When treating cataplexy, all three systems— adrenergic ,  cholinergic  and  dopaminergic —must be considered. The adrenergic system can be inhibited by antidepressants. In mouse models, cataplexy is regulated by the dopaminergic system via the  D2-like receptor , which when blocked decreases cataplectic attacks. [ clarification needed ]  The role of the cholinergic system has been observed in canine models, where stimulation of this system may lead to severe cataplexy episodes. [ 17 ]


There are no behavioral treatments. People with  narcolepsy  will often try to avoid thoughts and situations that they know are likely to evoke strong emotions and thereby trigger cataplectic attacks. [ 9 ]


Gamma-hydroxybutyrate , also known as  sodium oxybate , has been found to be effective at reducing the number of cataplexy episodes. [ 18 ] [ 19 ]  Sodium oxybate is generally safe [ 19 ]  and is typically the recommended treatment. [ 20 ]


Sodium oxybate is a natural metabolite of GABA. Its main target is the dopaminergic system because at pharmacological concentrations it acts as an agonist and modulates the dopamine neurotransmitters and dopaminergic signalling. [ 17 ]  It is the only drug authorised by the  EMA  to treat the whole disease in adults, and by the  FDA  to treat patients who have cataplexy with the indication to be used for combating excessive daytime sleepiness. [ 4 ] [ 20 ]  This drug helps to normalise  sleep architecture  and inhibits the intrusion REM sleep elements like paralysis during the day. [ 4 ]


If the above treatment is not possible,  venlafaxine  is recommended. [ 20 ]  Evidence for benefit is not as good. [ clarification needed ] [ 20 ]


Previous treatments include  tricyclic antidepressants  such as  imipramine ,  clomipramine  or  protriptyline . [ 8 ]   Monoamine oxidase inhibitors  may be used to manage both cataplexy and the REM sleep-onset symptoms of sleep paralysis and  hypnagogic hallucinations . [ 21 ]


In clinical practice, venlafaxine and   clomipramine  are the most common antidepressants used to treat cataplexy. If the patient wishes to have a sedative effect, then clomipramine is prescribed. The effect of these drugs is to suppress the REM component and to increase the brainstem monoaminergic levels. [ 4 ]  Improvement can be seen within 48 hours after the drug is administered and at doses smaller than the ones used in depression. [ 17 ]  Nonetheless, antidepressants are not approved by the FDA for the treatment of cataplexy; [ 20 ]  some jurisdictions have approved clomipramine for this use, however. [ 22 ] [ 23 ] [ 24 ]  Frequently, tolerance is developed by the patients and typically the risk of cataplexy rebound or "status cataplecticus" appears when their intake is abruptly interrupted. [ 17 ]


Narcolepsy with cataplexy is considered an autoimmune-mediated disorder, so some therapies based on this hypothesis have been developed. Immunological therapies developed include: [ 20 ]


The histaminergic neurons have a very important role in preserving consciousness and in helping maintain wakefulness  and remain active during cataplexy. In narcolepsy, there seems to be an increase in these neurons, possibly to compensate for hypocretin loss. [ 25 ]  A promising therapy would be to increase the activation of histaminergic neurons by an inverse agonist of the histamine H3 receptor, which enhances histamine release in hypothalamus. [ 17 ]  An inverse agonist of the histamine H3 is  Pitolisant . [ 26 ]  Results after testing on animals have indicated increased wakefulness in normal animals, decreased sleepiness and blocked the abnormal transitions from REM sleep to awake state in the hypocretin knock-out mice. [ 17 ]  Also placebo-controlled studies suggest some positive effects of  Pitolisant  on cataplexy symptoms increasing the levels of alertness and wakefulness. [ 4 ]


There are several protective devices used that can help to manage the dangers as a results of falls due to cataplexies:


It is important for people with narcolepsy and cataplexy to work with their healthcare team to determine the best protective devices for their specific needs and to ensure their safety and well-being.


Research is being conducted on hypocretin gene therapy and hypocretin cell transplantation for narcolepsy-cataplexy. [ 27 ] [ 28 ]


A  charley horse  is an American term for a very painful involuntary  cramp , most commonly occurring in the  legs  (usually located in the  calf muscle ) and/or foot, lasting anywhere from a few seconds to a couple of days. The phrase formerly referred more commonly to bruising of the  quadriceps  muscle of the anterior or lateral thigh, or  contusion  of the femur, that commonly results in a  haematoma  and sometimes several weeks of pain and disability. In this latter sense, such an injury is known as  dead leg . [ citation needed ]


Dead legs and charley horses are two different types of injuries: A charley horse involves the muscles contracting without warning, and can last from a few seconds to a couple days. A dead leg often occurs in  contact sports , such as football, when an athlete suffers a knee or other blunt trauma to the lateral quadriceps causing a haematoma or temporary  paresis  and  antalgic gait  as a result of pain. [ citation needed ]


Colloquially, taking a hit in the thigh area (thigh contusion) can also be referred to as a  charley horse [ 1 ]  or even simply as a  charley. [ 2 ]


The first known use of the term was in 1886 [ 3 ]  in a West Virginia newspaper. The originator of the phrase is credited to two baseball players,  Jack Glasscock  and  Joe Quest . [ 4 ]


Charley horses have many possible causes directly resulting from high or low pH or substrate concentrations in the blood, including  hormonal imbalances ,  dehydration , low levels of  magnesium ,  potassium , or  calcium  (evidence has been mixed), [ 5 ] [ 6 ] [ 7 ]  side effects of medication, or, more seriously, diseases such as  amyotrophic lateral sclerosis  and  neuropathy . [ 8 ]  Charley horses seem to be most common in individuals who engage in strenuous physical activities, such as those who work in construction or play sports. They are also a common complaint during  pregnancy . [ 9 ]


Relief is given by massaging or stretching the leg or foot in the opposite direction of the cramp. Relief also comes from standing up, which serves to counter the muscle-tightening signal. [ 10 ]


Chronic progressive external ophthalmoplegia  ( CPEO ) is a type of eye disorder characterized by slowly progressive inability to move the eyes and eyebrows. [ 1 ]  It is often the only feature of  mitochondrial disease , in which case the term CPEO may be given as the  diagnosis . In other people suffering from mitochondrial disease, CPEO occurs as part of a  syndrome  involving more than one part of the body, such as  Kearns–Sayre syndrome . Occasionally CPEO may be caused by conditions other than mitochondrial diseases.


CPEO is a rare disease that may affect those of all ages, but typically manifests in the young adult years.  CPEO is the most common manifestation of  mitochondrial myopathy , occurring in an estimated two-thirds of all cases of mitochondrial myopathy. Patients typically present with  ptosis  (drooping eyelids). Other diseases like  Graves' disease ,  myasthenia gravis  and glioma that may cause an external  ophthalmoplegia  must be ruled out. [ citation needed ]


CPEO is a slowly progressing disease. It may begin at any age and progresses over a period of 5–15 years. [ 1 ]  The first presenting symptom of  ptosis  is often unnoticed by the patient until the lids droop to the point of producing a visual field defect. Often, patients will tilt the head backwards to adjust for the slowly progressing ptosis of the lids. In addition, as the ptosis becomes complete, the patients will use the frontalis (forehead) muscle to help elevate the lids. The ptosis is typically bilateral but may be unilateral for a period of months to years before the fellow lid becomes involved. [ citation needed ]


Ophthalmoplegia (the inability or difficulty to move the eye) is usually symmetrical, therefore, patients are not affected by diplopia (double vision). The progressive ophthalmoplegia is often unnoticed till decreased ocular motility limits peripheral vision. Often someone else will point out the ocular disturbance to the patient. Patients will move their heads to adjust for the loss of peripheral vision caused by inability to abduct or adduct the eye. All directions of gaze are affected; however, downward gaze appears to be best spared. This is in contrast to  progressive supranuclear palsy  (PSP), which typically affects vertical gaze and spares horizontal gaze. [ citation needed ]


Mitochondrial retinopathy has been described in CPEO which presents with a spectrum of distinct retinal phenotypes. This includes mild, focal pigmentary abnormalities on funduscopy and widespread granular pigmented fundus alterations. Mild, asymptomatic retinopathy might be underreported; severe retinopathy may be associated with significant vision loss.  [ 2 ]


Weakness of extraocular muscle groups including, the  orbicularis oculi  muscle as well as facial and limb muscles may be present in up to 25% of patients with CPEO. As a result of the orbicularis oculi weakness, patients may suffer from exposure keratopathy (damage to cornea) from the inability to close the eyes tightly. Frontalis muscle weakness may exacerbate the ptotic lids with the inability to compensate for the ptosis. Facial muscles may be involved which lead to atrophy of facial muscle groups producing a thin, expressionless face with some having difficulty with chewing.  Neck, shoulder and extremity weakness with atrophy may affect some patients and can be mild or severe. [ citation needed ]


Mild visual impairment was seen in 95% of patients that were evaluated using the Visual Function Index (VF-14). [ 3 ]


The  ciliary muscles  that control the lens shape and the iris muscles are often unaffected by CPEO. [ citation needed ]


Additional symptoms are variable, and may include exercise intolerance,  cataracts , hearing loss, sensory axonal neuropathy,  ataxia , clinical depression,  hypogonadism , and  parkinsonism . [ citation needed ]


Kearns–Sayre syndrome  is characterized by onset before 15 years of age of CPEO, heart block and pigmentary retinopathy. [ 1 ]


Mitochondrial DNA  which is transmitted from the mother, encodes proteins that are critical to the respiratory chain required to produce  adenosine triphosphate  (ATP).  Deletions or mutations to segments of mtDNA lead to defective function of oxidative phosphorylation.  This may be made evident in highly oxidative tissues like skeletal muscle and heart tissue.  However,  extraocular muscles  contain a volume of mitochondria that is several times greater than any other muscle group.  As such, this results in the preferential ocular symptoms of CPEO. [ citation needed ]


Multiple mtDNA abnormalities exist which cause CPEO.  One mutation is located in a conserved region of mitochondrial tRNA at nucleotide 3243 in which there is an A to G nucleotide transition.  This mutation is associated with both CPEO and  mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes  (MELAS). [ 4 ]  A common deletion found in one-third of CPEO patients is a 4,977 base pair segment found between a 13 base pair repeat. [ citation needed ]


The mtDNA that is affected maybe a single or multiple point deletion, with associated nuclear DNA deletions.  One study showed that mtDNA deletion seen in CPEO patients also had an associated nuclear DNA deletion of the  Twinkle gene  which encodes specific mitochondrial protein; Twinkle. [ 5 ]


Whether a tissue is affected is correlated with the amount of oxidative demands in relation to the amount of mtDNA deletion. [ citation needed ] In most cases, PEO occurs due to a sporadic deletion or duplication within the mitochondrial DNA. [ 6 ]  However, transmission from the mother to the progeny appears only in few cases. Both  autosomal dominant  and  autosomal recessive  inheritance can occur, autosomal recessive inheritance being more severe.  Dominant and recessive forms of PEO can be caused by genetic mutations in the  ANT1 ,  POLG ,  POLG2  and  PEO1  genes. [ 7 ] [ 8 ]


It is important to differentiate CPEO from other pathologies that may cause an ophthalmoplegia.  There are specific therapies used for these pathologies. [ citation needed ]


CPEO is diagnosed via muscle biopsy. On examination of muscle fibers stained with  Gömöri trichrome stain , one can see an accumulation of enlarged mitochondria. This produces a dark red staining of the muscle fibers given the name "ragged red fibers".  While ragged red fibers are seen in normal aging, amounts in excess of normal aging give a diagnosis of a mitochondrial myopathy. [ citation needed ]   Polymerase chain reaction  (PCR) from a sample of blood or muscle tissue can determine a mutation of the mtDNA. [ citation needed ]


Elevated acetylcholine receptor antibody level which is typically seen in myasthenia gravis has been seen in certain patients of mitochondrial associated ophthalmoplegia. [ 9 ]
It is important to have a dilated eye exam to determine if there is pigmentary retinopathy that may signify  Kearns–Sayre syndrome  which is associated with cardiac abnormalities. [ citation needed ]


MRI may be helpful in the diagnosis, in one study volumes of medial rectus, lateral rectus, and inferior rectus muscles in CPEO were not smaller than normal (in contrast to the profound atrophy typical of neurogenic paralysis). Although volumes of the superior rectus muscle-levator complex and superior oblique were significantly reduced. [ 10 ]


There is currently no defined treatment to ameliorate the muscle weakness of CPEO.  Treatments used to treat other pathologies causing ophthalmoplegia has not been shown to be effective. [ citation needed ]  Experimental treatment with tetracycline has been used to improve ocular motility in one patient. [ 11 ]  Coenzyme Q 10  has also been used to treat this condition. [ 12 ]  However, most neuro-ophthalmologists do not ascribe to any treatment. [ citation needed ]


Ptosis associated with CPEO may be corrected with surgery to raise the lids, [ 13 ]  however due to weakness of the orbicularis oculi muscles, care must be taken not to raise the lids in excess causing an inability to close the lids.  This results in an exposure keratopathy.  Therefore, rarely should lid surgery be performed and only by a neuro-ophthalmologist familiar with the disease. [ citation needed ]


The most common strabismus finding is large angle exotropia which can be treated by maximal bilateral eye surgery, but due to the progressive nature of the disease, strabismus may recur. [ 14 ]  Those that have  diplopia  as a result of asymmetric ophthalmoplegia may be corrected with prisms or with surgery to create a better alignment of the eyes. [ citation needed ]


Compton-North congenital myopathy , also known as  congenital lethal myopathy, Compton-North type , is a rare, fatal  genetic disorder  of pre-natal onset that results in death shortly after birth and is characterized by  fetal akinesia  and movement restriction,  polyhydramnios , severe  hypotonia  of neonatal-onset, generalized weakness of the respiratory, bulbar, and skeletal muscles, presence of multiple congenital muscular contractures. [ 2 ]


Additional features include premature birth, low birth weight, failure to thrive, abnormal reflexes,  scaphocephaly ,  hypertelorbitism , oval-shaped face, small hands,  single transverse palmar crease ,  high-arched palate ,  arachnodactyly , and  camptodactyly  (causing overlapping fingers). Ultrastructural findings include sarcomeric disruptions, Z-band disorganization, and an absence of integrin alpha7, beta2-syntrophin, alpha-dystrobrevin. [ 3 ]  Only four infants from a heavily  consanguineous   Egyptian Australian  family have been described in the medical literature, [ 4 ]  and it is caused by homozygous mutations in the  CNTN1  gene, located in  chromosome 12 . [ 5 ] [ 6 ]


The condition wasn't named after the doctors who first discovered the condition, but rather the doctors who first described it in detail: Dr. Alison G. Compton and Dr. Kathryn N. North. [ 5 ]


This  genetic disorder  article is a  stub . You can help Wikipedia by  expanding it .


In  pathology , a  contracture  is a shortening of  muscles , tendons, skin, and nearby soft tissues that causes the  joints  to shorten and become very stiff, preventing normal movement. [ 1 ] [ 2 ]  A contracture is usually permanent, but less commonly can be temporary (such as in  McArdle disease ), [ 3 ]  or resolve over time but reoccur later in life (such as in  Bethlem myopathy  1). [ 4 ]


It is usually in response to prolonged  hypertonic   spasticity  in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like  spastic cerebral palsy , but can also be due to the congenital abnormal development of muscles and connective tissue in the womb.


Contractures develop usually when normally elastic tissues such as muscles or tendons are replaced by inelastic tissues ( fibrosis ). This results in the shortening and hardening of these tissues, ultimately causing rigidity, joint deformities and a total loss of movement around the joint.


Most of the  physical therapy ,  occupational therapy  and other exercise regimens targeted towards people with  spasticity  focuses on trying to prevent contractures from happening in the first place. However, research on sustained traction of connective tissue in approaches such as adaptive yoga has demonstrated that contracture can be reduced, [ 5 ]  at the same time that tendency toward spasticity is addressed.


Contractures can have a variety of causes other than spasticity. In regards to muscle, these include (but not limited to):


Wound contraction , where the edges of the skin are pulled together to close the wound, is a normal part of  wound healing . However, large wounds and abnormal wound healing cause skin contractures by excessively tightening the skin and limiting movement. [ 6 ] [ 7 ] [ 8 ]  A skin contracture due to a burn is known as a  burn scar contracture .


Large areas of missing skin (such as large burns, grazes, and gouges) drastically reduce the area of skin causing it to become tight when pulled together during wound healing. [ 6 ] [ 7 ]  Scars initially lack elasticity with synthesis of elastic tissue fibres ( elastogenesis ) being a function of duration and site of the scar. [ 9 ]  Deep wounds and abnormal wound healing causes abnormal scarring such as  hypertrophic scars . [ 8 ]  Studies on hypertrophic scars have shown a lack of improvement to both elasticity and stiffness suggesting a prolonged healing phase without amelioration seen in a normal wound-healing curve. [ 10 ] [ 11 ]


Surgery can help alleviate skin contractures in the form of skin grafts and removal of hypertrophic scars. [ 8 ] [ 6 ]  For hypertrophic scars, timing is important when considering surgery, as over time scars will mature and may show decreased contractures along with flattening, softening, and repigmentation without surgical intervention. [ 8 ]


A  cramp  is a sudden, involuntary, painful  skeletal   muscle contraction [ 1 ] [ 2 ]  or overshortening associated with electrical activity; [ 3 ]  while generally temporary and non-damaging, they can cause significant  pain  and a  paralysis -like immobility of the affected muscle. A cramp usually goes away on its own over a period of several seconds or (sometimes) minutes. [ 4 ]  Cramps are common and tend to occur at rest, usually at night (nocturnal leg cramps). [ 2 ] [ 5 ]  They are also often associated with  pregnancy ,  physical exercise  or overexertion, and age (common in older adults); in such cases, cramps are called  idiopathic , because there is no underlying pathology. In addition to those benign conditions cramps are also associated with many  pathological  conditions. [ 2 ] [ 6 ]


Cramp definition is narrower than the definition of muscle  spasm : spasms include any involuntary abnormal muscle contractions, while cramps are sustained and painful. [ 1 ] [ 7 ]  True cramps can be distinguished from other cramp-like conditions. Cramps are different from  muscle contracture , which is also painful and involuntary, but which is electrically silent. The main distinguishing features of cramps from  dystonia  are suddenness with acute onset of pain, involvement of only one muscle and spontaneous resolution of cramps or their resolution after stretching the affected muscle. [ 2 ]   Restless leg syndrome  is not considered the same as muscle cramps and should not be confused with rest cramps. [ 6 ]


Skeletal muscle cramps may be caused by  muscle fatigue  or a lack of  electrolytes [ citation needed ]  such as  sodium  (a condition called  hyponatremia ),  potassium  (called  hypokalemia ), or  magnesium  (called  hypomagnesemia [ 8 ] ). Some skeletal muscle cramps do not have a known cause. [ 6 ]  Motor neuron disorders (e.g.,  amyotrophic lateral sclerosis ),  metabolic disorders  (e.g.,  liver failure ), some medications (e.g.,  diuretics  and inhaled  beta‐agonists ), and  haemodialysis  may also cause muscle cramps. [ 6 ]


Causes of cramping include [ 9 ]   hyperflexion ,  hypoxia , exposure to large changes in temperature, dehydration, or  low blood salt . Muscle cramps can also be a symptom or complication of  pregnancy ;  kidney  disease;  thyroid  disease;  hypokalemia ,  hypomagnesemia , or  hypocalcaemia  (as conditions);  restless legs syndrome ;  varicose veins ; [ 10 ]  and  multiple sclerosis . [ 11 ]


As early as 1965, researchers observed that leg cramps and restless legs syndrome can result from excess  insulin , sometimes called  hyperinsulinemia . [ 12 ]


Under normal circumstances,  skeletal muscles  can be voluntarily controlled. Skeletal muscles that cramp the most often are the  calves ,  thighs , and  arches of the foot , and in North America are sometimes called a " Charley horse " or a "corky". Such cramping is associated with strenuous physical activity and can be intensely painful; however, they can even occur while inactive and relaxed. Around 40% of people who experience skeletal cramps are likely to endure extreme muscle pain, and may be unable to use the entire limb that contains the "locked-up" muscle group. It may take up to a week for the muscle to return to a pain-free state, depending on the person's fitness level, age, and several other factors. [ citation needed ]


Nocturnal  leg cramps are involuntary muscle contractions that occur in the  calves ,  soles  of the feet, or other muscles in the body during the night or (less commonly) while resting. The duration of nocturnal leg cramps is variable, with cramps lasting anywhere from a few seconds to several minutes. Muscle soreness may remain after the cramp itself ends. These cramps are more common in older people. [ 13 ]  They happen quite frequently in teenagers and in some people while exercising at night. Besides being painful, a nocturnal leg cramp can cause much  distress  and  anxiety . [ 14 ]  The precise cause of these cramps is unclear. Potential contributing factors include  dehydration , low levels of certain minerals ( magnesium ,  potassium ,  calcium , and  sodium , although the evidence has been mixed), [ 15 ] [ 16 ] [ 17 ]  and reduced blood flow through muscles attendant in prolonged sitting or lying down. Nocturnal leg cramps (almost exclusively calf cramps) are considered "normal" during the late stages of pregnancy. [ 18 ]  They can, however, vary in intensity from mild to extremely painful. [ citation needed ]


A lactic acid buildup around muscles can trigger cramps; however, they happen during anaerobic respiration when a person is exercising or engaging in an activity where the heartbeat rises. Medical conditions associated with leg cramps are cardiovascular disease, hemodialysis, cirrhosis, pregnancy, and lumbar canal stenosis. Differential diagnoses include  restless legs syndrome ,  claudication ,  myositis , and  peripheral neuropathy . All of them can be differentiated through careful history and physical examination. [ 17 ]


Gentle  stretching  and  massage , putting some pressure on the affected leg by walking or standing, or taking a warm bath or shower may help to end the cramp. [ 19 ]  If the cramp is in the calf muscle, dorsiflexing the foot (lifting the toes back toward the shins) will stretch the muscle and provide almost immediate relief. There is limited evidence supporting the use of magnesium,  calcium channel blockers ,  carisoprodol , and  vitamin B 12 . [ 17 ]


Quinine  is no longer recommended for treatment of nocturnal leg cramps due to potential fatal hypersensitivity reactions and  thrombocytopenia .  Arrhythmias ,  cinchonism , and  hemolytic uremic syndrome  can also occur at higher dosages. [ 17 ]


Various medications may cause nocturnal leg cramps: [ 17 ] [ 20 ]


Statins  may sometimes cause  myalgia  and cramps among other possible side effects.  Raloxifene  (Evista) is a medication associated with a high incidence of leg cramps. Additional factors, which increase the probability for these side effects, are physical exercise, age, history of cramps, and  hypothyroidism . Up to 80% of athletes using statins experience significant adverse muscular effects, including cramps; [ 21 ]  the rate appears to be approximately 10–25% in a typical statin-using population. [ 22 ] [ 23 ]  In some cases, adverse effects disappear after switching to a different statin; however, they should not be ignored if they persist, as they can, in rare cases, develop into more serious problems.  Coenzyme Q10  supplementation can be helpful to avoid some statin-related adverse effects, but currently there is not enough evidence to prove the effectiveness in avoiding myopathy or myalgia. [ 24 ]


Stretching, massage, and drinking plenty of liquids may be helpful in treating simple muscle cramps. [ 25 ]


The antimalarial drug  quinine  is a traditional treatment that may be slightly effective for reducing the number of cramps, the intensity of cramps, and the number of days a person experiences cramps. Quinine has not been shown to reduce the duration (length) of a muscle cramp. [ 6 ]  Quinine treatment may lead to haematologic and cardiac toxicity. Due to its low effectiveness and negative side effects, its use as a medication for treating muscle cramps is not recommended by the FDA. [ 26 ]


Magnesium is commonly used to treat muscle cramps. Moderate quality evidence indicates that magnesium is not effective for treating or preventing cramps in older adults. [ 6 ]  It is not known if magnesium helps cramps due to pregnancy, liver  cirrhosis , other medical conditions, or exercising. [ 6 ]  Oral magnesium treatment does not appear to have significant major side effects, however, it may be associated with diarrhea and nausea in 11–37% of people who use this medicine. [ 6 ]


With exertional heat cramps due to  electrolyte abnormalities  (primarily potassium loss and not calcium, magnesium, and sodium), appropriate fluids and sufficient potassium improves symptoms. [ 27 ]   Vitamin B complex ,  naftidrofuryl ,  lidocaine , and  calcium channel blockers  may be effective for muscle cramps. [ 26 ]


Adequate conditioning, stretching, mental preparation, hydration, and electrolyte balance are likely helpful in preventing muscle cramps. [ 25 ]


Cricopharyngeal spasms  occur in the  cricopharyngeus muscle  of the  pharynx . Cricopharyngeal spasm is an uncomfortable but harmless and  temporary  disorder.


There are two  sphincters  in the  oesophagus . They are normally contracted and they relax when one swallows so that food can pass through them going to the  stomach . They then squeeze closed again to prevent regurgitation of the stomach contents and prevent air from entering the digestive system. If this normal contraction becomes a  spasm , these symptoms begin.


Causes include stress and anxiety. Other causes are not yet clear.


The condition persists in the  autonomic nervous system  even when the original stress is relieved.


An assumption in  psychiatry  is that a lack of  serotonin  can be associated with  depression  and  anxiety . A further assumption is that a low levels of serotonin can causes spasms in the cervical area. [ 1 ]  A plausible explanation for the cricopharyngeal spasms is a lack of neurotransmitter preventing the  central nervous system  from detecting that the  eosophagus  is closed, so that the  upper esophagus sphincter  becomes, randomly, hypertonic.


The condition can appear as a symptom of the  generalized anxiety disorder . Early signs are other symptoms like difficulty or inability to eat (loss of appetite,  satiety  after swallowing minor quantities),  headache , dry mouth at night, sleeping issues,  tremor , tension in the neck, in the throat, abdominal, stomach or chest pain etc. The sequence can result from a recent  stress ,  panic attack  or  worry .


The subject heads to cricopharyngeal spasms when, for instance, eating pasty food requiring more throat cleanings, like peanuts, pumpkin seeds and other nuts, becomes painful [ citation needed ] . Continuous swallowing appears with the spasms as the brain interprets the feeling as something stuck.


The  vagus nerves  seems to play a role in the mother condition through a  neurovegetative hyperactivity  or  dysautonomia . It innerves the  inferior pharyngeal constrictor muscle  where the cricopharyngeal spasms occur.


Throat spasms can also appear after an accident, a disease, may be caused or worsened by  GERD . There may be hereditary factors.


In the context of  long covid  psychiatrists envisioned a potential relationship with an immune reaction, involving  cytokines , that would persist quietly. [ 2 ]  However, due the anxiogenic situation, stress was again present when the symptoms started.


These spasms are frequently misunderstood by the patient to be  cancer  due to the 'lump in the throat' feeling ( Globus pharyngis ) that is symptomatic of this syndrome.


All the anatomic examinations can appear normal despite the condition. The throat  endoscopy  can objectify that nothing is stuck, that there is no lesion or inflammation. The  barium swallow  can miss that the sphincter is hypertonic if it does not happen during the examination, or if the sphincter still relaxes enough for the food bolus to go through. The  esophageal manometry  cannot detect any abnormal wave.


The cricopharyngeal spasms ("feeling that something is stuck") occur in the cricopharyngeal part of the  inferior pharyngeal constrictor muscle , at the bottom of the throat. They cause muscle tension on the  cricoid cartilage , leading to a  globus feeling . Pharyngeal spasms, a more common source of a  globus feeling , cause tension on the  thyroid cartilage . They move up and down, left and right in the  pharyngeal muscles . Both may be present.


The patient complains about the signs and symptoms enumerated above. The pain causes dry deglutition and dry deglutition adds to the pain, triggering a vicious circle. The spams start after dry deglutition, after the meals or randomly during the day. They can start (and stop) brutally. Or softly, by the feeling that a small pill is stuck, frictions around it, then the impression that a ball is stuck. When the spasms last long they can give the impression of a knife stabbed in the throat.


The cricopharyngeal spasms can be, for instance, formally diagnosed as part of the more general condition. For instance, did the patient recently encounter other symptoms of the  generalized anxiety disorder ? Does the patient have  neurovegetative symptoms ? Are there symptoms of  dysautonomia ? Is there evidence of a lack of serotonin, like no sleep ( melatonin  is generated from serotonin)? Is there any other  psychiatric  condition?


Cricopharyngeal spasms remain a rare symptom. Difficulties for the patient to describe an unusual symptom and for the practitioners to figure out the condition can entail a prompt diagnosis.


The condition is known to be temporary. In some individuals it can disappear by itself without medication. For others, it can stagnate or worsen until appropriate medical care is given.


Since the problem can last, medical specialists are not readily available and potential treatments act slowly, patience is required. During that time, finding distractions and support is a first help. Attention should be paid to not increase the levels of stress and anxiety, or fall into  depression  because of the symptom or its root cause.


The medical specialists to consult are  ENT specialist  and  psychiatrist :


A cure for the condition exists and number of treatments may provide a relief.


Treatments based on medicines


A typical treatment that can be prescribed starts, for instance, with nidefipine (as long as it brings a relief), a benzodiazepine (one month maximum) that has a myorelaxant effect and that can be chosen to simultaneously address other faces of the problem (anxiety, sleeping issue) and a well-tolerated anti-depressant like escitalopram (long enough so that the problem does not come back).


Treatments based on other factors


Other therapies


Diastasis recti ,  or  rectus abdominis diastasis , is an  increased gap  between the right and left  rectus abdominis muscles . [ 1 ]  The increased distance between the muscles is created by the stretching of the  linea alba , a connective collagen sheath created by the  aponeurosis  insertions of the  transverse abdominis ,  internal oblique , and  external oblique . [ 2 ]  This condition has no associated morbidity or mortality. Physical therapy is often required to repair this separation and surgery is an option for more severe cases. Standard exercise rarely results in complete healing of the separated muscles. [ 3 ]


Diastasis of the rectus abdominis muscle most frequently occurs in  newborns  and  pregnant women ; however, it may occur in any adult woman or man. In the newborn, the rectus abdominis is not fully developed and may not be sealed together at midline. Diastasis recti is more common in  premature  newborns. In pregnant or  postpartum  women, the condition is caused by the stretching of the rectus abdominis by the growing uterus. It is more common in  multiparous  women (women who have had multiple pregnancies) owing to repeated episodes of stretching. When the defect occurs during pregnancy, the uterus can sometimes be seen bulging through the abdominal wall beneath the skin. Non-pregnant women are more susceptible to develop diastasis recti when over the age of 35 or with high birth weight of child, multiple birth pregnancy, or multiple pregnancies. Additional causes can be attributed to excessive abdominal exercises after the first trimester of pregnancy. [ 4 ]


Strength training of all the core muscles, including the abdominis recti muscle, may reduce the size of the gap in pregnant or postpartum women.  Crunches  may increase the diastasis recti separation. All corrective exercises should be in the form of pulling in the abdominal muscles rather than pushing them outwards. In extreme cases diastasis recti is corrected with a  cosmetic surgery  procedure known as an  abdominoplasty  by creating a plication, or folding, of the linea alba and suturing it together, which results in a tighter abdominal wall.


A diastasis recti may appear as a ridge running down the midline of the abdomen, anywhere from the  xiphoid process  to the  umbilicus . It becomes more prominent with straining and may disappear when the abdominal muscles are relaxed. The medial borders of the right and left halves of the muscle may be palpated during contraction of the rectus abdominis. [ 5 ]  The condition can be diagnosed by physical exam, and must be differentiated from an  epigastric hernia  or  incisional hernia , if the patient has had abdominal surgery. [ 3 ]  Hernias may be ruled out using ultrasound. [ 6 ]


In infants, they typically result from a minor defect of the linea alba between the rectus abdominis muscles. This allows tissue from inside the abdomen to herniate anteriorly. On infants, this may manifest as an apparent 'bubble' under the skin of the belly between the  umbilicus  and  xiphisternum  (bottom of the breastbone). [ 7 ]


Examination is performed with the subject lying on the back, knees bent at 90° with feet flat, head slightly lifted placing chin on chest. With muscles tense, the examiner then places fingers in the ridge that is presented. Measurement of the width of separation is determined by the number of fingertips that can fit within the space between the left and right  rectus abdominis  muscles. Separation consisting of a width of 2 fingertips (approximately 1 1/2 centimeters) or more is the determining factor for diagnosing diastasis recti. [ 8 ]


Diastasis recti can be diagnosed by  physical examination , which may include measuring the distance between the  rectus abdominis muscles  at rest and during contraction at several levels along the  linea alba . [ 9 ]  Diastasis recti is defined as a gap of about 2.7 cm or greater between the two sides of the  rectus abdominis muscle . [ 1 ]   Abdominal ultrasonography  provides objective evidence for the diagnosis, and also confirms that the bulge is not a  hernia . [ 9 ]  An  abdominal CT scan  may also visualise diastasis recti. [ 9 ]


A 2014 systematic review found that the width of the gap in diastasis recti may be reduced by exercising during and after pregnancy. [ 1 ]


A 2018 review mentions other techniques in addition to strengthening exercises: postural training; education and training for proper lifting mechanisms; manual therapy (which includes soft tissue mobilization);  myofascial release ; Noble technique (i.e., manual approximation of abdominal muscles during partial sit-up); and abdominal bracing and taping. Other techniques to strengthen abdominal muscles are using  Pilates  and functional training. [ 12 ]


In extreme cases, diastasis recti is corrected with a  cosmetic surgery  procedure known as an  abdominoplasty  by creating a plication or folding of the linea alba and suturing together. This creates a tighter abdominal wall. There are two surgical methods: one more common through plication of the anterior rectus sheath; and the other through  hernia repair , considering suture closure of the hernia sac combined with mesh reinforcement. Two studies showed few post-operative complications. [ 13 ]


Distal spinal muscular atrophy type 2  ( DSMA2 ), also known as  Jerash type distal hereditary motor neuropathy  ( HMNJ ), is a very rare childhood-onset genetic disorder characterised by progressive muscle wasting affecting lower and subsequently upper limbs. The disorder has been described in  Arab  inhabitants of  Jerash  region in  Jordan [ 1 ] [ 2 ]  as well as in a Chinese family. [ 3 ]


The condition is linked to a genetic  mutation  in the  SIGMAR1  gene on  chromosome 19  ( locus  19p13.3) and is likely inherited in an  autosomal recessive  manner. [ 3 ]


This article about a medical condition affecting the nervous system is a  stub . You can help Wikipedia by  expanding it .


Dynapenia  (pronounced dahy-nuh-pē-nē-a,  Greek  translation for poverty of strength, power, or force) is the loss of muscular strength not caused by neurological or muscular disease that typically is associated with older adults. [ 1 ]


Dynapenia is the loss of muscle strength, rather than the loss of muscle mass ( sarcopenia ). The preservation of muscular strength through the aging process has become increasingly significant with increasing life expectancy in the modern world.


The muscular degeneration that occurs throughout the aging process has been one of the greatest concerns of mankind for thousands of years. Greeks of the 4th and 5th centuries BC viewed aging as a chronic, incurable, and progressive disease. By the 1st century BC and 1st century AD, aging began to be thought of as something that is modifiable and should be resisted. In  Cicero ’s ‘Essay on Old Age’ from 44 BC he states that “it is our duty… to resist old age, to compensate for its defects, to fight against it as we would fight a disease; to adopt a regimen of health; to practice moderate exercise; and to take just enough food and drink to restore our strength.” [ 2 ]  Cicero also highlights the restrictions aging has forced upon mankind for centuries; restrictions that we are now trying to overcome with today's technology. “Old age,” it seems, “disqualifies us from taking an active part in the great scenes of business. But in what scenes? let me ask. If in those which require the strength and vivacity of youth, I readily admit the charge.”  [ 2 ]  Although aging has always been perceived as a paradox that plagues humanity, the idea of formulating preventative treatments didn't advance until the latter part of the 20th century. With the rapid advancement of today's technology and the unprecedented growth rate of the world's older population, the drive of the scientific community to delay the aging process has significantly increased. “The next imputation thrown upon old age is, that it impairs our
strength, and it must be acknowledged the charge is not altogether without foundation. But, for my part, I no more regret the want of that vigour which I possessed in my youth, than I lamented in my youth that I was not endowed with the force of a bull or an elephant. It is sufficient if we exert with spirit, upon every proper occasion, that degree of strength which still remains with us.”  [ 2 ]  The aging process remains an inevitable part of the life cycle, but science is now being used to treat the deterioration of the human body so that the aging population can live with independence and comfort. [ citation needed ]


Sarcopenia  is defined as loss of muscle tissue as a natural part of the aging process. [ 3 ]
This does not include loss of muscle strength, which is defined by dynapenia.  Muscle strength appears to be a critical component in maintaining physical function, mobility, and vitality in old age, which is why it's imperative to identify and study contributing factors of dynapenia. A longitudinal study on the age-related changes in muscle strength, quality, and inter muscular fat showed an increase in  adipose tissue  infiltration of mid thigh skeletal muscle in both men and women ranging between 70 and 79 years-old during a 5-year period. The increase in fatty tissue infiltration occurred regardless of changes in weight or subcutaneous thigh adipose tissue. The study also found that the decrease in muscle strength due to aging was 2-5 times greater than the loss of muscle size. These results demonstrate the age-related progression of muscle weakness and muscular fat infiltration regardless of changes in muscle mass or subcutaneous fat, reinforcing that muscle quality is lost with aging. [ 4 ]


The age-associated deterioration of force-generating properties of skeletal muscles can be directly associated with increased risk of physical disability, [ 5 ] [ 6 ]  functional impairments, [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  and increased mortality. [ 14 ] [ 15 ] [ 16 ] [ 17 ]  Dynapenia can contribute to increased risk of falling as well as feeling weak and/or fatigued. With regard to the relation of higher levels of muscular strength to a lower risk of premature death, studies by Newman et al. [ 14 ]  have shown that grip and  knee extensor  muscle strength are strongly correlated with mortality. For women, they observed crude  hazard ratios  of 1.84 for  grip strength  and 1.65 for knee extensor strength. For men, they observed crude hazard ratios of 1.36 for grip strength and 1.51 for knee extensor strength. More recent studies by Xue et al. [ 15 ]  have observed that faster decline in  hip flexor  and grip strengths individually predicted mortality after accounting for potential contributors. Manini et al. [ 18 ]  recently conducted an informal meta-analysis that showed significant correlation between low levels of muscle strength and poor physical performance and/or physical disability in 90% of the studies. Together, these studies provide evidence that dynapenia in older adults is strongly correlated with increased risk of physical disabilities and mortality, and decreased physical function. [ citation needed ]


There currently is no agreed upon algorithm to diagnose dynapenia. Lack of consensus upon how to properly diagnose the disease has prevented practitioners from determining if muscle weakness likely plays a role in an individual's disability or poor physical performance. Manini and Clark have proposed a decision algorithm for the diagnosis of dynapenia. [ 18 ]  The algorithm begins by screening individuals aged over 60 years for dynapenia, and those with high risk factors for the development of dynapenia are referred for a knee extension strength assessment. If an individual presents no or low risk factors, it is suggested that they undergo a grip strength test to decide if a lower extremity strength test is needed. Follow-up testing is then recommended based on the results of these tests to determine the etiology of dynapenia. It's important to note that dynapenia is defined based on muscle strength rather than muscle power because both factors perform similarly when identifying individuals with physical disability or poor physical performance. A recent study from Bean and colleagues [ 19 ]  showed that older adults with mobility limitations who participated in a 16-week “power-training” exercise program were able to raise their leg press power about 10% more than the group that participated in a traditional “strength-training” exercise program. Both groups exhibited equivalent increases in muscle strength and mobility performance, despite the 10% difference in muscle power. Also, there is a limited amount of data on muscle power from  epidemiological  studies of aging. The equipment to measure muscle strength is also more readily available than equipment used to measure muscle power. [ 18 ]  Together, these factors justify the reasoning behind using muscle strength to define dynapenia rather than muscle power. [ citation needed ]


Three principal risk factors stand out when considering preemptive components of dynapenia. [ citation needed ]


Possible biological contributors to dynapenia include the  nervous system ’s deteriorating control of  voluntary skeletal muscle  activation and a decreased number of functioning  motor units . [ 23 ] [ 24 ]  The nervous system's lowered ability to stimulate a full muscle contraction subsequently leads to loss of muscle strength and power. A study by Harridge et al. [ 21 ]  also showed that all dynapenic subjects had incomplete voluntary activation during a maximum contraction (69-93%), suggesting that loss of voluntary muscle activation plays an important role in the loss of muscle strength. Studies involving the dissection of  cadavers  have uncovered a 43% decrease in the cell body size of  neurons  found in the  premotor cortex  compared to those of younger adults. [ 25 ]  New studies have recently verified this finding in living subjects using high resolution  magnetic resonance imaging  (MRI). [ 26 ]


Recent evidence suggests that aging is also related to the loss of  myelinated  nerve fiber length and the mass of  white matter , with individuals losing approximately 45% of total nerve fiber length as they age. [ 27 ]
 [ 28 ]  These changes that develop through the aging process affect the connectivity of the cortex within itself as well as its connectivity to the rest of the central nervous system. [ 1 ]


Another potential contributor to dynapenia is a disruption of the process that converts electrical signal given for muscular activation into an actual contraction. Particularly, impairments in the release of  calcium  (Ca2+) from the  sarcoplasmic reticulum  have been suggested to explain why decreased muscle quality is so prevalent in older adults. [ 29 ]
 [ 30 ]
 [ 31 ]
 [ 32 ]
 [ 33 ]
 [ 34 ]
 [ 35 ]
 [ 36 ]
 [ 37 ]
 [ 38 ] [ 39 ]


A systematic review on the literature regarding the relationship between type II muscle fiber loss and aging found that the total number of fibers in the  vastus lateralis  decreases tremendously with age. [ 40 ]  This decline is first observed around 25 years of age and proceeds at an even greater rate throughout the lifespan. The age-related Type II fiber loss highlights the negative effect of aging on muscle power. [ citation needed ]


It has also been suggested that nutritional factors may contribute to the onset of dynapenia. It has been proposed that low levels of  Vitamin E , [ 41 ]
 [ 42 ] [ 43 ] carotenoids , [ 41 ] [ 44 ]  and  selenium [ 45 ]
 [ 46 ]  are associated with lower levels of muscle strength. The activity of  Vitamin D  receptors on muscle has been found to decrease with aging. These receptors initiate the nuclear response leading to  de novo synthesis  of proteins. [ 47 ]  However, the results of multiple studies on the relation between Vitamin D and muscle strength have been highly controversial, making the effect of Vitamin D on muscle strength in need of further investigation.  The Recommended Dietary Allowance (RDA) for protein is not very clear for older adults; it may underestimate the amount of protein needed to maintain optimal physical function with age. A study by Houston and colleagues showed how decreased protein intake may increase the risk of developing mobility limitations later on. [ 48 ]  The study revealed that 35.4% out of 43% of participants who consumed a significantly smaller amount of protein (mean: 0.38 g/kg body weight/d) than the RDA (0.8 g/kg body weight/d) developed mobility limitations over the 6 year follow-up. In contrast, participants who consumed more protein (mean: (≥1.0 g/kg body weight/d) than the RDA had a lower risk of developing mobility limitations over the 6 year follow-up. [ 48 ]


Resistance training  has been shown to greatly influence virtually all of the strength related physiological mechanisms of the nervous and skeletal muscle systems - even into very late life. Recent studies by Peterson et al. [ 49 ]  have uncovered two critical aspects of resistance training that must be implemented in the training process to achieve positive results. One factor is the positive correlation between higher intensity resistance training and greater improvements in muscle strength. The other factor is a direct relationship between increased resistance training volume, which is the total number of exercise sets performed in a session, and improvements in lean body mass. [ 50 ]  A meta-analysis on the effect of resistance exercise for multiple strength outcomes in older adults revealed a positive effect for each of the strength outcomes. Specifically, the estimate of mean strength change from baseline to post intervention for the leg press was 31.63 kg. There was a mean strength change of 9.83 kg for the chest press, 12.08 kg for the knee extension, and 10.63 kg for the lat pull. [ 49 ]  These results demonstrate that resistance training is an effective way to improve the muscular strength capacity of older adults.


By defining strength cutoff values and establishing a clinical definition of dynapenia, treatment and prevention plans could be developed to decrease the physical limitations of older adults. The creation of an agreed-upon definition of dynapenia could give clinicians the ability to diagnose patients with decreased muscle function and expand research on the subject by providing a universal standard, which in turn could lead to the development of effective interventions and treatment options. [ 1 ]  Gathering a firmer understanding of what causes dynapenia will help determine the degree of variance in the biological contributions of participants, and provide insight into how treatment options may be adapted to fit patients’ unique needs. [ citation needed ]


Although they vary in particulars,  polymyositis ,  dermatomyositis  and  inclusion body myositis  are idiopathic inflammatory myopathies (IIM) [ 1 ]  primarily characterized by chronic  inflammation  of human  skeletal muscle  tissue [ 2 ]  that ultimately causes the  necrosis  of muscle cells.  This degeneration leads to muscle tissue wasting, weakness and fatigue among other serious effects.  Until recently, exercise has been avoided as a type of therapy, and even forbidden due to the risk of triggering or amplifying inflammation.  However, several studies have been conducted to test this assumption and have shown that  aerobic exercise  as well as  resistance training  can maintain and even improve quality of life for IIM-affected individuals without increased  inflammatory response . [ 3 ]


With the main goals of treatment being improved functionality and quality of life, exercise programs should focus on "functional" exercises (e.g. walking, walking up/down stairs, sit-to-stand), when applicable. Performing functional exercises increases (a) the efficiency of the exercise program and (b) the likelihood the improvements will be transferred to activities of daily living. [ 4 ]


In 1993,  isometric exercise  training was applied for four weeks resulting in isometric peak power at 60% of maximal voluntary contraction. [ 5 ]  The increase in isometric power was later shown to have no significant effect on serum  creatine kinase  (CK) after two weeks of  strength training . [ 6 ]


A six-week training program in 1998 that included 30 minutes of  aerobic activity  three times per week set at 60% maximum heart rate (predicted by age) resulted in increased  VO 2  max  (i.e. maximal oxygen consumption or aerobic capacity), diminished pain, reduced muscle impairment, and improved quality of life. [ 7 ] [ 8 ]


The results produced by aerobic activity were repeated in 1999 [ 9 ]  where for 12 weeks, weight-bearing exercise was added for patients not exhibiting marked physical incapacity as measured by the Functional Index in Myositis [ 10 ]  (see Functional Assessment section). Confirmed by MRI and muscle biopsy, both the 1998 and 1999 studies showed that there were no significant changes in levels of creatine kinase and  aldolase , and no increase in muscle inflammation. In 2001, 22 patients were placed on a three-week physical therapy and exercise program, and found that creatine kinase levels actually dropped in 20 of the patients. [ 11 ]


The longest study to date was a six-month exercise program demonstrating a significant improvement in exercise capacity, VO 2 ,  isokinetic  strength, and the ability to perform daily tasks compared to controls. [ 7 ]


Chest expansion and thoracic extension exercises may offer preventive support to those at risk of  restrictive lung disease  through the effects of IIM, and patients with inclusion body myositis may also be able to prevent contracture and extend functional daily activities through stretching and range of motion exercises. [ 12 ]


It is important to recognize that all described exercise programs were conducted by physicians or physiotherapists during the stable phase of the disease (except Painelli [ 3 ] ). Patients were monitored closely for indicators of deleterious effects, such as increases in serum creatine kinase, inflammation or weakness.  Monitoring of this kind can only be done in conjunction with a medical team who is aware of the risks posed by increased  inflammatory response  in patients with IIM. [ citation needed ]


The pathophysiology of IIMs is not well understood. Muscle weakness can be caused by a single or combined effect on muscle tissue by inflammation, inflammatory infiltrates, muscle atrophy, metabolic abnormalities that indicate disordered energy metabolism, [ 2 ]  and possibly neuropathy, [ 13 ]  among others. Therefore, physical exercise has the potential to cause harm.


However, the results of these exercise studies, at minimum, show that exercise can attenuate muscle damage due to disease, inactivity and steroid use. [ 3 ]   They reflect the benefit of exercise through the strengthening of complement (non-diseased) muscles, and should encourage further studies to confirm whether diseased muscle may experience regeneration. The definition of improvement must be established, [ 2 ]  and reproducible longitudinal studies must be conducted to determine the efficacy of exercise as therapy for IIM. [ citation needed ]


Exercise-associated muscle cramps  (EAMC) are defined as  cramping  (painful muscle spasms) during or immediately following exercise. [ 1 ] [ 2 ] [ 3 ]  Muscle cramps during exercise are very common, even in elite athletes. EAMC are a common condition that occurs during or after exercise, often during endurance events such as a triathlon or marathon. [ 1 ] [ 3 ]  Although EAMC are extremely common among athletes, the cause is still not fully understood because muscle cramping can occur as a result of many underlying conditions. Elite athletes experience cramping due to paces at higher intensities. [ 2 ] [ 3 ]  The cause of exercise-associated muscle cramps is hypothesized to be due to altered neuromuscular control,  dehydration , or  electrolyte  depletion. [ 1 ] [ 2 ] [ 3 ]


It is widely believed that excessive sweating due to strenuous exercise can lead to muscle cramps. Deficiency of sodium and other electrolytes may lead to contracted interstitial fluid compartments, which may exacerbate the muscle cramping. According to this theory, the increased blood plasma  osmolality  from sweating sodium losses causes a fluid shift from the interstitial space to the intervascular space, which causes the interstitial fluid compartment to deform and contributes to muscle hyperexcitability and risk of spontaneous muscle activity. [ 1 ] [ 2 ]


The second hypothesis is altered neuromuscular control.  In this hypothesis, it is suggested that cramping is due to altered neuromuscular activity.  The proposed underlying cause of the altered neuromuscular control is due to  fatigue . [ 2 ]   There are several disturbances, at various levels of the central and peripheral nervous system, and the skeletal muscle that contribute to cramping. These disturbances can be described by a series of several key events.  First and foremost, repetitive muscle exercise can lead to the development of fatigue due to one or more of the following: inadequate conditioning, hot and or humid environments, increased intensity, increased duration, and decreased supply of energy.  Muscle fatigue itself causes increased excitatory  afferent  activity within the  muscle spindles  and decreased inhibitory afferent activity within the Golgi tendon.  The coupling of these events leads to altered neuromuscular control from the spinal cord. A cascade of events follow the altered neuromuscular control; this includes increased alpha- motor neuron  activity in the spinal cord, which overloads the lower motor neurons, and increased muscle cell membrane activity. [ 2 ]  Thus, the resultant of this cascade is a muscle cramp. [ citation needed ]


Medication has not been found to help reduce or prevent muscle cramping. To prevent or treat, athletes are recommended to stretch, stop movement and rest, massaging the area that is cramping, or drink fluids. Stretching helps to calm down spindles by lengthening the muscle fibers and increase firing duration to slow down the firing rate of the muscle. [ 1 ]  Recommended fluids during cramping are water or fluids that are high in electrolytes to replenish the system with sodium. [ 2 ] [ 3 ]


Exertional rhabdomyolysis  ( ER ) is the breakdown of  muscle  from extreme physical exertion. It is one of many types of  rhabdomyolysis  that can occur, and because of this, the exact  prevalence  and incidence are unclear.


ER is more likely to occur when strenuous exercise is performed under high temperatures and humidity. [ 1 ]  Poor  hydration  levels before, during, and after strenuous bouts of  exercise  have also been reported to lead to ER. [ 2 ]  This condition and its signs and symptoms are not well known amongst the sport and fitness community and because of this it is believed that the incidence is greater but highly underreported. [ 2 ]


Risks that lead to ER include exercise in hot and humid conditions, improper hydration, inadequate recovery between bouts of exercise, intense physical training, and inadequate  fitness  levels for beginning high-intensity workouts. [ 3 ]   Eccentric contraction  of muscles can result in ER more often than  concentric contraction . [ 4 ]   Dehydration is one of the biggest factors that can give almost immediate feedback from the body by producing very dark-colored urine. [ 5 ]


Exertional rhabdomyolysis results from damage to the intercellular proteins inside the  sarcolemma .  Myosin  and  actin  break down in the  sarcomeres  when  ATP  is no longer available due to injury to the  sarcoplasmic reticulum . [ 6 ]  Damage to the sarcolemma and sarcoplasmic reticulum from direct trauma or high force production causes a high influx of  calcium  ions into the muscle fibers increasing calcium permeability. Calcium ions build up in the  mitochondria , impairing cellular respiration. [ 7 ]  The mitochondria are unable to produce enough ATP to power the cell properly. Reduction in ATP production impairs the cells' ability to extract calcium from the muscle cell.


The ion imbalance causes calcium-dependent enzymes to activate which break down muscle proteins even further. [ 8 ]  A high concentration of calcium activates muscle cells, causing the muscle to contract while inhibiting its ability to relax.


The increase of sustained muscle contraction leads to oxygen and ATP depletion with prolonged exposure to calcium. The muscle cell membrane pump may become damaged allowing free form myoglobin to leak into the bloodstream. [ 9 ]


Rhabdomyolysis causes the  myosin  and  actin  to degenerate into smaller proteins that travel into the circulatory system. The body reacts by increasing intracellular swelling to the injured tissue to send repair cells to the area. This allows  creatine kinase  and  myoglobin  to be flushed from the tissue where it travels in the blood until reaching the kidneys. [ 10 ]  In addition to the proteins released, large quantities of ions such as intracellular potassium, sodium, and chloride find their way into the circulatory system. Intracellular potassium ion has deleterious effects on the heart's ability to generate action potentials leading to cardiac arrhythmias. [ 11 ]   Consequently, this can affect peripheral and central perfusion which in turn can affect all major organ systems in the body. [ citation needed ]


When the protein reaches the kidneys it causes a strain on the anatomical structures reducing its effectiveness as a filter for the body. The protein acts as a dam as it forms into tight aggregates when it enters the renal tubules. [ 11 ]  In addition, the increased intracellular  calcium  has greater time to bind due to the blockage allowing for renal calculi to form. [ 12 ]  As a result this causes urine output to decrease allowing for the uric acid to build up inside the organ. The increased acid concentration allows the iron from the aggregate protein to be released into the surrounding renal tissue. [ 13 ]  Iron then strips away molecular bonds of the surrounding tissue which eventually will lead to kidney failure if the tissue damage is too great. [ citation needed ]


Muscle degeneration from rhabdomyolysis destroys the myosin and actin filaments in the affected tissue. This initiates the body's natural reaction to increasing  perfusion  to the area allowing for an influx of specialized cells to repair the injury. However, the swelling increases the intracellular pressure beyond normal limits. As the pressure builds in the muscle tissue, the surrounding tissue is crushed against the underlying tissue and bone. [ 14 ]  This is known as  compartment syndrome  which leads to greater death of the surrounding muscle tissue around the injury. [ 14 ]   As the muscle dies this will cause pain to radiate from the affected area into the compartmentalized tissue. A loss of range of motion from swelling will also be seen in the affected limb. Along with muscle strength weakness associated with the muscles involved from loss of filament interaction. [ 15 ]


Dehydration  is a common risk factor for exertional rhabdomyolysis because it causes a reduction of plasma volume during exertion. This leads to a reduction of blood flow through the vascular system which inhibits blood vessel constriction. [ 16 ]


Exertional rhabdomyolysis, the exercise-induced muscle breakdown that results in muscle pain/soreness, is commonly diagnosed using the urine myoglobin test accompanied by high levels of  creatine kinase  (CK).  Myoglobin  is the protein released into the bloodstream when  skeletal muscle  is broken down. The urine test simply examines whether myoglobin is present or absent. When results are positive the  urine  normally obtains a dark, brown color followed by serum CK level evaluation to determine the severity of muscle damage. Elevated levels of serum CK greater than 5,000 U/L that are not caused by myocardial infarction,  brain injury  or disease, generally indicate serious muscle damage confirming the diagnosis of ER. [ 17 ]
Urine is often a dark "cola" color as a result of the excretion of muscle cell components. [ citation needed ]


Military data suggest that the risk of exertional rhabdomyolysis can be lowered by engaging in prolonged lower-intensity  exercise , as opposed to high-intensity exercise over a shorter time period.  In all athletic programs, three features should be present: (1) emphasizing prolonged lower-intensity exercise, as opposed to repetitive max intensity exercises; (2) adequate rest periods and a high- carbohydrate  diet, to replenish  glycogen  stores; and (3) proper hydration, to enhance renal clearance of myoglobin. [ 18 ]  Also, exercise in above-average temperature and  humidity  can increase risk for ER. [ 19 ]  ER can be avoided by gradually increasing intensity during new exercise regimens, properly hydrating,  acclimatization , and avoidance of diuretics during times of strenuous activity. [ 20 ]


After ER is diagnosed, treatment is applied to 1) avoid renal dysfunction and 2) alleviate  symptoms . This should be followed by recommended  rehabilitation  program,  exercise prescription  (ExRx).  Treatment  involves extensive  hydration  normally done through IV fluid replacement with administration of normal saline until CK levels reduce to a maximum of 1,000 U/L. [ 21 ]  Proper treatment will ensure hydration and normalize muscle discomfort (pain), flu-like symptoms, CK levels, and myoglobin levels for patient to begin ExRx. [ citation needed ]


Although sufficient evidence is currently lacking, supplementation with a combination of sodium bicarbonate and mannitol is commonly utilized to prevent kidney failure in rhabdomyolysis patients. Sodium bicarbonate alkalizes urine to stop myoglobin from precipitating in renal tubules.  Mannitol  has several effects, including vasodilatation of the renal vasculature, osmotic diuresis, and free-radical scavenging. [ 22 ]


Before initiating any form of physical activity, the individual must demonstrate a normal level of functioning with all previous  symptoms  absent. Physical activity should be supervised by a health care professional in case of a recurrence. However, in some low-risk individuals, supervision by a medical professional is not required as long as the individual follows up with weekly checkups. [ 23 ]  Proper hydration prior to performing physical activity and performing  exercise  in cool, dry environments may reduce the chances of developing a reoccurring episode of ER. [ 23 ]   Lastly, it is imperative for  urine  and blood values to be monitored along with careful observation for the redevelopment of any signs or symptoms. [ citation needed ]


The recovery program focuses on progressive conditioning/reconditioning the individual and improving  functional  mobility. However, special considerations prior to participating in the rehabilitation program include the individual's 1) extent of muscle injury, if any 2) level of fitness before the incident and 3) weight training experience. [ 19 ]  These special considerations collectively are a form of assessing the individual's capacity to perform physical activity, which is ultimately used to specify the ExRx design. [ citation needed ]


The actual cost for this condition is unknown and also dependent on the level of the condition. In some cases ER can lead to  acute kidney failure  and bring medical costs up due to the need for  hemodialysis  for recovery/treatment. [ 5 ]


Fanconi–Bickel syndrome  is a form of  glycogen storage disease  named for  Guido Fanconi  and  Horst Bickel , [ 1 ] [ 2 ]  who first described it in 1949.


It is associated with  GLUT2 , [ 3 ] [ 4 ]  a glucose transport protein which, when functioning normally, allows glucose to exit several tissues, including the liver, nephrons, and enterocytes of the intestines, and enter the blood. The syndrome results in hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature. [ 5 ]


This article about an endocrine, nutritional, or metabolic disease is a  stub . You can help Wikipedia by  expanding it .


Fibrodysplasia ossificans progressiva  ( / ˌ f aɪ b r oʊ d ɪ ˈ s p l eɪ ʒ ( i ) ə   ɒ ˈ s ɪ f ɪ k æ n z   p r ə ˈ ɡ r ɛ s ɪ v ə / ; [ 1 ]   abbr.   FOP ),  also called  Münchmeyer disease  or formerly  myositis ossificans progressiva , is an extremely rare  connective tissue disease  in which fibrous  connective tissue  such as  muscle ,  tendons , and  ligaments  turn into  bone  tissue ( ossification ). It is the only known medical condition where one  organ system  changes into another. [ 2 ]  It is a severe, disabling disorder with no cure.


FOP is caused by a  mutation  of the gene  ACVR1 . The mutation affects the body's repair mechanism, causing  fibrous tissue  including  muscle ,  tendons , and  ligaments  to become  ossified , either spontaneously or when damaged as the result of trauma. In many cases, otherwise minor injuries can cause  joints  to become permanently fused as new bone forms, replacing the damaged muscle tissue. This new bone formation (known as "heterotopic ossification") eventually forms a secondary skeleton and progressively restricts the patient's ability to move. Bone formed as a result of this process is identical to "normal" bone, simply in improper locations. Circumstantial evidence suggests that the disease can cause joint degradation separate from its characteristic bone growth. [ 3 ]


Surgical removal of the extra bone growth has been shown to cause the body to "repair" the affected area with additional bone. Although the rate of bone growth may differ depending on the patient, the condition ultimately leaves sufferers immobilized as new bone replaces musculature and fuses with the existing skeleton. This has earned FOP the nickname " stone man disease ". [ 4 ]


For unknown reasons, children born with FOP often have malformed  big toes , sometimes missing a joint or, in other cases, simply presenting with a notable lump at the minor joint. [ 5 ]  The first "flare-up" that leads to the formation of FOP bone usually occurs before the age of 10. [ 5 ]  The bone growth generally progresses from the top of the body downward, just as bones grow in fetuses. A child with FOP will typically develop additional bones starting at the neck, then at the shoulders, arms, chest area, and finally at the feet. [ 6 ]


Specifically, ossification is typically first seen in the dorsal, axial, cranial, and proximal regions of the body. Later, the disease progresses in the ventral, appendicular, caudal, and distal regions. [ 5 ]  However, it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize a flare-up of the disease appear suddenly.


Bone growth occurring during flare-ups may result in the loss of mobility to affected joints, including, if the jaw/mandible is involved, the inability to fully open the mouth, limiting speech and eating. A specific occurrence of a flare-up of this condition in the foot/ankle joints can result in the limited ability to put a foot flat on the ground. [ citation needed ]  Bone growth can also result in the immobilization of the hip or knee, affecting the individual's ability to walk. Extra bone formation around the rib cage restricts the expansion of lungs and diaphragm causing respiratory complications. [ 5 ]


Since the disorder is incredibly rare, only occurring in 1 out of 2 million people, the condition may be misdiagnosed as  cancer  or  fibrosis . Misdiagnoses can lead  physicians  to order  biopsies , potentially exacerbating the growth of FOP bone. [ 7 ]  The presence of malformed toes or thumbs in those born with FOP helps distinguish this disorder from other skeletal problems. [ 8 ]


With proper medical management the median age of survival is 40 years. However, delayed diagnosis, trauma, and infections can decrease life expectancy. [ 9 ]


FOP is caused by an  autosomal   dominant allele  on chromosome 2q23-24. [ 10 ]  The allele has variable  expressivity , but complete  penetrance . Most cases are caused by spontaneous mutation in the  gametes ; most people with FOP cannot or choose not to have children.  A similar but less catastrophic disease is  fibrous dysplasia , which is caused by a  post-zygotic mutation .


A mutation in the gene  ACVR1  (also known as activin-like kinase 2 (ALK2)) is responsible for the disease. [ 10 ]  ACVR1 encodes  activin  receptor type-1, a  BMP  type-1 receptor. The mutation causes substitution of  codon  206 from  arginine  to  histidine  in the ACVR1 protein. [ 11 ] [ 12 ]  This substitution causes abnormal activation of ACVR1, leading to the transformation of connective tissue and muscle tissue into a secondary skeleton. This causes  endothelial cells  to transform to  mesenchymal stem cells  and then to bone. [ 13 ]
Normally, the ACVR1 gene encodes the activin receptor type-1 transmembrane  kinase  that bind BMP receptors (Type I BMPR and Type II BMPR) for  chondrogenesis  signaling. BMPs belong to a superfamily of proteins known as Transforming growth factor-beta ( TGF- β ) proteins. The binding of ACVR1 protein to BMP receptors start a signaling cascade that is crucial for inducing  endochondral  bone formation during development, as well as, skeletal and tissue  homeostasis . [ 14 ]


FOP is an  autosomal dominant  disorder. Thus, a child of an affected heterozygous parent and an unaffected parent has a 50% probability of being affected. Two affected individuals can produce unaffected children. Two unaffected individuals can produce an affected offspring as a result of the mutation of the gene. The homozygous dominant form is more severe than the heterozygous form. [ 15 ]


The protein that causes ossification is normally deactivated by an inhibitory protein after a fetus's bones are formed in the womb, but in patients with FOP, the protein keeps working. Aberrant bone formation in patients with FOP occurs when injured connective tissue or muscle cells at the sites of injury or growth incorrectly express an enzyme for bone repair during  apoptosis  (self-regulated cell death), resulting in lymphocytes containing excess  bone morphogenetic protein 4  (BMP4) provided during the immune system response. The bone that results occurs independently of the normal skeleton, forming its own discrete skeletal elements.  These elements, however, can fuse with normal skeletal bone. [ 16 ]  The diaphragm, tongue, and extra-ocular muscles are spared in this process, as well as cardiac and  smooth muscle . [ 5 ]  Since the incorrect enzyme remains unresolved within the immune response, the body continues providing the incorrect BMP4-containing lymphocytes. BMP4 is a product that contributes to the development of the skeleton in the normal embryo. [ 17 ]


The  ACVR1  gene encodes a bone morphogenic protein (BMP) receptor; this gene is mutated in FOP. It is responsible for growth and development of bone and muscles. The typical mutation, R202H, makes the inhibitor  FKBP1A  bind less tightly to the activation GS-loop. [ 18 ]  The result is that ACVR1 is not effectively turned off, and an overgrowth of bone and cartilage and fusion of joints occurs. [ 19 ]  Atypical mutations involving other residues work similarly. In some cases, the receptor can end up signalling that it's active without being bound to its activating ligand. [ 20 ]


Most cases of FOP are the result of a new gene mutation: these people had no history of this particular disorder in their family. There are some cases where the individual has inherited the mutation from one affected parent. [ 19 ]


Generally, FOP can be diagnosed with  radiographs . Early diagnosis of this disorder through radiology is very important to avoid unnecessary invasive investigations like  biopsies . The smallest or trivial trauma or intramuscular injections can amplify progression of the disease through inflammation hence the favorability of radiology. Clinicians should be aware of this rare entity, as it is frequently misdiagnosed as cancer or other benign entities such as infection, resulting in biopsies that can often hasten disease progression. [ 21 ]


Outbreaks may be measurable clinically by elevated levels of  alkaline phosphatase  and  bone-specific alkaline phosphatase . [ 22 ]  Another telltale sign of FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal first phalanx and/or interphalangeal joint. [ 23 ]


While FOP remains without a cure, a promising breakthrough lies in the approved treatment, Sohonos ( palovarotene ). [ 24 ]  Notably, attempts to surgically remove bone in a FOP patient may result in explosive growth of new bone. [ 25 ]  While undergoing  anesthesia , people with FOP may encounter difficulties with  intubation ,  restrictive pulmonary disease , and changes in the  electrical conduction system of the heart . [ 26 ]  Activities that increase the risk of falling or soft tissue injury should be avoided, as even minor trauma may provoke  heterotopic ossification . [ 27 ]  Intramuscular injections, including immunizations, should likewise be avoided in individuals with FOP, as these can also trigger ossification  [ 28 ]


Although there are no effective definitive treatments of the disorder, there are intermittent treatments such as anti-inflammatory drugs to suppress  inflammation  as a result of flare-ups or inflammation from muscle damage. Currently, surgery is not usually recommended for people with FOP as it can incite rapid bone formation at incision sites or where sutures have been applied to muscle or connective tissue. Life-saving surgery may be considered, however developing a surgical plan with input from a FOP specialist may be considered best practice. Surgical release of joint contractures is generally unsuccessful and risks new, trauma-induced heterotopic ossification. [ 29 ]


Antisense-mediated therapy, specifically using allele-selective LNA gapmers, has emerged as a promising strategy for FOP [ 30 ] . This approach targets the mutated ACVR1 gene, which causes heterotopic ossification by responding aberrantly to activin A. In recent studies, LNA gapmers effectively reduced the expression of the pathogenic ACVR1R206H transcript while sparing the wild-type ACVR1 gene, thus selectively suppressing osteogenic differentiation associated with FOP. This novel antisense approach offers potential for therapeutic application in FOP, representing a breakthrough in targeted genetic treatment for this and potentially other autosomal dominant disorders


As of 2017 [update] , approximately 800 cases of FOP have been confirmed worldwide, making FOP one of the rarest diseases known. [ 31 ]  The estimated  incidence  of FOP is 0.5 cases per million people and affects all ethnicities. [ 31 ]


Medical reports describing individuals affected by FOP date back to Dr.  Guy Patin  in 1692. [ 31 ]  FOP was originally called myositis ossificans progressiva and was thought to be caused by muscular inflammation ( myositis ) that caused bone formation. [ 31 ]  The disease was renamed by  Victor A. McKusick  in 1970 following the discovery that soft tissue other than muscles (e.g.  ligaments ) were also affected by the disease process. [ 31 ]


The best known FOP case is that of  Harry Eastlack  (1933–1973). His condition began to develop at the age of ten, and by the time of his death from pneumonia in November 1973, six days before his 40th birthday, his body had completely ossified, leaving him able to move only his lips. Eastlack never met another person with FOP during his lifetime. [ 32 ]


Eastlack donated his body to science and his skeleton is now at the  Mütter Museum  in  Philadelphia , and has proven to be an invaluable source of information in the study of FOP. Another person with FOP,  Carol Orzel  (April 20, 1959 – February 2018), also donated her body to the museum and her skeleton was placed on exhibit there, adjacent to Eastlack's, in February 2019. [ 33 ] [ 34 ]


Clinical trials of  isotretinoin ,  etidronate  with oral  corticosteroids , and  perhexiline  maleate have failed to demonstrate effectiveness, though the variable course of the disease and small prevalence induces uncertainty. [ 22 ]


A handful of pharmaceutical companies focused on rare diseases are currently in varying stages of investigation into different therapeutic approaches for FOP.


In August 2015, the U.S.  Food and Drug Administration  (FDA) Office of Orphan Products Development granted La Jolla Pharmaceuticals  orphan drug  designation for two novel compounds for FOP. The compounds are small-molecule  protein kinase inhibitors  designed to selectively block ACVR1 (ALK2). [ 40 ]


In August 2015,  Clementia Pharmaceuticals  also began the enrollment of children (ages 6 and above) into its Phase II clinical trial investigating  palovarotene  for the treatment of FOP. [ 41 ]  Preclinical studies demonstrated that palovarotene, a retinoic acid receptor gamma agonist, blocked abnormal bone formation in animal models by inhibition of secondary messenger systems in the BMP pathway. [ 42 ]  Clementia licensed palovarotene from Roche Pharmaceuticals, which previously evaluated the compound in more than 800 individuals including healthy volunteers and patients with chronic obstructive pulmonary disease. Palovarotene received Fast Track designation from the FDA and orphan designations for the treatment of FOP from both the FDA and the  European Medicines Agency  (EMA). [ 41 ]


In September 2015,  Regeneron  announced new insight into the mechanism of disease involving the activation of the ACVR1 receptor by activin A. In 2016, the company initiated a phase 1 study of its activin antibody,  REGN 2477 , in healthy volunteers; a phase 2 trial in FOP patients was conducted in 2017. [ 43 ]


Another potential therapeutic approach involves allele-specific  RNA interference  that targets mutated mRNA for degradation while preserving normal ACVR1 gene expression. [ 44 ]


Further investigation into the mechanisms of heterotopic bone formation in FOP could aid in the development of treatments for other disorders involving extra-skeletal bone formation.


Fibro/adipogenic progenitors (FAPs) may be the disease-causing cell type responsible for activin A dependent ectopic bone formation in both the muscles and tendons of mice bearing the FOP causing ACVR1(R206H) mutation. [ 45 ]


In December 2019,  Ipsen  issued a partial clinical hold for people under the age of 14, due to reports of early fusion of growth plates.


Recently, as of 2021 [update] , a potential therapeutic candidate,  saracatinib , is in phase III clinical trials as a potent heterotopic ossification inhibitor in wild-type and ACVR1 mutant mice. [ 46 ]


A  glycogen storage disease  ( GSD , also  glycogenosis  and  dextrinosis ) 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. [ 1 ]


GSD has two classes of cause: genetic and environmental. Genetic GSD is caused by any  inborn error of carbohydrate metabolism  (genetically defective enzymes or transport proteins) involved in these processes.  In livestock, environmental GSD is caused by  intoxication  with the  alkaloid   castanospermine . [ 2 ]


However, not every inborn error of carbohydrate metabolism has been assigned a GSD number, even if it is known to affect the muscles or liver. For example,  phosphoglycerate kinase deficiency  (gene PGK1) has a myopathic form.


Also,  Fanconi-Bickel syndrome  (gene SLC2A2) and  Danon disease  (gene LAMP2) were declassed as GSDs due to being defects of  transport proteins  rather than  enzymes ; however,  GSD-1  subtypes b, c, and d are due to defects of transport proteins (genes SLC37A4, SLC17A3) yet are still considered GSDs.


Phosphoglucomutase deficiency  (gene PGM1) was declassed as a GSD due to it also affecting the formation of N-glycans; however, as it affects both  glycogenolysis  and  glycosylation , it has been suggested that it should re-designated as GSD-XIV. [ 3 ]


(See  inborn errors of carbohydrate metabolism  for a full list of inherited diseases that affect glycogen synthesis, glycogen breakdown, or glucose breakdown.)


(Lewis' disease) [ 5 ]


Muscle 0b: No


(Muscle 0b) Risk of sudden death in childhood due to cardiac arrest. [ 7 ]


(Liver 0a) Epilepsy [ 9 ]


(Muscle 0b) Rarely epilepsy, tonic-clonic seizures. [ 7 ]  Arrhythmia, long QT syndrome. [ 8 ]


( GAA )


The symptoms of both Pompe and Danon diseases are very similar due to a defect in lysosomes. However, in Danon disease, some show abnormal glycogen accumulation, but not all. [ 15 ]


myogenic  hyperuricemia [ 18 ]


Exercise-induced muscle cramps, stiffness, pain. [ 28 ]


Yes


Myopathy (including exercise-related fatigue,  exercise intolerance , muscle weakness).
Muscle biopsy shows glycogen accumulation. [ 31 ]


Second Wind  phenomenon in some [ 32 ]  but not all [ 3 ]


Methods to diagnose glycogen storage diseases include  history  and  physical examination  for associated symptoms,  blood tests  for associated metabolic disturbances, and  genetic testing  for suspected mutations. [ 16 ] [ 45 ]  It may also include a non-ischemic forearm test,  exercise stress test , or 12-minute walk test (12MWT). [ 45 ]  Advancements in genetic testing are slowly diminishing the need for biopsy; however, in the event of a  VUS  and inconclusive exercise tests, a biopsy would then be necessary to confirm diagnosis. [ 45 ]


Glycogen storage diseases that involve skeletal muscle typically have exercise-induced ( dynamic ) symptoms, such as premature  muscle fatigue , rather than fixed  weakness  ( static ) symptoms. [ 46 ]  Differential diagnoses for glycogen storage diseases that involve fixed muscle weakness, particularly of the  proximal  muscles, would be an  inflammatory myopathy  or a  limb-girdle muscular dystrophy . [ 46 ]


For those with exercise intolerance and/or proximal muscle weakness, the  endocrinopathies  should be considered. [ 47 ] [ 48 ] [ 49 ]  The timing of the symptoms of exercise intolerance, such as muscle fatigue and cramping, is important in order to help distinguish it from other  metabolic myopathies  such as  fatty acid metabolism disorders . [ 50 ]


Problems originating within the circulatory system, rather than the muscle itself, can produce exercise-induced muscle fatigue, pain and cramping that alleviates with rest, resulting from inadequate blood flow ( ischemia ) to the muscles. Ischemia that often produces symptoms in the leg muscles includes  intermittent claudication ,  popliteal artery entrapment syndrome , and  chronic venous insufficiency .


Diseases disrupting the neuromuscular junction can cause abnormal muscle fatigue, such as  myasthenia gravis , an autoimmune disease. [ 51 ]  Similar, are  Lambert–Eaton myasthenic syndrome  (autoimmune) and the  congenital myasthenic syndromes  (genetic).


Diseases can disrupt glycogen metabolism  secondary  to the primary disease. Abnormal thyroid function—hypo- and hyperthyroidism—can manifest as myopathy with symptoms of exercise-induced muscle fatigue, cramping, muscle pain and may include proximal weakness or muscle hypertrophy (particularly of the calves). [ 52 ] [ 48 ]   Hypothyroidism  up-regulates glycogen synthesis and down-regulates glycogenolysis and glycolysis; conversely,  hyperthyroidism  does the reverse, up-regulating glycogenolysis and glycolysis while down-regulating glycogen synthesis. [ 53 ] [ 54 ] [ 55 ] [ 48 ] [ 56 ]


Prolonged hypo- and hyperthyroid myopathy leads to atrophy of type II (fast-twitch/glycolytic)  muscle fibres , and a predominance of type I (slow-twitch/oxidative) muscle fibres. [ 54 ] [ 48 ] [ 49 ]  Muscle biopsy shows abnormal muscle glycogen: high accumulation in hypothyroidism and low accumulation in hyperthyroidism. [ 56 ] [ 53 ] [ 54 ]  Hypothyroid myopathy includes  Kocher-Debre-Semelaigne syndrome  (childhood-onset),  Hoffman syndrome  (adult-onset), myasthenic syndrome, and atrophic form. [ 56 ]


In patients with increased growth hormone, muscle biopsy includes, among other features, excess glycogen deposition. [ 57 ]


EPG5-related  Vici syndrome  is a multisystem disorder, a congenital disorder of  autophagy , with muscle biopsy showing excess glycogen accumulation, among other myopathic features. [ 58 ]


It is interesting to note, in comparison to hypothyroid myopathy, that McArdle disease ( GSD-V ), which is by far the most commonly diagnosed of the muscle GSDs and therefore the most studied, [ 59 ] [ 45 ] [ 60 ]  has as its second highest  comorbidity  endocrine disease (chiefly hypothyroidism) [ 61 ] [ 45 ]  and that some patients with McArdle disease also have hypertrophy of the calf muscles. [ 21 ]  Late-onset Pompe disease ( GSD-II ) also has calf hypertrophy and hypothyroidism as comorbidities. [ 14 ] [ 62 ] [ 63 ]


Poor diet and  malabsorption  diseases (such as celiac disease) may lead to malnutrition of essential vitamins necessary for glycogen metabolism within the muscle cells. Malnutrition typically presents with systemic symptoms, but in rare instances can be limited to myopathy. [ 64 ]   Vitamin D deficiency  myopathy (also known as  osteomalic  myopathy due to the interplay between vitamin D and calcium) results in muscle weakness, predominantly of the proximal muscles; with muscle biopsy showing abnormal glycogen accumulation, atrophy of type II (fast-twitch/glycolytic) muscle fibres, and diminished calcium uptake by the sarcoplasmic reticulum (needed for muscle contraction). [ 65 ] [ 66 ] [ 67 ]  Although Vitamin D deficiency myopathy typically includes muscle atrophy, [ 65 ]  rarely calf muscle hypertrophy has been reported. [ 68 ] [ 69 ]


Exercise-induced, electrically silent, muscle cramping and stiffness (transient muscle contractures or "pseudomyotonia") are seen not only in GSD types V, VII, IXd, X, XI, XII, and XIII, but also in  Brody disease ,  Rippling muscle disease  types 1 and 2, and  CAV3 -related hyperCKemia (Elevated serum creatine phosphokinase). [ 26 ]  Unlike the other myopathies, in Brody disease the muscle cramping is painless. [ 70 ] [ 71 ]  Like GSD types II, III, and V, a pseudoathletic appearance of muscle hypertrophy is also seen in some with Brody disease and Rippling muscle disease. [ 70 ] [ 72 ] [ 73 ]


Erythrocyte lactate transporter defect (formerly  Lactate transporter defect, myopathy due to ) also includes exercise-induced, electrically silent, painful muscle cramping and transient contractures; as well as exercise-induced muscle fatigue. [ 26 ] [ 74 ]  EMG and muscle biopsy is normal however, as the defect is not in the muscle but in the red blood cells that should clear lactate buildup from exercising muscles. [ 74 ]


Although most muscular dystrophies have fixed muscle weakness rather than exercise-induced muscle fatigue and/or cramping, there are a few exceptions. Limb–girdle muscular dystrophy autosomal recessive 23 (LGMD R23) has calf hypertrophy and exercise-induced cramping. [ 75 ]  Myofibrillar myopathy 10 (MFM10) has exercise-induced muscle fatigue, cramping and stiffness, with hypertrophic neck and shoulder girdle muscles. [ 76 ]  LGMD R28 has calf hypertrophy and exercise-induced muscle fatigue and pain. [ 77 ]  LGMD R8 has calf pseudohypertrophy and exercise-induced weakness (fatigue) and pain. [ 78 ]  LGMD R15 (a.k.a MDDGC3) has muscle hypertrophy, proximal muscle weakness, and muscle fatigue. [ 79 ]


DMD-related myopathies of  Duchenne  and  Becker muscular dystrophy  are known for fixed muscle weakness and pseudohypertrophic calf muscles, but they also have secondary  muscular mitochondrial impairment  causing low ATP production; as well as decreasing type II (fast-twitch/glycolytic) muscle fibres, producing a predominance of type I (slow-twitch/oxidative) muscle fibres. [ 80 ]  DMD-related childhood-onset milder phenotypes present with exercise-induced muscle cramping, stiffness, pain, fatigue, and elevated CK. [ 81 ]  Becker muscular dystrophy has adult-onset exercise-induced muscle cramping, pain, and elevated CK. [ 82 ]


Tubular aggregate myopathy  (TAM) types 1 and 2 has exercise-induced muscle pain, fatigue, stiffness, with proximal muscle weakness and calf muscle pseudohypertrophy. TAM1 has cramping at rest, while TAM2 has cramping during exercise. [ 83 ] [ 84 ] [ 85 ] [ 86 ]  Stormorken syndrome includes the symptoms of TAM, but is a more severe presentation including short stature and other abnormalities. [ 84 ]   Satoyoshi syndrome  has exercise-induced painful muscle cramps, muscle hypertrophy, and short stature. [ 87 ]  Dimethylglycine dehydrogenase deficiency has muscle fatigue, elevated CK, and fishy body odour. [ 88 ]  Myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR) has exercise-induced muscle cramps, pain, and fatigue; with some exhibiting proximal muscle weakness. [ 89 ]


(help wikipedia by contributing to this subsection)


Glycogenosis-like phenotype of  congenital hyperinsulinism  due to  HNF4A  mutation or  MODY1  (maturity-onset diabetes of the young, type 1). This phenotype of MODY1 has  macrosomia  and infantile-onset hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in liver and erythrocytes, increased liver transaminases, transient  hepatomegaly , renal  Fanconi syndrome , and later develop liver cirrhosis, decreased succinate-dependent respiration (mitochondrial dysfunction), rickets,  nephrocalcinosis , chronic kidney disease, and diabetes. [ 90 ] [ 91 ] [ 92 ]


Treatment is dependent on the type of glycogen storage disease. Von Gierke disease ( GSD-I ) is typically treated with frequent small meals of  carbohydrates  and  cornstarch , called  modified cornstarch therapy , to prevent low blood sugar, while other treatments may include  allopurinol  and  human granulocyte colony stimulating factor . [ 93 ]


Cori/Forbes disease ( GSD-III ) treatment may use modified cornstarch therapy, a high protein diet with a preference to complex carbohydrates. However, unlike GSD-I,  gluconeogenesis  is functional, so simple sugars (sucrose, fructose, and lactose) are not prohibited. [ 16 ]


A ketogenic diet has demonstrated beneficial for McArdle disease ( GSD-V ) as ketones readily convert to acetyl CoA for oxidative phosphorylation, whereas free fatty acids take a few minutes to convert into acetyl CoA. [ 94 ] [ 95 ]


For  phosphoglucomutase deficiency  (formerly GSD-XIV), D-galactose supplements and exercise training has shown favourable improvement of signs and symptoms. [ 30 ]  In terms of exercise training, some patients with phosphoglucomutase deficiency also experience "second wind." [ 30 ] [ 32 ]


For McArdle disease (GSD-V), regular aerobic exercise utilizing " second wind " to enable the muscles to become aerobically conditioned, as well as anaerobic exercise (strength training) that follows the activity adaptations so as not to cause muscle injury, helps to improve exercise intolerance symptoms and maintain overall health. [ 45 ] [ 60 ] [ 96 ] [ 97 ]  Studies have shown that regular low-moderate aerobic exercise increases peak power output, increases peak oxygen uptake ( V̇O 2 peak ), lowers heart rate, and lowers serum CK in individuals with McArdle disease. [ 96 ] [ 97 ]


Regardless of whether the patient experiences  symptoms  of muscle pain, muscle fatigue, or cramping, the phenomenon of second wind having been achieved is demonstrable by the  sign  of an increased heart rate dropping while maintaining the same speed on the treadmill. [ 97 ]  Inactive patients experienced second wind, demonstrated through relief of typical symptoms and the sign of an increased heart rate dropping, while performing low-moderate aerobic exercise (walking or brisk walking). [ 97 ]


Conversely, patients that were regularly active did not experience the typical symptoms during low-moderate aerobic exercise (walking or brisk walking), but still demonstrated second wind by the sign of an increased heart rate dropping. [ 97 ] [ 98 ]  For the regularly active patients, it took more strenuous exercise (very brisk walking/jogging or bicycling) for them to experience both the typical symptoms and relief thereof, along with the sign of an increased heart rate dropping, demonstrating second wind. [ 97 ] [ 98 ] [ 99 ]


In young children (<10 years old) with McArdle disease (GSD-V), it may be more difficult to detect the second wind phenomenon. They may show a normal heart rate, with normal or above normal peak cardio-respiratory capacity ( V̇O 2max ). [ 45 ] [ 100 ]  That said, patients with McArdle disease typically experience symptoms of exercise intolerance before the age of 10 years, [ 45 ]  with the median symptomatic age of 3 years. [ 59 ] [ 101 ]


Tarui disease ( GSD-VII ) patients do not experience the "second wind" phenomenon; instead are said to be "out-of-wind." [ 45 ] [ 60 ] [ 102 ]  However, they can achieve sub-maximal benefit from lipid metabolism of free fatty acids during aerobic activity following a warm-up. [ 45 ]


Overall, according to a study in  British Columbia , approximately 2.3 children per 100,000 births (1 in 43,000) have some form of glycogen storage disease. [ 103 ]  In the United States, they are estimated to occur in 1 per 20,000–25,000 births. [ 10 ]  Dutch incidence rate is estimated to be 1 per 40,000 births.
While a Mexican incidence showed 6.78:1000 male newborns. [ 12 ] [ 104 ]


Within the category of muscle glycogenoses (muscle GSDs), McArdle disease (GSD-V) is by far the most commonly diagnosed. [ 59 ]