Congenital myopathy

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Congenital Myopathy
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Congenital myopathy is a very broad term for any muscle disorder present at birth. This defect primarily affects skeletal muscle fibres and causes muscular weakness and/or hypotonia. Congenital myopathies account for one of the top neuromuscular disorders in the world today, comprising approximately 6 in 100,000 live births every year. [1] As a whole, congenital myopathies can be broadly classified as follows:

Contents

Classification

Myopathies with inclusion bodies and abnormal protein accumulation

Congenital myopathies with inclusion bodies and protein accumulation is a broad category, and some congenital myopathies that fall within this group are well understood, such as nemaline myopathy (see below). Typically, the development error in this category occurs when muscle proteins aggregate and build up in the sarcoplasm, which leads to muscle dysfunction.[ citation needed ]

Myopathies with cores

'Core myopathies' such as multicore myopathy and central core disease are characterized by sharply-demarcated areas devoid of oxidative enzymes NADH, SDH, and COX, in muscle fibres.[ citation needed ]

Myopathies with central nuclei

Myopathies with central nuclei, such as myotubular myopathy, involves an error in the gene involved in vesicle movement throughout the cell. This creates problems in vesicles reaching the plasma membrane with the cellular components necessary to fuse myoblast, a major step in the formation of the skeletal muscle. This creates structural problems throughout the skeletal muscle and in the Z line of the sarcomere, creating the weakness in the muscle. [2]

Myopathies with fiber size variation

Myopathies with varying fiber size, such as congenital fiber type disproportion, occurs when type 1 fibers, the slow twitch fibers involved in sustaining activity, are smaller than type 2 fibers, the fast twitch fibers involved in quick activity. Since smaller type 1 fibers is not associated with nemaline myopathy, the most common type of congenital myopathy, it has not been studied in as great detail as many of the others. However, the smaller type 1 fibers explains why patients typically can participate in activities for shorter periods of time, but struggle with extended activity. [2]

Cause

Diagnosis

There are rarely any specific tests for the congenital myopathies except for muscle biopsy. Tests can be run to check creatine kinase in the blood, which is often normal or mildly elevated in congenital myopathies. Electromyography can be run to check the electrical activity of the muscle. Diagnosis heavily relies on muscle pathology, where a muscle biopsy is visualised on the cellular level. Diagnosis usually relies on this method, as creatine kinase levels and electromyography can be unreliable and non-specific. [3] Since congenital myopathies are genetic, there have been advancements in prenatal screenings. [2]

Types

The conditions included under the term "congenital myopathy" can vary. One source includes nemaline myopathy, myotubular myopathy, central core myopathy, congenital fiber type disproportion, and multicore myopathy. [4] The term can also be used more broadly, to describe conditions present from birth.[ citation needed ]

Nemaline myopathy

Nemaline myopathy was first described in 1963 [5] and is the most common congenital myopathy. It is characterized by generalized muscle weakness and low muscle tone. In its severest form, affected babies often die from respiratory failure. [6] To date, 9 gene mutations have been found to cause nemaline myopathy. 6 of the identified genes are associated with the actin filament, which is the basis for muscle contraction. Histologically, nemaline rods stain red with Gomori's trichrome and are mostly seen in the subsarcolemmal region of muscle fibres. [7] Nemaline rods have also been observed in the intermyofibrillar region of muscle fibres and within the nucleus. [8] Nemaline myopathy is an autosomal dominant and sometimes an autosomal recessive genetic disorder. Sporadic cases have also been described.[ citation needed ]

Myotubular myopathy

Myotubular myopathy, also known as centronuclear myopathy, is recognized by pain during exercise and difficulty walking. People affected by this disease typically are wheelchair-reliant by middle adulthood, have weakness in the muscles involved in eye movement, nerve function disorders, and some form of intellectual disability. Myotubular myopathy is very rare, with less than 50 families currently affected. Genetically, myotubular myopathy can have two causes: autosomal dominant and autosomal recessive. When caused by a mutation in the DNM2 gene, the disorder is autosomal dominant, meaning it can be passed on by one mutated gene. When the mutation takes place in the BIN1 gene, the disease is instead autosomal recessive, and both genes must be mutated for the disease to be inherited. Autosomal recessive onset is most common. [9]

Central core disease

Central core disease or central core myopathy was first described in 1956 [10] and usually presents in infancy or early childhood as non-progressive mild proximal weakness that persists throughout life. Central core disease is believed to be more prevalent than currently reported, as it is hard to recognize and often misdiagnosed in early childhood. [1] Central core disease has been found to be allelic with malignant hyperthermia, [11] which is a life-threatening anesthetic reaction that causes a rise in body temperature, muscular rigidity and muscular breakdown, grossly elevated creatine kinase, and acidosis. Central core disease is caused by a mutation in the RYR1 gene. [1]

Congenital fiber type disproportion

Congenital fiber type disproportion affects skeletal muscle, typically causing weakness in the shoulders, upper arms, thighs, and hips. Skeletal muscle is made up of two kinds of fiber, type 1 and type 2. In congenital fiber type disproportion, type 1 fibers are not only smaller but often more abundant than type 2 fibers. [12] This leads to affected individuals being able to maintain an active lifestyle, though they usually have lower levels of stamina. [13] Severity with this disease varies greatly, but people typically present symptoms by the age of one. Individuals do not usually worsen with time, and cases have even been reported of improvements. [13]

Multicore myopathy

Multicore myopathy also referred to as minicore myopathy, is associated with small areas of decreased oxidative activities, resulting in areas that appear in this histology as "cores". These appear through microscopy very similar to central core, however the cores are typically smaller in multicore myopathy. As with congenital fiber type disproportion, patients have a greater number of type 1 fibers. Overall, approximately half of diagnosed individuals report no progression of muscle weakness, while half report a very slow progression. [14]

Cylindrical spirals myopathy

Cylindrical spirals myopathy is very rare with only 18 individual cases described as of 2013. The majority of cases are sporadic, and has been observed in only 3 families. It is characterized by the presence of cylindrical spirals as the main pathological finding in muscle biopsies. Cylindrical spirals are unusual membrane structures that have a spiral pattern. These membrane structures are seen during electron microscopic examination of the affected muscle. These structures merge into or are surrounded by tubular structures that resemble tubular aggregates. Tubular aggregates are abnormal accumulations of membranous tubules and have been observed in a wide variety of muscle diseases and originate from the sarcoplasmic reticulum. [15] Cylindrical spirals were first described in 1979 and were thought to be a non-specific reaction of skeletal muscle secondary to a metabolic disturbance or muscle fibre injury. [16] The molecular basis of cylindrical spiral myopathy is currently unknown, however a genetic mutation affecting the sarcoplasmic reticulum in some patients seems likely, as SERCA1, calsequestrin, and RYR1 have been shown to bind to cylindrical spirals. [17] Cylindrical spirals have also been shown to react with the mitochondrial enzyme succinate dehydrogenase, [18] which suggests that cylindrical spirals originate from mitochondria.

Phenotypes are quite variable, and manifestations can include weakness, abnormal gait, myotonia, cramps, and scoliosis. [19] [20] [21]

Myosin storage myopathy

In myosin storage myopathies, myosin accumulates beneath sarcolemma and between myofibrils, forming protein aggregates. [22] A myopathy associated with the gene MYH7 is autosomal dominant myosin storage congenital myopathy-7A (CMYP7A). [22] [23]

Tubular aggregate myopathy

Although tubular aggregates are seen in a variety of myopathies, both genetic and environmental, [24] [25] the congenital myopathies associated with genes STIM1 and ORAI1 are known as tubular aggregate myopathy (TAM) types 1 and 2. [23] [26]

Treatment

Currently, there are no treatments for any of the congenital myopathies. Depending on the severity, there are different therapies available to help alleviate any pain and aid patients in performing varying activities. For example, many congenital myopathy patients are involved in physical or occupational therapy in an attempt to strengthen their skeletal muscles. Orthopedic surgery is usually necessary to correct skeletal deformities secondary to muscle weakness, such as scoliosis. Survival is typically determined by the level of respiratory muscle insufficiency. [2]

Related Research Articles

<span class="mw-page-title-main">Myasthenia gravis</span> Autoimmune disease resulting in skeletal muscle weakness

Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, and difficulties in talking and walking. Onset can be sudden. Those affected often have a large thymus or develop a thymoma.

<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.

Myotonia is a symptom of a small handful of certain neuromuscular disorders characterized by delayed relaxation of the skeletal muscles after voluntary contraction or electrical stimulation, and the muscle shows an abnormal EMG.

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. Myopathy means muscle disease. This meaning implies that the primary defect is within the muscle, as opposed to the nerves or elsewhere.

Nemaline myopathy is a congenital, often hereditary neuromuscular disorder with many symptoms that can occur such as muscle weakness, hypoventilation, swallowing dysfunction, and impaired speech ability. The severity of these symptoms varies and can change throughout one's life to some extent. The prevalence is estimated at 1 in 50,000 live births. It is the most common non-dystrophic myopathy.

Myotonia congenita is a congenital neuromuscular channelopathy that affects skeletal muscles. It is a genetic disorder. The hallmark of the disease is the failure of initiated contraction to terminate, often referred to as delayed relaxation of the muscles (myotonia) and rigidity. Symptoms include delayed relaxation of the muscles after voluntary contraction (myotonia), and may also include stiffness, hypertrophy (enlargement), transient weakness in some forms of the disorder, severe masseter spasm, and cramping. The condition is sometimes referred to as fainting goat syndrome, as it is responsible for the eponymous 'fainting' seen in fainting goats when presented with a sudden stimulus. Of note, myotonia congenita has no association with malignant hyperthermia (MH).

<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">Centronuclear myopathy</span> Medical condition

Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in the center of muscle cells instead of their normal location at the periphery.

<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">Bethlem myopathy</span> Medical condition

Bethlem myopathy is predominantly an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy. There are two types of Bethlem myopathy, based on which type of collagen is affected.

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">Central core disease</span> Autosomal dominant genetic disorder

Central core disease (CCD), also known as central core myopathy, is an autosomal dominant inherited muscle disorder present from birth that negatively affects the skeletal muscles. It was first described by Shy and Magee in 1956. It is characterized by the appearance of the myofibril under the microscope.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

<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.

Multi/minicore myopathy is a congenital myopathy usually caused by mutations in either the SEPN1 and RYR1 genes. It is characterised the presence of multifocal, well-circumscribed areas with reduction of oxidative staining and low myofibrillar ATPase on muscle biopsy. It is also known as Minicore myopathy, Multicore myopathy, Multiminicore myopathy, Minicore myopathy with external ophthalmoplegia, Multicore myopathy with external ophthalmoplegia and Multiminicore disease with external ophthalmoplegia.

<span class="mw-page-title-main">Congenital fiber type disproportion</span> Medical condition

Congenital fiber type disproportion (CFTD) is an inherited form of myopathy with small type 1 muscle fibers that may occur in a number of neurological disorders. It has a relatively good outcome and follows a stable course. While the exact genetics is unclear, there is an association with mutations in the genes TPM3, ACTA1 and SEPN1. It is a rare condition.

Desmin-related myofibrillar myopathy, is a subgroup of the myofibrillar myopathy diseases and is the result of a mutation in the gene that codes for desmin which prevents it from forming protein filaments, instead forming aggregates of desmin and other proteins throughout the cell.

Sporadic late-onset nemaline myopathy, or SLONM, is a very rare disease, one of the nemaline myopathies, causing loss of muscle bulk and weakness in the legs but sparing the cranial nerves, and beginning its clinical course after age 40. It was first identified in 1966 at the Mayo Clinic, by A.G. Engel, and that same year W.K. Engel and J.S. Resnick noted another case that they elaborated in 1975. The diagnosis of the disease rests on subacutely evolving weakness after age 40, normal to low CK level, a myopathic EMG with fibrillations, and often a monoclonal gammopathy. The diagnosis is confirmed by visualizing rods in cryosections on light and electron microscopy. The associated monoclonal gammopathy has an unfavorable prognosis.

References

  1. 1 2 3 Jungbluth, Heinz (2007). "Central core disease". Orphanet Journal of Rare Diseases. 2: 25. doi: 10.1186/1750-1172-2-25 . PMC   1887524 . PMID   17504518.
  2. 1 2 3 4 North, Kathryn (2008). "What's new in congenital myopathies?". Neuromuscular Disorders. 18 (6): 433–42. doi:10.1016/j.nmd.2008.04.002. PMID   18482838. S2CID   5490760.
  3. ↑ "Congenital Myopathy Information Page". National Institute of Neurological Disorders and Stroke. September 30, 2011. Archived from the original on February 13, 2007. Retrieved January 23, 2007.
  4. ↑ Rubin, M. (August 2009). "Congenital Myopathies". Merck Manuals. Merck Sharp & Dohme Corp.
  5. ↑ Shy, G. Milton; Engel, W. King; Somers, J. E.; Wanko, Theodor (1963). "Nemaline Myopathy". Brain. 86 (4): 793–810. doi:10.1093/brain/86.4.793. PMID   14090530.
  6. ↑ Ryan MM, Schnell C, Strickland CD, et al. (September 2001). "Nemaline myopathy: a clinical study of 143 cases". Annals of Neurology. 50 (3): 312–20. doi:10.1002/ana.1080. PMID   11558787. S2CID   8648543.
  7. ↑ North KN, Laing NG, Wallgren-Pettersson C (September 1997). "Nemaline myopathy: current concepts. The ENMC International Consortium and Nemaline Myopathy". Journal of Medical Genetics. 34 (9): 705–13. doi:10.1136/jmg.34.9.705. PMC   1051052 . PMID   9321754.
  8. ↑ Ilkovski B, Cooper ST, Nowak K, et al. (June 2001). "Nemaline myopathy caused by mutations in the muscle alpha-skeletal-actin gene". American Journal of Human Genetics. 68 (6): 1333–43. doi:10.1086/320605. PMC   1226120 . PMID   11333380.
  9. ↑ "Centronuclear myopathy". Genetics Home Reference. Lister Hill National Center for Biomedical Communications, U.S. National Library of Medicine, National Institutes of Health, U.S. Department of Health & Human Services. November 25, 2012.
  10. ↑ Afifi, Adel K.; Smith, James W.; Zellweger, Hans (April 1, 1965). "A New Congenital Non-Progressive Myopathy – Central core disease and nemaline myopathy in one family" (PDF). Neurology. 15 (4): 371. doi:10.1212/WNL.15.4.371.
  11. ↑ Denborough, M. A.; Dennett, X; Anderson, R. M. (1973). "Central-core disease and malignant hyperpyrexia". British Medical Journal. 1 (5848): 272–3. doi:10.1136/bmj.1.5848.272. PMC   1588091 . PMID   4265427.
  12. ↑ "Fibre-type disproportion". Muscular Dystrophy Campaign. 2012. Archived from the original on 2013-03-29. Retrieved 2012-11-27.
  13. 1 2 "Congenital fiber-type disproportion". Genetics Home Reference. U.S. National Library of Medicine. December 2, 2012.
  14. ↑ Myong, NH; Kang, YK; Chi, JG; Suk, SI (1993). "Multicore myopathy--a case report". Journal of Korean Medical Science. 8 (4): 312–7. doi:10.3346/jkms.1993.8.4.312. PMC   3053753 . PMID   8198769.
  15. ↑ Chevessier, F; Marty, I; Paturneau-Jouas, M; Hantaı̈, D; Verdière-Sahuqué, M (2004). "Tubular aggregates are from whole sarcoplasmic reticulum origin: Alterations in calcium binding protein expression in mouse skeletal muscle during aging". Neuromuscular Disorders. 14 (3): 208–16. doi:10.1016/j.nmd.2003.11.007. PMID   15036331. S2CID   41282763.
  16. ↑ Carpenter, S.; Karpati, G.; Robitaille, Y.; Melmed, C. (Jul–Aug 1979). "Cylindrical spirals in human skeletal muscle". Muscle Nerve. 2 (4): 282–7. doi:10.1002/mus.880020407. PMID   492204. S2CID   46064876.
  17. ↑ Yan, C.Z.; Xu, J.W.; Zhao, Y.Y.; Li, W. (2014). "G.p.159". Neuromuscular Disorders. 24 (9–10): 849. doi:10.1016/j.nmd.2014.06.189. S2CID   54312844.
  18. ↑ Rapuzzi, S; Prelle, A; Moggio, M; Rigoletto, C; Ciscato, P; Comi, G; Francesca, F; Scarlato, G (1995). "High serum creatine kinase levels associated with cylindrical spirals at muscle biopsy". Acta Neuropathologica. 90 (6): 660–4. doi:10.1007/bf00318582. PMID   8615090. S2CID   12346602.
  19. ↑ Malfatti, Edoardo; Chaves, Marcelo; Bellance, Remi; Sarrazin, Elizabeth; Fardeau, Michel; Romero, Norma (February 12, 2013). "Cylindrical Spirals Congenital Myopathy Associated with Epileptic Encephalopathy (P07.050)". Neurology. American Academy of Neurology. 80.
  20. ↑ Bove, KE; Iannaccone, ST; Hilton, PK; Samaha, F. (June 1980). "Cylindrical spirals in a familial neuromuscular disorder". Annals of Neurology. 7 (6): 550–6. doi:10.1002/ana.410070608. PMID   7436360. S2CID   32326168.
  21. ↑ Taratuto, AL; Matteucci, M; Barreiro, C; Saccolitti, M; Sevlever, G (1991). "Autosomal dominant neuromuscular disease with cylindrical spirals". Neuromuscular Disorders. 1 (6): 433–41. doi:10.1016/0960-8966(91)90006-e. PMID   1822355. S2CID   39873188.
  22. 1 2 Tajsharghi, Homa; Oldfors, Anders (January 2013). "Myosinopathies: pathology and mechanisms". Acta Neuropathologica. 125 (1): 3–18. doi:10.1007/s00401-012-1024-2. ISSN   1432-0533. PMC   3535372 . PMID   22918376.
  23. 1 2 Gineste, Charlotte; Laporte, Jocelyn (February 2023). "Therapeutic approaches in different congenital myopathies". Current Opinion in Pharmacology. 68: 102328. doi: 10.1016/j.coph.2022.102328 .
  24. ↑ Gang, Qiang; Bettencourt, Conceição; Brady, Stefen; Holton, Janice L.; Healy, Estelle G.; McConville, John; Morrison, Patrick J.; Ripolone, Michela; Violano, Raffaella; Sciacco, Monica; Moggio, Maurizio; Mora, Marina; Mantegazza, Renato; Zanotti, Simona; Wang, Zhaoxia (January 2022). "Genetic defects are common in myopathies with tubular aggregates". Annals of Clinical and Translational Neurology. 9 (1): 4–15. doi:10.1002/acn3.51477. ISSN   2328-9503. PMC   8791796 . PMID   34908252.
  25. ↑ "Tubular aggregates: Other occasional associations". neuromuscular.wustl.edu. Retrieved 2023-11-11.
  26. ↑ "Phenotypic Series - PS160565 - Tubular aggregate myopathy". www.omim.org. Retrieved 2023-11-11.

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