstein RS, Wang DD, Haruno LS, Lotze TE, Scott AC, Rosenfeld SB
J Pediatr Orthop 2023 Feb 1;43(2):e163-e167. Epub 2022 Oct 26 doi: 10.1097/BPO.0000000000002283. PMID: 36607927
Oliveira R, Sotero FD, Coelho J, Roque R, Moreno T, Oliveira Santos M
J Clin Neurosci 2022 Dec;106:43-48. Epub 2022 Oct 17 doi: 10.1016/j.jocn.2022.10.007. PMID: 36265364
Vissing CR, Hedermann G, Vissing J
Muscle Nerve 2019 Aug;60(2):183-188. Epub 2019 May 9 doi: 10.1002/mus.26498. PMID: 31026058
Kim SY, Kim WJ, Kim H, Choi SA, Lee JS, Cho A, Jang SS, Lim BC, Kim KJ, Kim JI, Hahn SH, Chae JH
Muscle Nerve 2018 Sep;58(3):381-388. doi: 10.1002/mus.26093. PMID: 29406609
Quijano-Roy S, Khirani S, Colella M, Ramirez A, Aloui S, Wehbi S, de Becdelievre A, Carlier RY, Allamand V, Richard P, Azzi V, Estournet B, Fauroux B
Neuromuscul Disord 2014 Feb;24(2):125-33. Epub 2013 Nov 16 doi: 10.1016/j.nmd.2013.11.002. PMID: 24314752

Diagnosis

Silverstein RS, Wang DD, Haruno LS, Lotze TE, Scott AC, Rosenfeld SB
J Pediatr Orthop 2023 Feb 1;43(2):e163-e167. Epub 2022 Oct 26 doi: 10.1097/BPO.0000000000002283. PMID: 36607927
Oliveira R, Sotero FD, Coelho J, Roque R, Moreno T, Oliveira Santos M
J Clin Neurosci 2022 Dec;106:43-48. Epub 2022 Oct 17 doi: 10.1016/j.jocn.2022.10.007. PMID: 36265364
Bazrafshan S, Kushlaf H, Kakroo M, Quinlan J, Becker RC, Sadayappan S
Cells 2021 Feb 8;10(2) doi: 10.3390/cells10020349. PMID: 33567613Free PMC Article
Kim SY, Kim WJ, Kim H, Choi SA, Lee JS, Cho A, Jang SS, Lim BC, Kim KJ, Kim JI, Hahn SH, Chae JH
Muscle Nerve 2018 Sep;58(3):381-388. doi: 10.1002/mus.26093. PMID: 29406609
Quijano-Roy S, Khirani S, Colella M, Ramirez A, Aloui S, Wehbi S, de Becdelievre A, Carlier RY, Allamand V, Richard P, Azzi V, Estournet B, Fauroux B
Neuromuscul Disord 2014 Feb;24(2):125-33. Epub 2013 Nov 16 doi: 10.1016/j.nmd.2013.11.002. PMID: 24314752

Therapy

Natera-de Benito D, Foley AR, Domínguez-González C, Ortez C, Jain M, Mebrahtu A, Donkervoort S, Hu Y, Fink M, Yun P, Ogata T, Medina J, Vigo M, Meilleur KG, Leach ME, Dastgir J, Díaz-Manera J, Carrera-García L, Expósito-Escudero J, Alarcon M, Cuadras D, Montiel-Morillo E, Milisenda JC, Dominguez-Rubio R, Olivé M, Colomer J, Jou C, Jimenez-Mallebrera C, Bönnemann CG, Nascimento A
Neurology 2021 Mar 9;96(10):e1413-e1424. Epub 2021 Jan 13 doi: 10.1212/WNL.0000000000011499. PMID: 33441455Free PMC Article
Tiepolo T, Angelin A, Palma E, Sabatelli P, Merlini L, Nicolosi L, Finetti F, Braghetta P, Vuagniaux G, Dumont JM, Baldari CT, Bonaldo P, Bernardi P
Br J Pharmacol 2009 Jul;157(6):1045-52. Epub 2009 Jun 10 doi: 10.1111/j.1476-5381.2009.00316.x. PMID: 19519726Free PMC Article
Bernardi P, Bonaldo P
Ann N Y Acad Sci 2008 Dec;1147:303-11. doi: 10.1196/annals.1427.009. PMID: 19076452

Prognosis

Silverstein RS, Wang DD, Haruno LS, Lotze TE, Scott AC, Rosenfeld SB
J Pediatr Orthop 2023 Feb 1;43(2):e163-e167. Epub 2022 Oct 26 doi: 10.1097/BPO.0000000000002283. PMID: 36607927
Zhong J, Xie Y, Dang Y, Zhang J, Song Y, Lan D
Int J Mol Med 2021 Mar;47(3) Epub 2021 Feb 4 doi: 10.3892/ijmm.2021.4861. PMID: 33537799Free PMC Article
Kim SY, Kim WJ, Kim H, Choi SA, Lee JS, Cho A, Jang SS, Lim BC, Kim KJ, Kim JI, Hahn SH, Chae JH
Muscle Nerve 2018 Sep;58(3):381-388. doi: 10.1002/mus.26093. PMID: 29406609
Quijano-Roy S, Khirani S, Colella M, Ramirez A, Aloui S, Wehbi S, de Becdelievre A, Carlier RY, Allamand V, Richard P, Azzi V, Estournet B, Fauroux B
Neuromuscul Disord 2014 Feb;24(2):125-33. Epub 2013 Nov 16 doi: 10.1016/j.nmd.2013.11.002. PMID: 24314752
van der Kooi AJ, de Voogt WG, Bertini E, Merlini L, Talim FB, Ben Yaou R, Urtziberea A, de Visser M
Arch Neurol 2006 Nov;63(11):1617-21. doi: 10.1001/archneur.63.11.1617. PMID: 17101832

Clinical prediction guides

Bazrafshan S, Kushlaf H, Kakroo M, Quinlan J, Becker RC, Sadayappan S
Cells 2021 Feb 8;10(2) doi: 10.3390/cells10020349. PMID: 33567613Free PMC Article
Kim SY, Kim WJ, Kim H, Choi SA, Lee JS, Cho A, Jang SS, Lim BC, Kim KJ, Kim JI, Hahn SH, Chae JH
Muscle Nerve 2018 Sep;58(3):381-388. doi: 10.1002/mus.26093. PMID: 29406609
Deconinck N, Richard P, Allamand V, Behin A, Lafôret P, Ferreiro A, de Becdelievre A, Ledeuil C, Gartioux C, Nelson I, Carlier RY, Carlier P, Wahbi K, Romero N, Zabot MT, Bouhour F, Tiffreau V, Lacour A, Eymard B, Stojkovic T
J Neurol Neurosurg Psychiatry 2015 Dec;86(12):1337-46. Epub 2014 Dec 22 doi: 10.1136/jnnp-2013-307245. PMID: 25535305
Quijano-Roy S, Khirani S, Colella M, Ramirez A, Aloui S, Wehbi S, de Becdelievre A, Carlier RY, Allamand V, Richard P, Azzi V, Estournet B, Fauroux B
Neuromuscul Disord 2014 Feb;24(2):125-33. Epub 2013 Nov 16 doi: 10.1016/j.nmd.2013.11.002. PMID: 24314752
Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M, Messina S, Mercuri E, Franchella A, Ferlini A, Bonaldo P, Merlini L
Neurology 2009 Dec 1;73(22):1883-91. doi: 10.1212/WNL.0b013e3181c3fd2a. PMID: 19949035

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