Brody myopathy

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Brody myopathy
Other namesBrody disease (BD)
Autosomal recessive - en.svg
This condition is inherited in an autosomal recessive manner
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg

Brody myopathy, also called Brody disease, [1] is a rare disorder that affects skeletal muscle function. [2] BD was first characterized in 1969 by Dr. Irwin A. Brody at Duke University Medical Center. [3] Individuals with BD have difficulty relaxing their muscles after exercise. [3] This difficulty in relaxation leads to symptoms including cramps, stiffness, and discomfort in the muscles of the limbs and face. [3] Symptoms are heightened by exercise and commonly progress in severity throughout adulthood. [2]

Contents

Signs and symptoms

Symptoms include stiffness [1] and sometimes muscle cramping [4] after exercise (pseudo-myotonia) [5] and especially when exposed to cold. The most commonly affected muscles are in the arms, legs, and eyelids. [1] [4] Individuals with Brody myopathy also sometimes experience weakness, [4] myalgia, and rhabdomyolysis. [1] Some have a pseudoathletic appearance with hypertrophic muscles. [6]

Cause

Most cases of BD are inherited through autosomal recessive mutations in ATP2A1, where each copy of the affected individual's gene contain a mutation. [2] The gene involved in BD encodes the fast-twitch skeletal muscle ATPase, SERCA1. [7] SERCA1 is a protein pump that uses ATP to pump Ca2+ ions from the cytosol to the sarcoplasmic reticulum in skeletal muscle. [7] In those with BD, SERCA1 pumps are unable to effectively move Ca2+ across the membrane, leading to increased levels of cytoplasmic Ca2+. [7] Increases in cytoplasmic Ca2+ levels interfere with muscle contraction, leading to the characteristic symptoms of BD. [7]

In some cases of BD, no mutations in ATP2A1 have been observed. [2] Disease transmission in cases of non-ATP2A1 BD have been characterized as autosomal dominant pattern of inheritance. [2] These cases have revealed that the cause of the disease likely exhibits genetic heterogeneity, meaning the disease involves mutations in other locations within the genome (although no other loci have been identified in the development of BD as of now). [8]

Diagnosis

Diagnosis of BD begins with clinical evaluation of individuals for characteristic symptoms of cramping and stiffness of exercised muscles. [3]

Blood testing may be used to measure serum creatine kinase, which ranges from normal to slightly elevated in those with BD. [9] Skeletal muscle biopsies are used to examine muscle fibers. Biopsies in individuals with BD often show variation in muscle fiber size, atrophied fast-twitch muscle fibers, and increased nuclei number. [10] Electromyography (EMG) can be used in diagnosis to rule out myotonia, or muscle stiffness that is detected by EMG. Individuals with BD have stiff muscles but normal EMG results (pseudo-myotonia), where no myotonic discharges are detected. [5] [2] Genetic testing may also be used in the diagnosis of BD to look for mutations in ATP2A1. [11]

Treatment

There is no cure for BD, although treatment options are available for reducing the negative symptoms of BD. The drugs dantrolene and verapamil are used in BD treatment due to their effects on Ca2+. [2] Dantrolene is a muscle relaxer that decreases the symptoms of BD by inhibiting Ca2+ release channels in the sarcoplasmic reticulum, while verapamil sequesters Ca2+ in the sarcoplasmic reticulum of muscle cells by functioning as a Ca2+ channel blocker. [12] [13]

These drugs act by limiting the amount of Ca2+ from being released from the sarcoplasmic reticulum. When a muscle is stimulated, Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm where it binds to a protein called troponin. [14] This event allows the muscle fibers to overlap, causing a contraction. [14] In BD, Ca2+ levels are high in the cytoplasm, which means Ca2+ can readily bind troponin, leading to muscles that are in an extended state of contraction. [7]

Related Research Articles

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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.

<i>Paramyotonia congenita</i> Failure of muscles to relax after contraction, which is worsened by exercise

Paramyotonia congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.

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Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) also known as Calcium pump 1, is an enzyme that in humans is encoded by the ATP2A1 gene.

<span class="mw-page-title-main">Ryanodine receptor 1</span> Protein and coding gene in humans

Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by the RYR1 gene.

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<span class="mw-page-title-main">Acquired non-inflammatory myopathy</span> Medical condition

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References

  1. 1 2 3 4 "Brody myopathy: MedlinePlus Genetics". MedlinePlus . Retrieved 2022-07-27.
  2. 1 2 3 4 5 6 7 "Brody myopathy | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2018-09-07. Retrieved 2018-09-07.
  3. 1 2 3 4 Brody IA (July 1969). "Muscle contracture induced by exercise. A syndrome attributable to decreased relaxing factor". The New England Journal of Medicine. 281 (4): 187–92. doi:10.1056/NEJM196907242810403. PMID   4239835.
  4. 1 2 3 Molenaar, Joery P; Verhoeven, Jamie I; Rodenburg, Richard J; Kamsteeg, Erik J; Erasmus, Corrie E; Vicart, Savine; Behin, Anthony; Bassez, Guillaume; Magot, Armelle; Péréon, Yann; Brandom, Barbara W (2020-02-01). "Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients". Brain. 143 (2): 452–466. doi: 10.1093/brain/awz410 . ISSN   0006-8950. PMC   7009512 . PMID   32040565.
  5. 1 2 Braz, Luís; Soares-Dos-Reis, Ricardo; Seabra, Mafalda; Silveira, Fernando; Guimarães, Joana (October 2019). "Brody disease: when myotonia is not myotonia". Practical Neurology. 19 (5): 417–419. doi:10.1136/practneurol-2019-002224. ISSN   1474-7766. PMID   30996034. S2CID   122401141.
  6. ↑ Molenaar, Joery P.; Verhoeven, Jamie I.; Rodenburg, Richard J.; Kamsteeg, Erik J.; Erasmus, Corrie E.; Vicart, Savine; Behin, Anthony; Bassez, Guillaume; Magot, Armelle; Péréon, Yann; Brandom, Barbara W.; Guglielmi, Valeria; Vattemi, Gaetano; Chevessier, Frédéric; Mathieu, Jean (2020-02-01). "Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients". Brain: A Journal of Neurology. 143 (2): 452–466. doi:10.1093/brain/awz410. ISSN   1460-2156. PMC   7009512 . PMID   32040565.
  7. 1 2 3 4 5 Reference, Genetics Home. "ATP2A1 gene". Genetics Home Reference. Retrieved 2018-09-07.
  8. ↑ McKusick, Victor; O'Neill, Marla (2017-12-27). "OMIM Entry - # 601003 - BRODY MYOPATHY". www.omim.org. Retrieved 2018-09-25.
  9. ↑ Poels PJ, Wevers RA, Braakhekke JP, Benders AA, Veerkamp JH, Joosten EM (July 1993). "Exertional rhabdomyolysis in a patient with calcium adenosine triphosphatase deficiency". Journal of Neurology, Neurosurgery, and Psychiatry. 56 (7): 823–6. doi:10.1136/jnnp.56.7.823. PMC   1015068 . PMID   8331362.
  10. ↑ Taylor DJ, Brosnan MJ, Arnold DL, Bore PJ, Styles P, Walton J, Radda GK (November 1988). "Ca2+-ATPase deficiency in a patient with an exertional muscle pain syndrome". Journal of Neurology, Neurosurgery, and Psychiatry. 51 (11): 1425–33. doi:10.1136/jnnp.51.11.1425. PMC   1032814 . PMID   2976810.
  11. ↑ "Brody myopathy - Conditions - GTR - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-09-25.
  12. ↑ "CALAN - verapamil hydrochloride tablet, film coated" (PDF). FDA. 2009.
  13. ↑ Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (April 2004). "Dantrolene--a review of its pharmacology, therapeutic use and new developments". Anaesthesia. 59 (4): 364–73. doi: 10.1111/j.1365-2044.2004.03658.x . PMID   15023108.
  14. 1 2 "Sliding Filament Theory, Sarcomere, Muscle Contraction, Myosin | Learn Science at Scitable". www.nature.com. Retrieved 2018-09-25.
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