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Bethlem myopathy(BTHLM1; LGMDD5)

MedGen UID:
331805
Concept ID:
C1834674
Disease or Syndrome
Synonyms: Benign Congenital Muscular Dystrophy; Benign Congenital Myopathy with Contractures; Muscular dystrophy, benign congenital; Myopathy, benign congenital, with contractures
SNOMED CT: Bethlem myopathy (718572004); Benign autosomal dominant myopathy (718572004)
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.
 
Monarch Initiative: MONDO:0008029
OMIM®: 120220; 120240; 120250; 158810
OMIM® Phenotypic series: PS158810
Orphanet: ORPHA610

Definition

Bethlem myopathy-1 (BTHLM1) is a congenital muscular dystrophy characterized by distal joint laxity and a combination of distal and proximal joint contractures. Weakness usually begins in mid-childhood or adolescence, but progression is slow and ambulation is retained into adulthood (summary by Butterfield et al., 2013). Genetic Heterogeneity of Bethlem Myopathy Bethlem myopathy-2 (BTHLM2; 616471) is caused by mutation in the COL12A1 gene (120320) on chromosome 6q. [from OMIM]

Additional description

From MedlinePlus Genetics
Individuals with collagen VI-related dystrophy often have signs and symptoms of multiple forms of this condition, so it can be difficult to assign a specific diagnosis. The overlap in disease features, in addition to their common cause, is why these once separate conditions are now considered part of the same disease spectrum.

People with Ullrich congenital muscular dystrophy have severe muscle weakness beginning soon after birth. Some affected individuals are never able to walk and others can walk only with support. Those who can walk often lose the ability, usually in early adolescence. Individuals with Ullrich congenital muscular dystrophy develop contractures in their shoulders, elbows, hips, and knees, which further impair movement. Many individuals with this form of the condition have loose joints (joint laxity) in the fingers, wrists, toes, ankles, and other joints. Affected individuals need continuous mechanical ventilation to help them breathe while sleeping, and some may need it in the daytime. As in Bethlem muscular dystrophy, some people with Ullrich congenital muscular dystrophy have follicular hyperkeratosis; soft, velvety skin on the palms and soles; and abnormal wound healing.

The intermediate form of collagen VI-related dystrophy is characterized by muscle weakness that begins in infancy. Affected children are able to walk, although walking becomes increasingly difficult starting in early adulthood. They develop contractures in their fingers, elbows, shoulders, and ankles in childhood. In some affected people, the respiratory muscles are weakened, requiring people to use a machine to help them breathe (mechanical ventilation), particularly during sleep.

People with Bethlem muscular dystrophy usually have low muscle tone (hypotonia) in infancy. Muscle weakness can begin at any age but often appears in childhood to early adulthood. The muscle weakness is slowly progressive, with about two-thirds of affected individuals over age 50 needing walking assistance, particularly when outdoors. Affected individuals usually develop contractures by adulthood, typically in their fingers, elbows, shoulders, and ankles. Older individuals may develop weakness in respiratory muscles, which can cause breathing problems. Some people with this mild form of collagen VI-related dystrophy have skin abnormalities, including small bumps called follicular hyperkeratosis on the arms and legs; soft, velvety skin on the palms of the hands and soles of the feet; and abnormal wound healing that creates shallow scars.

Collagen VI-related dystrophy is a group of disorders that affect skeletal muscles (which are the muscles used for movement) and connective tissue (which provides strength and flexibility to the skin, joints, and other structures throughout the body). Most affected individuals have muscle weakness and joint deformities called contractures that restrict movement of the affected joints and worsen over time. Researchers have described several forms of collagen VI-related dystrophy, which range in severity: Bethlem muscular dystrophy is the mildest, an intermediate form is moderate in severity, and Ullrich congenital muscular dystrophy is the most severe.  https://medlineplus.gov/genetics/condition/collagen-vi-related-myopathy

Clinical features

From HPO
Ankle flexion contracture
MedGen UID:
332440
Concept ID:
C1837407
Anatomical Abnormality
Limb-girdle muscle weakness
MedGen UID:
347625
Concept ID:
C1858127
Finding
Weakness of the limb-girdle muscles (also known as the pelvic and shoulder girdles), that is, lack of strength of the muscles around the shoulders and the pelvis.
Abnormality of the cardiovascular system
MedGen UID:
116727
Concept ID:
C0243050
Congenital Abnormality
Any abnormality of the cardiovascular system.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Myopathy
MedGen UID:
10135
Concept ID:
C0026848
Disease or Syndrome
A disorder of muscle unrelated to impairment of innervation or neuromuscular junction.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Elbow flexion contracture
MedGen UID:
98367
Concept ID:
C0409338
Acquired Abnormality
An elbow contracture that limits the ability of the elbow joint to be extended (straightened), meaning that the elbow is fixed in an flexed (bent) position.
Camptodactyly of finger
MedGen UID:
98041
Concept ID:
C0409348
Finding
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers cannot be extended to 180 degrees by either active or passive extension.
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).
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
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.
Congenital muscular torticollis
MedGen UID:
86902
Concept ID:
C0079352
Congenital Abnormality
A congenital form of torticollis resulting from shortening of the sternocleidomastoid muscle and leading to a limited range of motion in both rotation and lateral bending.
Decreased fetal movement
MedGen UID:
68618
Concept ID:
C0235659
Finding
An abnormal reduction in quantity or strength of fetal movements.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVBethlem myopathy
Follow this link to review classifications for Bethlem myopathy in Orphanet.

Professional guidelines

PubMed

Kwong AK, Zhang Y, Ho RS, Gao Y, Ling X, Tsang MH, Luk HM, Chung BH, Bönnemann CG, Javed A, Chan SH
Neuromuscul Disord 2023 May;33(5):371-381. Epub 2023 Mar 12 doi: 10.1016/j.nmd.2023.03.003. PMID: 37023487
Voermans NC, Bonnemann CG, Hamel BC, Jungbluth H, van Engelen BG
J Neurol 2009 Jan;256(1):13-27. Epub 2009 Feb 9 doi: 10.1007/s00415-009-0105-1. PMID: 19221853

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
Caria F, Cescon M, Gualandi F, Pichiecchio A, Rossi R, Rimessi P, Cotti Piccinelli S, Gallo Cassarino S, Gregorio I, Galvagni A, Ferlini A, Padovani A, Bonaldo P, Filosto M
Neuromuscul Disord 2019 Sep;29(9):657-663. Epub 2019 Jul 30 doi: 10.1016/j.nmd.2019.07.007. PMID: 31471117
Panadés-de Oliveira L, Rodríguez-López C, Cantero Montenegro D, Marcos Toledano MDM, Fernández-Marmiesse A, Esteban Pérez J, Hernández Lain A, Domínguez-González C
J Neurol 2019 Apr;266(4):934-941. Epub 2019 Jan 31 doi: 10.1007/s00415-019-09217-z. PMID: 30706156
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
Voermans NC, Bonnemann CG, Hamel BC, Jungbluth H, van Engelen BG
J Neurol 2009 Jan;256(1):13-27. Epub 2009 Feb 9 doi: 10.1007/s00415-009-0105-1. PMID: 19221853

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
Panadés-de Oliveira L, Rodríguez-López C, Cantero Montenegro D, Marcos Toledano MDM, Fernández-Marmiesse A, Esteban Pérez J, Hernández Lain A, Domínguez-González C
J Neurol 2019 Apr;266(4):934-941. Epub 2019 Jan 31 doi: 10.1007/s00415-019-09217-z. PMID: 30706156
Jfri A, Alajmi A
Dermatology 2018;234(3-4):127-130. Epub 2018 Aug 16 doi: 10.1159/000491924. PMID: 30114700
Bushby KM, Collins J, Hicks D
Adv Exp Med Biol 2014;802:185-99. doi: 10.1007/978-94-007-7893-1_12. PMID: 24443028
Lampe AK, Bushby KM
J Med Genet 2005 Sep;42(9):673-85. doi: 10.1136/jmg.2002.002311. PMID: 16141002Free PMC Article

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
Castagnaro S, Pellegrini C, Pellegrini M, Chrisam M, Sabatelli P, Toni S, Grumati P, Ripamonti C, Pratelli L, Maraldi NM, Cocchi D, Righi V, Faldini C, Sandri M, Bonaldo P, Merlini L
Autophagy 2016 Dec;12(12):2484-2495. Epub 2016 Sep 22 doi: 10.1080/15548627.2016.1231279. PMID: 27656840Free PMC Article
Bernardi P, Bonaldo P
Ann N Y Acad Sci 2008 Dec;1147:303-11. doi: 10.1196/annals.1427.009. PMID: 19076452
Merlini L, Bernardi P
Neurotherapeutics 2008 Oct;5(4):613-8. doi: 10.1016/j.nurt.2008.08.004. PMID: 19019314Free PMC Article
Hicks D, Lampe AK, Barresi R, Charlton R, Fiorillo C, Bonnemann CG, Hudson J, Sutton R, Lochmüller H, Straub V, Bushby K
Neurology 2008 Apr 1;70(14):1192-9. doi: 10.1212/01.wnl.0000307749.66438.6d. PMID: 18378883

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
Panadés-de Oliveira L, Rodríguez-López C, Cantero Montenegro D, Marcos Toledano MDM, Fernández-Marmiesse A, Esteban Pérez J, Hernández Lain A, Domínguez-González C
J Neurol 2019 Apr;266(4):934-941. Epub 2019 Jan 31 doi: 10.1007/s00415-019-09217-z. PMID: 30706156
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
Finsterer J, Stöllberger C
Scand Cardiovasc J 2008 Feb;42(1):9-24. doi: 10.1080/14017430701854953. PMID: 18273731
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
Antoniel M, Traina F, Merlini L, Andrenacci D, Tigani D, Santi S, Cenni V, Sabatelli P, Faldini C, Squarzoni S
Cells 2020 Feb 11;9(2) doi: 10.3390/cells9020409. PMID: 32053901Free 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
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
Voermans NC, Bonnemann CG, Hamel BC, Jungbluth H, van Engelen BG
J Neurol 2009 Jan;256(1):13-27. Epub 2009 Feb 9 doi: 10.1007/s00415-009-0105-1. PMID: 19221853

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