Bethlem myopathy

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Bethlem myopathy
Other namesMuscular dystrophy, limb-girdle, autosomal dominant 5, (LGMDD5); Muscular dystrophy, limb-girdle, autosomal recessive 22, (LGMDR22); Ehlers–Danlos syndrome, myopathic type (EDSMYP)
Autosomal dominant - en.svg
Bethlem myopathy has an autosomal dominant pattern of inheritance (autosomal recessive form exists as well [1] ).

Bethlem myopathy is predominantly an autosomal dominant myopathy, classified as a congenital form of limb-girdle muscular dystrophy. [2] There are two types of Bethlem myopathy, based on which type of collagen is affected. [3]

Contents

Bethlem myopathy 1 (BTHLM1) is caused by a mutation in one of the three genes coding for type VI collagen. [4] [3] These include COL6A1, COL6A2, and COL6A3. [5] [3] It is typically autosomal dominant, though uncommonly can be autosomal recessive. [3]

Bethlem myopathy 2 (BTHLM2), formerly known as myopathic-type Ehlers–Danlos syndrome, is caused by a mutation on the COL12A1 gene coding for type XII collagen. [3] It is autosomal dominant. [3]

In 2017, an international workshop proposed a redefined criteria and naming system for limb-girdle muscular dystrophies. Bethlem myopathy 1 (collagen VI) was included into the proposed list and renamed LGMDD5 for autosomal dominant mutations and LGMDR22 for recessive mutations. Bethlem myopathy 2 (collagen XII) was not addressed. [2]

Gowers's sign, toe walking, multiple contractures of the joints (especially the fingers: 'Bethlem sign'), skin abnormalities, and muscle weakness (proximal more than distal) are typical signs and symptoms of the disease. Initially, in early childhood, there may also be joint laxity. There is no cardiac involvement in either Bethlem myopathy 1 or 2, which helps to differentiate it from Emery–Dreifuss muscular dystrophy. [6] Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. [7]

Bethlem myopathy may be diagnosed based on clinical examinations and laboratory tests may be recommended. Genetic testing for known pathological variants is preferred. In the case of a VUS, testing of dermal fibroblast culture is used for an accurate diagnosis. [6]

Bethlem myopathy 1 is a rare disease, affecting about 1 in 200,000 people. [8] Bethlem myopathy 2 is an ultra-rare disease, affecting less than 1 in 1,000,000 people. [9]

The condition was described by J. Bethlem and G. K. van Wijngaarden in 1976. [10]

Signs and symptoms

Individual demonstrates lack of finger contractures, thus lack of Bethlem sign, by being able to make full contact of palms and fingers with elbows raised. Gassho Meditation.jpg
Individual demonstrates lack of finger contractures, thus lack of Bethlem sign, by being able to make full contact of palms and fingers with elbows raised.

Bethlem myopathy is a slowly progressive muscle disease characterized predominantly by contractures, rigidity of the spine, skin abnormalities and proximal muscle weakness. [5] [11] Symptoms may present as early as infancy, with typical contractures and hyperlaxity of joints; however, in some patients, symptoms may go unnoticed until adolescence or adulthood. [11] Serum creatine kinase (CK) is usually normal to mildly elevated (<5×). [11]

Much like in this painting, Bethlem sign is an inability to make full contact of palms and fingers while elbows are raised, due to finger contractures. Cosme Tura 011.jpg
Much like in this painting, Bethlem sign is an inability to make full contact of palms and fingers while elbows are raised, due to finger contractures.

Early on, there may be distal laxity (hypermobility), but all of those with Bethlem myopathy eventually develop multiple joint contractures: long finger flexors, wrists, elbows, hips, knees and ankles. [5] [11] There may also be club foot, scoliosis or rigid spine. [5] [11] Skin abnormalities are common, including keloid formation, ‘cigarette paper scarring’ (atrophic scarring), velvety soft skin, and follicular hyperkeratosis. [11] [6]

'Bethlem sign' is the typical sign in Bethlem myopathy patients demonstrating long finger flexor contractures. With palms facing each other and with elbows raised, patients try, but fail, to make full contact of one hand against the other (in what looks like the gesture of hands during prayer). [12]

Bethlem myopathy 1

(Collagen VI genes)

See Bethlem myopathy 1 Clinical synopsis on OMIM: 158810

In Bethlem myopathy 1, in the calf, one of the first signs is often a 'rim' of fatty infiltration between the soleus and gastrocnemius muscles. [12] [13] [14] Although there is fatty infiltration, the calf muscles do not appear pseudohypertrophic, in fact they may appear slender. [15] [12] [16] [17] [18] In the thighs, there is also significant fatty infiltration of the vasti muscles, with a rim of fatty infiltration on the periphery of the muscles, while the center is more or less spared (characteristic "outside-in" pattern). [12] [19] This "outside-in" pattern distinguishes it from other myopathies known to have contractures, such as Emery-Dreifuss muscular dystrophy. [12]

The exception is the rectus femoris muscle of the thigh, where fatty infiltration occurs in the center of the muscle, but spares the periphery. This unusual pattern is described as a "central cloud" and is also a distinguishing feature, as it is not seen in the rectus femoris of LMNA-related Emery-Dreifuss myopathy. [12]

Bethlem myopathy 1 may also include neonatal-onset torticollis (neck contracture) and hypotonia ("floppy baby"), delayed motor mile stones, with respiratory difficulties potentially occurring later in life. [20] [12] Contractures presenting in infancy may resolve by age 2 years, but reoccur as the disease progresses, typically by late of the first decade or early teens. [12]

Bethlem myopathy 2

(Collagen XII gene)

See Bethlem myopathy 2 Clinical synopsis on OMIM: 616471

In Bethlem myopathy 2, there is phenotypic variability. In one family, the only notable finding on T1-weighted MR images (used to detect fatty infiltration) was atrophy of the rectus femoris muscles of the thigh, with the degree of atrophy matching the severity of the disease, but no fatty infiltration. [14] [11] In another family, only the more severely affected older patient showed significant abnormality, by having symmetrical fatty atrophy of the femoral quadriceps of the thigh, the adductor and medial gastrocnemius muscles of the calf; as well as asymmetrical fatty atrophy of the adductor longus of the thigh. [11] No muscle hypertrophy was reported and the muscles of the patients without fatty atrophy appeared normal. [11]

Bethlem myopathy 2 also differs by including the possibility of scapula winging, pectus excavatum, stooped posture, kyphosis (hunchback), micrognathia, retrognathia, and a high-arched palate. [14] Childhood muscle weakness improves in teen years, but muscle weakness returns by the third decade of life. [11]

Diagnosis

The disease may be diagnosed based on a clinical examination, which identifies signs and symptoms generally associated with the people who have the condition. Genetic testing for known pathological variants is preferred, by testing of the COL6A1, COL6A2, COL6A3 and COL12A1 genes. [7] [3] In the case of a VUS, testing of dermal fibroblast culture is used for an accurate diagnosis. [6]

Additional laboratory tests may be performed before genetic testing, such as creatine kinase (CK) blood test, MRI of the muscles, and electromyography (EMG).

Phenotypes of overlap between Ullrich congenital muscular dystrophy (UCMD) and Bethlem can be assumed. In the differential diagnosis of UCMD, even in patients without finger contractures, Bethlem myopathy could be considered. [21]

Differential diagnosis

Ullrich congenital muscular dystrophy (UCMD) involves mutations on the same genes as Bethlem myopathy, but has a more severe presentation, with the ability to walk (ambulation) typically being lost between the ages of 5–15 years. [12] Autosomal recessive myosclerosis myopathy is allelic to the COL6A2 gene, it includes multiple contractures of the joints with slender muscles which are infiltrated by connective tissue and fibrosis, giving them a firm, "woody" feel upon palpitation. [22] [23]

The symptoms of Bethlem myopathy may overlap with other conditions including Emery–Dreifuss muscular dystrophy, congenital muscular dystrophies, limb girdle muscular dystrophies, FHL1 -related myopathies (X-linked myopathy with postural muscle atrophy, reducing body myopathy, and scapuloperoneal myopathy), and some forms of Ehlers–Danlos syndrome. [11] Tubular aggregate myopathy (TAM1 & TAM2) includes, among other symptoms, contractures, muscle weakness, and fatty atrophy of muscle. [24] [25] [26]

Typical to Bethlem myopathy 1 and 2 are the presence of multiple contractures. [11] [5] A contracture can be caused by a variety of reasons, from disease to lifestyle (see Muscle contractures ). If the patient lacks multiple contractures, as well as lacks other common symptoms of Bethlem myopathy, and in addition has muscular symptoms which are not known to be associated with Bethlem myopathy such as muscle hypertrophy, exercise-induced (dynamic) symptoms rather than fixed muscle weakness (static) symptoms, or cardiac involvement such as arrhythmia, then other myopathies should be considered.

Treatment

Currently there is no cure for the disease. Symptomatic treatment, which aims to relieve symptoms and improve quality of life is the main treatment method of Bethlem myopathy. It is believed that physical therapy, stretching exercises, orthoses such as braces and splints, and mobility aids like a walker or wheelchair are beneficial to patient's condition. [7]

Surgical options could be considered in rare instances, in order to help with joint contractures or scoliosis. [7] Contractures of the legs can be alleviated with heel-cord surgery followed by bracing and regular physical therapy. Repeated surgeries to lengthen the heel cords may be needed as the child grows to adulthood. [4]

Epidemiology

According to a Japanese study from 2007, Bethlem myopathy 1 affects about 1 in 200,000 people. [8] A 2009 study, concerning the prevalence of genetic muscle disease in Northern England, estimated the prevalence of Bethlem myopathy 1 to be at 0.77:100,000. [27] Together with Ullrich congenital muscular dystrophy 1, Bethlem myopathy 1 is believed to be underdiagnosed. Both conditions have been described in individuals from a variety of ethnic backgrounds. [28] Bethlem myopathy 2 affects less than 1 in 1,000,000 people. [9]

Related Research Articles

<span class="mw-page-title-main">Muscular dystrophy</span> Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

<span class="mw-page-title-main">Glycogen storage disease</span> Medical condition

A glycogen storage disease is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.

<span class="mw-page-title-main">Limb–girdle muscular dystrophy</span> Medical condition

Limb–girdle muscular dystrophy (LGMD) is a genetically heterogeneous group of rare muscular dystrophies that share a set of clinical characteristics. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles. LGMD usually has an autosomal pattern of inheritance. It currently has no known cure or treatment.

Hereditary inclusion body myopathies (HIBM) are a group of rare genetic disorders which have different symptoms. Generally, they are neuromuscular disorders characterized by muscle weakness developing in young adults. Hereditary inclusion body myopathies comprise both autosomal recessive and autosomal dominant muscle disorders that have a variable expression (phenotype) in individuals, but all share similar structural features in the muscles.

<span class="mw-page-title-main">Mitochondrial myopathy</span> Medical condition

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

<span class="mw-page-title-main">Congenital muscular dystrophy</span> Medical condition

Congenital muscular dystrophies are autosomal recessively-inherited muscle diseases. They are a group of heterogeneous disorders characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place.

<span class="mw-page-title-main">Emery–Dreifuss muscular dystrophy</span> Medical condition

Emery–Dreifuss muscular dystrophy (EDMD) is a type of muscular dystrophy, a group of heritable diseases that cause progressive impairment of muscles. EDMD affects muscles used for movement, causing atrophy, weakness and contractures. It almost always affects the heart, causing abnormal rhythms, heart failure, or sudden cardiac death. It is rare, affecting 0.39 per 100,000 people. It is named after Alan Eglin H. Emery and Fritz E. Dreifuss.

<span class="mw-page-title-main">NIM811</span> Chemical compound

NIM811 is a mitochondrial permeability transition inhibitor. Also known as N-methyl-4-isoleucine cyclosporin, it is a four-substituted cyclosporine analogue that binds to cyclophilin, however this binary complex cannot bind to calcineurin, and therefore lacks immunosuppressive activity.

<span class="mw-page-title-main">Collagen, type VI, alpha 1</span> Protein found in humans

Collagen alpha-1(VI) chain is a protein that in humans is encoded by the COL6A1 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 2</span> Protein found in humans

Collagen alpha-2(VI) chain is a protein that in humans is encoded by the COL6A2 gene.

<span class="mw-page-title-main">Collagen, type VI, alpha 3</span> Mammalian protein found in humans

Collagen alpha-3(VI) chain is a protein that in humans is encoded by the COL6A3 gene. This protein is an alpha chain of type VI collagen that aids in microfibril formation. As part of type VI collagen, this protein has been implicated in Bethlem myopathy, Ullrich congenital muscular dystrophy (UCMD), and other diseases related to muscle and connective tissue.

<span class="mw-page-title-main">Muscle contracture</span> Permanent shortening of a muscle

Muscle contractures can occur for many reasons, such as paralysis, muscular atrophy, and forms of muscular dystrophy. Fundamentally, the muscle and its tendons shorten, resulting in reduced flexibility.

<span class="mw-page-title-main">X-linked spinal muscular atrophy type 2</span> Medical condition

X-linked spinal muscular atrophy type 2, also known as arthrogryposis multiplex congenita X-linked type 1 (AMCX1), is a rare neurological disorder involving death of motor neurons in the anterior horn of spinal cord resulting in generalised muscle wasting (atrophy). The disease is caused by a mutation in UBA1 gene and is passed in an X-linked recessive manner by carrier mothers to affected sons.

<span class="mw-page-title-main">Ullrich congenital muscular dystrophy</span> Medical condition

Ullrich congenital muscular dystrophy (UCMD) is a form of congenital muscular dystrophy. There are two forms: UCMD1 and UCMD2.

Collagen VI (ColVI) is a type of collagen primarily associated with the extracellular matrix of skeletal muscle. ColVI maintains regularity in muscle function and stabilizes the cell membrane. It is synthesized by a complex, multistep pathway that leads to the formation of a unique network of linked microfilaments located in the extracellular matrix (ECM). ColVI plays a vital role in numerous cell types, including chondrocytes, neurons, myocytes, fibroblasts, and cardiomyocytes. ColVI molecules are made up of three alpha chains: α1(VI), α2(VI), and α3(VI). It is encoded by 6 genes: COL6A1, COL6A2, COL6A3, COL6A4, COL6A5, and COL6A6. The chain lengths of α1(VI) and α2(VI) are about 1,000 amino acids. The chain length of α3(VI) is roughly a third larger than those of α1(VI) and α2(VI), and it consists of several spliced variants within the range of 2,500 to 3,100 amino acids.

<span class="mw-page-title-main">Pseudohypertrophy</span> False enlargement of muscle due to infiltration of fat or other tissue

Pseudohypertrophy, or false enlargement, is an increase in the size of an organ due to infiltration of a tissue not normally found in that organ. It is commonly applied to enlargement of a muscle due to infiltration of fat or connective tissue, famously in Duchenne muscular dystrophy. This is in contrast with typical muscle hypertrophy, in which the muscle tissue itself increases in size. Because pseudohypertrophy is not a result of increased muscle tissue, the muscles look bigger but are actually atrophied and thus weaker. Pseudohypertrophy is typically the result of a disease, which can be a disease of muscle or a disease of the nerve supplying the muscle.

<span class="mw-page-title-main">Pseudoathletic appearance</span> Medical sign

Pseudoathletic appearance is a medical sign meaning to have the false appearance of a well-trained athlete due to pathologic causes instead of true athleticism. It is also referred to as a Herculean or bodybuilder-like appearance. It may be the result of muscle inflammation, muscle hyperplasia, muscle hypertrophy, muscle pseudohypertrophy, or symmetrical subcutaneous deposits of fat or other tissue.

Rigid spine syndrome, also known as congenital muscular dystrophy with rigidity of the spine (CMARS), is a rare and often debilitating neuromuscular disorder. It is characterized by progressive muscle stiffness and rigidity, particularly in the spine, which can severely limit mobility and impact quality of life. This condition is typically present from birth or early childhood and tends to worsen over time.

<span class="mw-page-title-main">LAMA2 related congenital muscular dystrophy</span> Medical condition neuromuscular disorders

LAMA2 muscular dystrophy (LAMA2-MD) is a genetically determined muscle disease caused by pathogenic mutations in the LAMA2 gene. It is a subtype of a larger group of genetic muscle diseases known collectively as congenital muscular dystrophies. The clinical presentation of LAMA2-MD varies according to the age at presentation. The severe forms present at birth and are known as early onset LAMA2 congenital muscular dystrophy type 1A or MDC1A. The mild forms are known as late onset LAMA2 muscular dystrophy or late onset LAMA2-MD. The nomenclature LGMDR23 can be used interchangeably with late onset LAMA2-MD.

References

  1. ↑ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Bethlem myopathy". www.orpha.net. Retrieved 23 December 2017.{{cite web}}: CS1 maint: numeric names: authors list (link)
  2. 1 2 Straub, Volker; Murphy, Alexander; Udd, Bjarne; LGMD workshop study group (August 2018). "229th ENMC international workshop: Limb girdle muscular dystrophies - Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017". Neuromuscular Disorders. 28 (8): 702–710. doi: 10.1016/j.nmd.2018.05.007 . ISSN   1873-2364. PMID   30055862.
  3. 1 2 3 4 5 6 7 "Phenotypic Series - PS158810 Bethlem myopathy - PS158810 - 4 Entries". OMIM - Online Mendelian Inheritance in Man.
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  9. 1 2 "Myopathic EDS (mEDS)". The Ehlers Danlos Society. Retrieved 2023-05-01.
  10. ↑ "Entry - #158810 - BETHLEM MYOPATHY 1; BTHLM1 - OMIM". Online Mendelian Inheritance in Man . Retrieved 2023-09-15.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 Hicks, D.; Farsani, G. T.; Laval, S.; Collins, J.; Sarkozy, A.; Martoni, E.; Shah, A.; Zou, Y.; Koch, M.; Bonnemann, C. G.; Roberts, M.; Lochmuller, H.; Bushby, K.; Straub, V. (2014-05-01). "Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy". Human Molecular Genetics. 23 (9): 2353–2363. doi: 10.1093/hmg/ddt637 . ISSN   0964-6906. PMID   24334769.
  12. 1 2 3 4 5 6 7 8 9 Bönnemann, Carsten G. (2011-06-21). "The collagen VI-related myopathies: muscle meets its matrix". Nature Reviews. Neurology. 7 (7): 379–390. doi:10.1038/nrneurol.2011.81. ISSN   1759-4758. PMC   5210181 . PMID   21691338.
  13. ↑ Morrow, Jasper M.; Pitceathly, Robert D. S.; Quinlivan, Ros M.; Yousry, Tarek A. (2013-04-16). "Muscle MRI in Bethlem myopathy". BMJ Case Reports. 2013: bcr2013008596. doi:10.1136/bcr-2013-008596. ISSN   1757-790X. PMC   3645630 . PMID   23595177.
  14. 1 2 3 "# 616471 BETHLEM MYOPATHY 2; BTHLM2 Alternative titles; symbols EHLERS-DANLOS SYNDROME, MYOPATHIC TYPE; EDSMYP EDS, MYOPATHIC TYPE". OMIM - Online Mendelian Inheritance in Man.
  15. ↑ Nalini, A; Gayathri, N (2010). "Bethlem myopathy: A study of two families". Neurology India. 58 (4): 665–666. doi: 10.4103/0028-3886.68684 . ISSN   0028-3886. PMID   20739820.
  16. ↑ Suh, B.; Choi, Young-Chul; Kim, S. M.; Choi, Byung-Ok; Shim, D.; Lee, D. H.; Sunwoo, I. (2006). "A Family of Bethlem Myopathy". Journal of the Korean Neurological Association. S2CID   74251729.
  17. ↑ Souza, Paulo Victor Sgobbi de; Bortholin, Thiago; Pinheiro, Jhonatan Rafael Siqueira; Naylor, Fernando George Monteiro; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bulle (2017-10-01). "Collagen type VI-related myopathy". Practical Neurology. 17 (5): 406–407. doi:10.1136/practneurol-2017-001661. ISSN   1474-7758. PMID   28578317. S2CID   755149.
  18. ↑ Telles, Juliana Aparecida Rhein; Voos, Mariana Calil; Anequini, Isabella Pessa; Favero, Francis Meire; Silva, Thiago Henrique; Caromano, Fátima Aparecida (June 2018). "Genetic and functional differences between Bethlem miopathyand Ullrich congenital muscular dystrophy - case studies". Cadernos de Pós-Graduação em Distúrbios do Desenvolvimento. 18 (1): 148–163. doi:10.5935/cadernosdisturbios.v18n1p148-163. ISSN   1519-0307.
  19. ↑ Mercuri, Eugenio; Lampe, Anne; Allsop, Joanna; Knight, Ravi; Pane, Marika; Kinali, Maria; Bonnemann, Carsten; Flanigan, Kevin; Lapini, Ilaria; Bushby, Kate; Pepe, Guglielmina; Muntoni, Francesco (April 2005). "Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy". Neuromuscular Disorders. 15 (4): 303–310. doi:10.1016/j.nmd.2005.01.004. ISSN   0960-8966. PMID   15792870. S2CID   25600853.
  20. ↑ "BETHLEM MYOPATHY 1; BTHLM1". www.omim.org. Retrieved 2023-09-30.
  21. ↑ Reed, Umbertina Conti; Ferreira, Lucio Gobbo; Liu, Enna Cristina; Resende, Maria Bernadete Dutra; Carvalho, Mary Souza; Marie, Suely Kazue; Scaff, Milberto (September 2005). "Ullrich congenital muscular dystrophy and bethlem myopathy: clinical and genetic heterogeneity". Arquivos de Neuro-Psiquiatria. 63 (3B): 785–790. doi: 10.1590/S0004-282X2005000500013 . ISSN   0004-282X. PMID   16258657.
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  24. ↑ "MYOPATHY, TUBULAR AGGREGATE, 1; TAM1". www.omim.org. Retrieved 2023-11-11.
  25. ↑ "MYOPATHY, TUBULAR AGGREGATE, 2; TAM2". www.omim.org. Retrieved 2023-11-11.
  26. ↑ "Tubular aggregate myopathy - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Retrieved 2023-11-11.
  27. ↑ Norwood, Fiona L. M.; Harling, Chris; Chinnery, Patrick F.; Eagle, Michelle; Bushby, Kate; Straub, Volker (2009). "Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population". Brain: A Journal of Neurology. 132 (Pt 11): 3175–3186. doi:10.1093/brain/awp236. ISSN   1460-2156. PMC   4038491 . PMID   19767415.
  28. ↑ Lampe, Anne Katrin; Flanigan, Kevin M.; Bushby, Katharine Mary; Hicks, Debbie (1993). "Collagen VI-Related Dystrophies". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.). Collagen Type VI-Related Disorders. Seattle (WA): University of Washington, Seattle. PMID   20301676 . Retrieved 2020-10-19.{{cite book}}: |work= ignored (help)
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