Glycogen storage disease type V  ( GSD5 ,  GSD-V ), [ 1 ]  also known as  McArdle's disease , [ 2 ]  is a  metabolic disorder , one of the  metabolic myopathies , more specifically a muscle  glycogen storage disease , caused by a deficiency of  myophosphorylase . [ 3 ] [ 4 ]  Its incidence is reported as one in 100,000, roughly the same as  glycogen storage disease type I . [ 2 ]


The disease was first reported in 1951 by British physician  Brian McArdle  of  Guy's Hospital , London. [ 5 ]


In the classic  phenotype , the onset of this disease is usually noticed in childhood, [ 6 ] [ 7 ] [ 8 ]  but often not diagnosed until the third or fourth decade of life, frequently due to misdiagnosis and dismissal of symptoms. [ 6 ] [ 8 ]  The median age of symptom onset is 3 years, with the median diagnostic delay being 29 years. [ 8 ]  Misdiagnosis is overwhelmingly common, with approximately 90% of patients being misdiagnosed, and approximately 62% receiving multiple misdiagnoses before a correct diagnosis. [ 8 ]  The prolonged diagnostic delay, misdiagnosis or multiple misdiagnoses, or being given inappropriate exercise advice (such as ignore pain or avoid exercise) severely impacts quality of life (QoL), physically and mentally. [ 6 ] [ 8 ]


There is an ultra-rare adult-onset,  limb–girdle  phenotype that presents very late in life (70+ years of age) due to a recessive  homozygous  PYGM mutation (p. Lys42Profs*48) resulting in severe upper and lower limb atrophy, with the possibility of ptosis (drooping eyelids) and camptocormia (stooped posture). [ 9 ]  As of 2017, there have been two reported cases of this specific homozygous mutation and phenotype. [ 9 ]  In 1980, a woman also had a limb–girdle phenotype with onset at age 60, histochemical staining showed myophosphorylase deficiency; however the genetic mutation was unknown. [ 10 ]


There is an ultra-rare, fatal infantile-onset phenotype that results in profound muscle weakness (" floppy baby ") and respiratory failure within weeks of birth (perinatal asphyxia). Post mortem biopsy showed deficiency of myophosphorylase and abnormal glycogen accumulation in skeletal muscle tissue. This phenotype may also include premature birth and joint contractures. [ 11 ] [ 12 ]  Two reported cases, in 1978 and 1989. [ 13 ]


There is an ultra-rare mild phenotype caused by recessive  heterozygous  alleles in the PYGM gene, where one allele is a common  exon  mutation and the other allele is an ultra-rare  intronic  mutation. It can also be caused by recessive homozygous intronic mutations. These intronic mutations result in a milder phenotype compared to the classic phenotype of McArdle disease. There is residual myophosphorylase activity, between 1-2% residual activity compared to unaffected individuals. This results in greater exercise capacity compared to classic phenotype McArdle individuals, particularly for sustained aerobic activity, but the capacity was still below that of unaffected individuals. In this mild phenotype, since their early teens, they did experience cramping and premature muscle fatigue during sudden vigorous exercise and prolonged isometric exercise; however, due to their less diminished capacity for aerobic activity, they were able to keep up with their peers in sports and everyday activities. [ 14 ] [ 15 ]  As of 2009, there have been 3 reported cases of non-related individuals, a reported  Druze  family of  consanguineous  (related) individuals and 9 reported cases in two  Finnish  families. [ 14 ] [ 16 ] [ 15 ] [ 17 ]


The most prominent symptom is that of  exercise intolerance  which includes:


Heart rate during exercise is a key indicator as, unlike the symptoms of muscle fatigue and cramping, it is a medical sign (meaning that it is observable and measurable by a third party rather than felt subjectively by the patient). In regularly active individuals with McArdle disease, they may not feel the usual symptoms of muscle fatigue and cramping until they increase their speed to very brisk walking, jogging or cycling; however, they will still show an inappropriate rapid heart rate response to exercise, with a declining heart rate once second wind has been achieved. [ 20 ] [ 21 ] [ 22 ]


"In McArdle's, our heart rate tends to increase in what is called an 'inappropriate' response. That is, after the start of exercise it increases much more quickly than would be expected in someone unaffected by McArdle's." [ 19 ]


Myoglobinuria  (reddish-brown urine) may be seen due to the breakdown of  skeletal muscle  known as  rhabdomyolysis  (a condition in which muscle cells breakdown, sending their contents into the bloodstream). [ 23 ]  In 2020, the largest study to-date of 269 GSD-V patients, 39.4% reported no previous episodes of myoglobinuria and 6.8% had normal CK (including those with fixed muscle weakness); so an absence of myoglobinuria and normal CK should not rule out the possibility of the disease. [ 24 ]  Between 33-51.4% develop fixed  muscle weakness , typically of the trunk and upper body, with the onset of muscle weakness usually occurring later in life (40+ years of age). [ 25 ] [ 24 ]


Younger people may display unusual symptoms, such as difficulty in chewing, swallowing or utilizing normal oral motor functions. [ 26 ]  Idiopathic leg pains were common in children, usually occurring at night, often presumed to be "growing pains" and not investigated further. [ 27 ]  A number of comorbidities were found in GSD-V individuals at a higher rate than in the general population, including (but not limited to): hypertension (17%), endocrine diseases (15.7%), musculoskeletal/rheumatic disease (12.9%), hyperuricemia/gout (11.6%), gastrointestinal diseases (11.2%), neurological disease (10%), respiratory disease (9.5%), and coronary artery disease (8.3%). [ 24 ]  They may have a  pseudoathletic appearance  of muscle hypertrophy (24%), particularly of the legs, and may have lower bone mineral content and density in the legs. [ 28 ] [ 27 ] [ 29 ] [ 30 ]


Besides exercise-induced premature muscle fatigue, GSD-V individuals may also have comorbidities of mental fatigue, general fatigue, reduced motivation, sleep disturbances, anxiety and depression. [ 31 ] [ 27 ]


As skeletal muscle relies predominantly on  glycogenolysis  for the first few minutes as it transitions from rest to activity, as well as throughout high-intensity aerobic activity and all anaerobic activity, individuals with GSD-V experience during exercise:  sinus tachycardia ,  tachypnea , muscle fatigue and pain, during the aforementioned activities and time frames. [ 18 ] [ 32 ]  They may exhibit a  "second wind" phenomenon , which is characterized by the individual's better tolerance for aerobic exercise such as walking and cycling after approximately 10 minutes. [ 33 ]   This is attributed to the combination of increased blood flow and the ability of the body to find alternative sources of energy, like fatty acids, proteins, and increased blood glucose uptake. [ 6 ] [ 18 ]


AMP is primarily produced from the  myokinase  (adenylate kinase) reaction, [ 34 ]  which runs when the ATP reservoir is low. The myokinase reaction is one of three reactions in the  phosphagen system (ATP-PCr) , with the myokinase reaction occurring after phosphocreatine (creatine phosphate) has been depleted. In McArdle disease individuals, their muscle cells produce far more AMP than non-affected individuals as the reduced glycolytic flux from impaired glycogenolysis results in a chronically low ATP reservoir during exercise. [ 34 ]  The muscle cells need  ATP  (adenosine triphosphate) as it provides energy for  muscle contraction  by actively transporting calcium ions into the sarcoplasmic reticulum before muscle contraction, and it is used during muscle contraction for the release of myosin heads in the sliding filament model during the cross-bridge cycle.


Along with the myokinase reaction, AMP is also produced by the  purine nucleotide cycle , which also runs when the ATP reservoir in muscle cells is low, and is a part of  protein metabolism . In the purine nucleotide cycle, three nucleotides:  AMP  (adenosine monophosphate),  IMP  (inosine monophosphate), and  S-AMP  (adenylosuccinate) are converted in a circular fashion; the byproducts are fumarate (which goes on to produce ATP via oxidative phosphorylation), ammonia (from the conversion of AMP into IMP), and uric acid (from excess AMP). GSD-V patients may experience myogenic  hyperuricemia  (exercise-induced accelerated breakdown of purine nucleotides in skeletal muscle). [ 35 ] [ 36 ]


To avoid health complications, GSD-V patients need to get their ATP primarily from free fatty acids ( lipid metabolism ) rather than  protein metabolism .  Over-reliance on protein metabolism can be best avoided by not depleting their ATP reservoir, such as by not pushing through the pain and by not going too fast, too soon. [ 19 ] [ 22 ]


"Be wary of pushing on when you feel pain start. This pain is a result of damaging muscles, and repeated damage will cause problems in the long term. But also this is counterproductive–it will stop you from getting into second wind. By pressing on despite the pain, you start your protein metabolism which then effectively blocks your glucose and  fat metabolism . If you ever get into this situation, you need to stop completely for 30 minutes or more and then start the whole process again." [ 22 ]


Patients may present at emergency rooms with a transient  contracture  of the muscles and often severe pain (e.g. "clawed hand"). These require urgent assessment for  rhabdomyolysis  as in about 30% of cases this leads to  acute kidney injury , which left untreated can be life-threatening. In a small number of cases  compartment syndrome  has developed, requiring prompt surgical referral. [ 25 ] [ 37 ] [ 38 ]


McArdle disease (GSD-V) is inherited in an  autosomal recessive  manner. If both parents are carriers (not having the disease, but each parent having one copy of the mutated allele), then each child of the couple will have a 25% chance of being affected (having McArdle disease), a 50% chance of being a carrier, and a 25% chance of being unaffected (neither a carrier nor diseased). [ 26 ]


Two autosomal recessive forms of this disease occur, childhood-onset and adult-onset. The gene for myophosphorylase,  PYGM  (the muscle-type of the glycogen phosphorylase gene), is located on chromosome 11q13. According to the most recent publications, 95 different mutations have been reported.  The forms of the mutations may vary between ethnic groups. For example, the  R50X  (Arg50Stop) mutation (previously referred to as  R49X ) is most common in North America and western Europe, and the  Y84X  mutation is most common among central Europeans. [ 9 ]


The exact method of protein disruption has been elucidated in certain mutations. For example,  R138W  is known to disrupt to pyridoxal phosphate binding site. [ 39 ]  In 2006, another mutation (c.13_14delCT) was discovered which may contribute to increased symptoms in addition to the common Arg50Stop mutation. [ 40 ]


The myophosphorylase structure consists of 842 amino acids. Its molecular weight of the unprocessed precursor is 97 kDa. The three-dimensional structure has been determined for this protein. The interactions of several amino acids in myophosphorylase's structure are known. Ser-14 is modified by phosphorylase kinase during activation of the enzyme. Lys-680 is involved in binding the pyridoxal phosphate, which is the active form of  vitamin B 6 , a cofactor required by myophosphorylase. By similarity, other sites have been estimated: Tyr-76 binds AMP, Cys-109 and Cys-143 are involved in subunit association, and Tyr-156 may be involved in allosteric control. [ citation needed ]


Myophosphorylase  is the form of the glycogen phosphorylase found in muscle that catalyses the following reaction: [ 41 ] [ 42 ] [ 43 ]


((1→4)-alpha-D-glucosyl)  (n)  +  phosphate  = ((1→4)-alpha-D-glucosyl)  (n-1)  + alpha-D-glucose 1-phosphate


During exercise, a deficiency of this enzyme ultimately leads to rapid depletion of phosphocreatine, a decrease in available ATP, and an exaggerated rise of ADP and AMP. [ 44 ] [ 45 ]  McArdle disease individuals also have increased maximum fat oxidation compared to unaffected individuals. [ 46 ]  During exercise, in affected individuals, there is no significant rise in lactic acid production compared to resting levels (it may even fall below resting levels), and plasma  pH levels rise  (become more alkaline) rather than fall (become more acidic). [ 47 ] [ 48 ]


Myophosphorylase  is involved in the breakdown of glycogen to glucose-1-phosphate for use in muscle. The enzyme removes 1,4 glycosyl residues from outer branches of glycogen and adds inorganic phosphate to form  glucose-1-phosphate . Ordinarily, the removal of 1,4 glycosyl residues by myophosphorylase leads to the formation of glucose-1-phosphate during glycogen breakdown and the polar, phosphorylated glucose cannot leave the cell membrane and so is marked for intracellular catabolism. In McArdle's disease, deficiency of myophosphorylase leads to accumulation of intramuscular glycogen and a lack of glucose-1-phosphate for cellular fuel. [ citation needed ]


Myophosphorylase comes in two forms: form 'a' is phosphorylated by  phosphorylase kinase , form 'b' is not phosphorylated. Form 'a' is de-phosphorylated into form 'b' by the enzyme  phosphoprotein phosphatase , which is activated by elevated insulin. Both forms have two  conformational  states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate. Myophosphorylase-b is  allosterically  activated by elevated AMP within the cell, and allosterically inactivated by elevated ATP and/or glucose-6-phosphate. Myophosphorylase-a is active, unless allosterically inactivated by elevated glucose within the cell. In this way, myophosphorylase-a is the more active of the two forms as it will continue to convert glycogen into glucose-1-phosphate even with high levels of glycogen-6-phosphate and ATP.  [ citation needed ]


There are some  laboratory tests  that may aid in diagnosis of GSD-V. A  muscle biopsy  will note the absence of myophosphorylase in muscle fibers. In some cases, abnormal accumulation of glycogen stained by  periodic acid-Schiff  can be seen with microscopy. [ 25 ] [ 9 ]


Genetic sequencing  of the PYGM gene (which codes for the muscle isoform of  glycogen phosphorylase [ 49 ] [ 50 ] ) may be done to determine the presence of  gene mutations , determining if McArdle's is present. This type of testing is considerably less invasive than a muscle biopsy. [ 26 ]


The  physician  can also perform an ischemic forearm exercise test as described below (see  History ). Some findings suggest a nonischemic test could be performed with similar results. [ 51 ]  The nonischemic version of this test would involve not cutting off the blood flow to the exercising arm. Findings consistent with McArdle's disease would include a failure of  lactate  to rise in  venous blood  and exaggerated  ammonia  levels. These findings would indicate a severe muscle glycolytic block.


Serum lactate may fail to rise in part because of increased uptake via the  monocarboxylate transporter (MCT1) , which is upregulated in  skeletal muscle  in McArdle disease. Lactate may be used as a fuel source once converted to  pyruvate . Ammonia levels may rise given ammonia is a by-product of  AMP deaminase  which follows after the production of AMP by  adenylate kinase , an alternative pathway for ATP production. In this pathway, adenylate kinase combines two ADP molecules to make ATP and AMP; AMP is then  deaminated , producing  inosine monophosphate (IMP)  and  ammonia (NH 3 )  as part of  purine nucleotide cycle . [ 45 ]


Physicians may also check resting levels of  creatine kinase , which are moderately increased in 90% of patients. [ 18 ]  In some, the level is increased by multitudes - a person without GSD-V will have a CK between 60 and 400IU/L, while a person with the syndrome may have a level of 5,000 IU/L at rest, and may increase to 35,000 IU/L or more with muscle exertion. This can help distinguish McArdle's syndrome from  carnitine palmitoyltransferase II deficiency  (CPT-II), a lipid-based metabolic disorder which prevents fatty acids from being transported into  mitochondria  for use as an energy source. Also, serum electrolytes and endocrine studies (such as thyroid function, parathyroid function and growth hormone levels) will also be completed. Urine studies are required only if rhabdomyolysis is suspected. Urine volume, urine sediment and myoglobin levels would be ascertained. If rhabdomyolysis is suspected, serum myoglobin, creatine kinase, lactate dehydrogenase, electrolytes and renal function will be checked. [ citation needed ]


Physicians may also conduct an  exercise stress test  to test for an inappropriate rapid heart rate ( sinus tachycardia ) in response to exercise. Due to the rare nature of the disease, the inappropriate rapid heart rate in response to exercise may be misdiagnosed as  inappropriate sinus tachycardia  (which is a  diagnosis of exclusion ). The 12 Minute Walk Test (12MWT) can be used to determine " second wind ," which requires a treadmill (no incline), heart rate monitor, stop watch, pain scale, and that the patient has rested for 30 minutes prior to the test to ensure that "second wind" has stopped (that is, that increased ATP production primarily from free fatty acids has returned to resting levels). [ 20 ] [ 52 ]


Electromyography  (EMG) may show normal or myopathic results (short duration, polyphasic, small amplitude  MUAPs ). [ 9 ] [ 53 ]  Before exercise, a minority of GSD-V patients show myopathic results (5/25 patients); whereas after 5 minutes of high-intensity isometric exercise, the majority showed myopathic results (22/25 patients). The myopathic results were a decrease in  CMAP  amplitude, which was evident immediately after exercise and, after a plateau phase of a few minutes, reached its maximum after 30 minutes. [ 53 ]


Dynamic symptoms of exercise intolerance (e.g. muscle fatigue and cramping) with or without fixed proximal muscle weakness:


Exercise-induced muscle fatigue without cramping:


Fixed symptom of muscle weakness, predominantly of the proximal muscles:


Allelic to McArdle disease (GSD-V) is a recently discovered disease that has a pathogenic autosomal dominant mutation in exon 16 of the PYGM gene c.1915G>C (p.Asp639His). Discovered in 2020, it affected 13 members of a family over four generations and has yet to be assigned a GSD number. Unlike McArdle disease (GSD-V), this disease does not have an overall deficiency of myophosphorylase, only a deficiency of functioning myophosphorylase-a with plenty of functioning myophosphorylase-b (similar to  GSD-IXd ). Myophosphorylase-b can be  allosterically  activated to break down glycogen (glycogenolysis) by high levels of AMP, and as the AMP-dependent activity was preserved, the individuals of this family had normal muscle glycogen concentrations as well as lacked exercise intolerance (which are prominent distinguishing features from McArdle disease). The only symptom was adult-onset (40+ years of age) fixed muscle weakness, initially of the proximal muscles of the legs, followed by proximal arms, then distal leg muscles. Muscle biopsy also showed accumulation of the intermediate filament desmin in the myofibres. [ 54 ] [ 55 ]


Supervised exercise programs have been shown in small studies to improve exercise capacity by several measures: lowering heart rate, lowering serum creatine kinase (CK), increasing the exercise intensity threshold before symptoms of muscle fatigue and cramping are experienced, and the skeletal muscles becoming  aerobically conditioned . [ 56 ] [ 57 ] [ 30 ] [ 6 ]


Oral sucrose treatment (for example a sports drink with 75 grams of sucrose in 660 ml.) taken 30 minutes prior to exercise has been shown to help improve exercise tolerance, including a lower heart rate and lower perceived level of exertion compared with placebo. [ 58 ]  This is because the ingestion of a high-carbohydrate meal or drink causes transient hyperglycaemia, with the exercising muscle cells utilizing the high glucose in the blood for the glycolytic pathway. However, the ingestion of a high-carbohydrate meal or drink is problematic as a frequent form of treatment since it will increase the release of  insulin , which inhibits the release of fatty acids [ 59 ]  and subsequently will delay the ability to get into  second wind . [ 19 ]  The frequent ingestion of sucrose (e.g. sugary drinks), in order to avoid premature muscle fatigue and cramping, is also problematic in that it can lead to obesity as insulin will also stimulate triglyceride synthesis (develop body fat), [ 59 ]  and obesity-related ill health (e.g. type II diabetes and heart disease). [ 19 ] [ 60 ]


A low dosage treatment with  creatine  showed a significant improvement of muscle problems compared to placebo in a small clinical study, while other studies have shown minimal subjective benefit. [ 61 ] [ 62 ]  High dosage treatment of creatine has been shown to worsen symptoms of myalgia (muscle pain). [ 62 ]


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. [ 63 ] [ 64 ]  Ketones are a part of fat metabolism, [ 59 ]  the ketones can act as the main fuel before fatty acid catabolism takes over (second wind), during which the ketones would act as a supplementary fuel alongside the fatty acids to produce adenosine triphosphate (ATP) by oxidative phosphorylation.


The deficiency was the first  metabolic myopathy  to be recognized, when the physician  Brian McArdle  described the first case in a 30-year-old man who always experienced pain and weakness after exercise. McArdle noticed this patient's cramps were electrically silent and his venous  lactate  levels failed to increase upon ischemic exercise. (The ischemic exercise consists of the patient squeezing a hand dynamometer at maximal strength for a specific period of time, usually a minute, with a blood pressure cuff, which is placed on the upper arm and set at 250 mmHg, blocking blood flow to the exercising arm.)


Notably, this is the same phenomenon that occurs when muscle is poisoned in vitro by  iodoacetate , which inhibits the breakdown of glycogen into glucose and prevents the formation of lactate; as well as produces an electronically silent muscle contracture. Knowing what occurs to muscle poisoned by iodoacetate, helped McArdle speculate that a glycogenolytic block might be occurring when he first described the disease. [ 65 ]  McArdle accurately concluded that the patient had a disorder of glycogen breakdown that specifically affected skeletal muscle. The associated enzyme deficiency was discovered in 1959 by  W. F. H. M. Mommaerts  et al. [ 66 ]


Naturally-occurring myophosphorylase deficiency (GSD-V; McArdle disease) has been found in  Charolais cattle  and  Merino sheep . [ 67 ]  The cattle were asymptomatic at rest, but when forced to exercise, would become noticeably fatigued and recumbent (having to lie down) for approximately 10 minutes before being able to resume exercise (the second wind phenomenon). [ 68 ] [ 69 ]


Artificially-induced myophosphorylase deficiency was created in mice, by altering their embryonic DNA, for use in laboratory experiments. [ 67 ] [ 70 ]


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


HIBMs are a group of  muscle wasting  disorders that are uncommon in the general world population. One autosomal recessive form of HIBM is known as IBM2 or  GNE myopathy , which is a common genetic disorder amongst people of Iranian Jewish descent. [ 1 ]  IBM2 has also been identified in other minorities throughout the world, including those of Asian, European, and South American, and Middle Eastern descent. In Japan and other East Asian countries, this disorder is known as  distal myopathy with rimmed vacuoles  (DMRV).


IBM2 causes progressive muscle weakness and wasting. Muscle wasting usually starts around the age of 20 – 30 years, although young onset at 17 and old onset at 52 has been recorded. It can progress to marked disability within 10 to 15 years, causing many people with IBM2 to become full-time wheelchair users. The weakness and severity can vary from person to person. In some, weakness in the legs is noticed first. In some others, the hands are weakened more rapidly than the legs. IBM2 does not seem to affect the brain, internal organs or sensation. The  quadriceps  are relatively spared, and remain strong until the late stages of disease, which is the reason IBM2 is often referred to as quadriceps sparing myopathy (QSM).


Some early signs of HIBMs includes:


The different forms have different mutations and inheritance patterns. See the detailed descriptions for details


The exact mechanisms of these diseases are not well understood.    GNE/MNK  a key enzyme in the  sialic acid biosynthetic pathway , and loss-of-function mutations in GNE/MNK may lead to a lack of sialic acid, which in turn could affect  sialoglycoproteins .  GNE  knockout mice  show problems similar to people with IBM and in people with IBM  dystroglycan  has been found to lack sialic acid.  However, the part of the dystroglycan that is important in muscle function does not seem to be affected.  Another protein,  neural cell adhesion molecule  is under-sialyated in people with IBM, but as of 2016 it had no known role in muscle function. [ 2 ]


The most useful information for accurate diagnosis is the symptoms and weakness pattern. If the quadriceps are spared but the hamstrings and iliopsoas are severely affected in a person between ages of 20 - 40, it is very likely HIBM will be at the top of the differential diagnosis. The doctor may order any or all of the following tests to ascertain if a person has IBM2:


Types of hereditary inclusion body myopathy:


The condition now called  Desmin-related myofibrillar myopathy  (also called myofibrillar myopathy-1) was formerly known as inclusion body myopathy 1 (IBM1). [ 13 ]


More types of HIMBs, linked to other genes, may be identified in the future.


Treatment is  palliative , not curative (as of 2009). [ 14 ]


Treatment options for lower limb weakness such as foot drop can be through the use of Ankle Foot Orthoses (AFOs) which can be designed or selected by an Orthotist based upon clinical need of the individual.  Sometimes tuning of rigid AFOs can enhance knee stability.


A 2009 review noted that muscle weakness usually begins after age 20 and after 20–30 years, the person usually requires a wheelchair for mobility. There was no mention of increased mortality. [ 14 ]


Because lack of sialic acid appears to be part of the pathology of IBM caused by GNE mutations, clinical trials with sialic acid supplements, and with a precursor of sialic acid,  N-Acetylmannosamine ,  have been conducted, and as of 2016 further trials were planned. [ 2 ]


Hereditary inclusion body myopathy (IBM) constitutes a unique group of neuromuscular disorders characterized by adult-onset slowly progressive distal and proximal weakness, and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. Autosomal dominant (IMB3; OMIM 605637  [1] ) and autosomal recessive (IBM2; OMIM 600737  [2] ) forms have been described. The autosomal recessive form, first characterized in Jews of Persian descent, is a myopathy that affects mainly leg muscles, but with an unusual distribution that spares the quadriceps, so-called quadriceps-sparing myopathy (QSM). This disorder was subsequently found in other Middle Eastern families, the gene was mapped to 9p13-p12, and in 104 affected persons from 47 Middle Eastern families the same mutation in homozygous state was found in the GNE gene. [ 15 ]  Affected individuals in families of other ethnic origins were found to be compound heterozygotes for other distinct mutations in the GNE gene. From OMIM 603824. [3]


Hoffmann syndrome  is a rare form of  hypothyroid   myopathy  and is not to be confused with  Werdnig-Hoffmann disease  (a type of spinal muscular atrophy).


It was first documented in 1897 by  Johann Hoffmann . [ 1 ]  It has adult-onset symptoms and is comparable to the childhood-onset  Kocher–Debré–Semelaigne syndrome . It is caused by low  thyroid hormones  (T3 and T4) with elevated TSH. [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Signs and symptoms include  exercise intolerance ,  muscle fatigue ,  muscle cramps ,  myalgia , delayed muscle relaxation (pseudo myotonia ), proximal  muscle weakness , delayed deep tendon reflexes ( hyporeflexia ) especially of the ankles, and a  pseudoathletic appearance  of  hypertrophic  calf muscles. There may also be  bradycardia , mild  anemia , dry skin, hoarse voice, and  cold intolerance .  EMG  may be normal, neuropathic, myopathic, or mixed type. Serum  CK  may be normal or raised. The sign of  myoedema  (raised muscle tissue in response to percussive tactile stimulus) may be observed. Treatment is thyroid hormone replacement therapy and  prognosis  is generally good. Hypertrophic calves typically return to normal after approximately 3 months of treatment. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


It is caused by low  thyroid hormones  (T3 and T4).  [ 2 ] [ 3 ] [ 4 ] [ 5 ]


Muscle biopsy of hypothyroid myopathy shows atrophy of type II (fast-twitch/glycolytic)  muscle fibres  and a predominance of type I (slow-twitch/oxidative) muscle fibres; as well as abnormally high glycogen accumulation. [ 7 ] [ 8 ] [ 9 ]  The reason for the muscle hypertrophy in Hoffmann syndrome is not clearly established; it may be due to altered  carbohydrate metabolism ,  mucoid  deposits, or  glycosaminoglycan  deposits. [ 3 ] [ 7 ]  In an individual diagnosed with Hoffmann syndrome whose hypertrophy did not improve after thyroid hormone replacement therapy, muscle biopsy showed hypertrophy of muscle fibres with increased nuclei, few necrotic fibres and  mucoid  deposits in places. [ 6 ]


Diseases known to have a  pseudoathletic appearance  of the calves ( hypertrophy  or  pseudohypertrophy ), including exercise intolerance and/or muscle weakness:


Thyroid metabolism can be disrupted secondary to a primary disease. A common  comorbidity  of the  metabolic myopathy  McArdle disease (Glycogen storage disease type V) is hypothyroidism. [ 14 ] [ 15 ]  It is also a comorbidity of late-onset Pompe disease (Glycogen storage disease type II). [ 16 ] [ 17 ]  As both hyper- and hypothyroidism disrupts muscle glycogen metabolism, it is important to keep in mind differential diagnoses and their comorbidities when trying to determine whether signs and symptoms are either  primary or secondary disease . [ 7 ] [ 8 ] [ 9 ] [ 18 ] [ 19 ]


β-Hydroxy β-methylbutyric acid [ note 1 ]  ( HMB ), otherwise known as its  conjugate base ,  β-hydroxy   β-methylbutyrate , is a  naturally produced  substance in humans that is used as a  dietary supplement  and as an ingredient in certain  medical foods  that are intended to promote  wound healing  and provide nutritional support for people with  muscle wasting  due to  cancer  or  HIV/AIDS . [ sources 1 ]  In healthy adults, supplementation with HMB has been shown to increase exercise-induced gains in  muscle  size, muscle strength, and  lean body mass , reduce  skeletal muscle  damage from exercise, improve aerobic exercise performance, and expedite recovery from exercise. [ sources 2 ]   Medical reviews  and  meta-analyses  indicate that HMB supplementation also helps to preserve or increase lean body mass and muscle strength in individuals experiencing  age-related muscle loss . [ note 2 ] [ 11 ] [ 12 ] [ 13 ]  HMB produces these effects in part by stimulating the  production of proteins  and inhibiting the  breakdown of proteins  in muscle tissue. [ 11 ] [ 14 ] [ 15 ]  No  adverse effects  from long-term use as a dietary supplement in adults have been found. [ 16 ] [ 17 ] [ 18 ]


HMB is sold as a dietary supplement at a cost of about  US$ 30–50  per month when taking 3 grams per day. [ 16 ] [ 19 ] [ 20 ]  HMB is also contained in several nutritional products, including certain formulations of  Ensure  and  Juven . [ 8 ] [ 21 ]  HMB is also present in insignificant quantities in certain foods, such as  alfalfa ,  asparagus ,  avocados ,  cauliflower ,  grapefruit , and  catfish . [ 22 ] [ 23 ]


The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at  Iowa State University  in the  mid-1990s . [ 8 ] [ 24 ]  As of 2018, [update]  HMB has not been banned by the  National Collegiate Athletic Association ,  World Anti-Doping Agency , or any other prominent national or international athletic organization. [ 25 ] [ 26 ] [ 27 ]  In 2006, only about 2% of college  student athletes  in the United States used HMB as a dietary supplement. [ 19 ] [ 28 ]  As of 2017, HMB has reportedly found widespread use as an  ergogenic supplement  among young athletes. [ 29 ]


HMB is sold as an  over-the-counter   dietary supplement  in the  free acid  form,  β-hydroxy β-methylbutyric acid  (HMB-FA), and as a  monohydrated  calcium  salt  of the  conjugate base ,  calcium  β-hydroxy β-methylbutyrate  monohydrate  (HMB-Ca, CaHMB). [ 19 ] [ 20 ]  Since only a small fraction of HMB's metabolic precursor,  L -leucine , is metabolized into HMB, pharmacologically active concentrations of the compound in  blood plasma  and muscle can only be achieved by supplementing HMB directly. [ 1 ] [ 30 ] [ 31 ]  A healthy adult produces approximately 0.3 grams per day, while supplemental HMB is usually taken in doses of  3–6  grams per day. [ 17 ]  HMB is sold at a cost of about  US$ 30–50  per month when taken in doses of 3 grams per day. [ 16 ]  HMB is also contained in several nutritional products and medical foods marketed by  Abbott Laboratories  (e.g., certain formulations of  Ensure  and  Juven ), [ 8 ] [ 21 ]  and is present in insignificant quantities in certain foods, such as  alfalfa ,  asparagus ,  avocados ,  cauliflower ,  grapefruit , and  catfish . [ 22 ] [ 23 ]


Supplemental HMB has been used in  clinical trials  as a treatment for preserving lean body mass in muscle wasting conditions, particularly  sarcopenia , and has been studied in clinical trials as an  adjunct therapy  in conjunction with  resistance exercise . [ 11 ] [ 16 ] [ 30 ]  Based upon two medical reviews and a  meta-analysis  of seven  randomized controlled trials , HMB supplementation can preserve or increase lean muscle mass and muscle strength in  sarcopenic  older adults. [ note 2 ] [ 11 ] [ 12 ] [ 13 ]  HMB does not appear to significantly affect fat mass in older adults. [ 11 ] [ 12 ]  Preliminary clinical evidence suggests that HMB supplementation may also prevent  muscle atrophy  during  bed rest . [ 11 ] [ 29 ]  A growing body of evidence supports the efficacy of HMB in nutritional support for reducing, or even reversing, the loss of muscle mass,  muscle function , and  muscle strength  that occurs in  hypercatabolic  disease states such as cancer  cachexia ; [ 16 ] [ 30 ] [ 32 ]  consequently, the authors of two 2016 reviews of the clinical evidence recommended that the prevention and treatment of sarcopenia and muscle wasting in general include supplementation with HMB, regular resistance exercise, and consumption of a  high-protein diet . [ 16 ] [ 30 ]


Clinical trials that used HMB for the treatment of muscle wasting have involved the administration of 3 grams of HMB per day under different dosing regimens. [ 16 ]  According to one review, an optimal dosing regimen is to administer it in one 1 gram dose, three times a day, since this ensures elevated plasma concentrations of HMB throughout the day; [ 16 ]  however, as of 2016 [update]  the best dosing regimen for muscle wasting conditions is still being investigated. [ 30 ]


Some branded products that contain HMB (i.e., certain formulations of Ensure and Juven) are  medical foods  that are intended to be used to provide nutritional support under the care of a doctor in individuals with  muscle wasting  due to  HIV/AIDS  or  cancer , to promote  wound healing  following surgery or injury, or when otherwise recommended by a medical professional. [ sources 3 ]  Juven, a nutrition product which contains 3 grams of  HMB-Ca , 14 grams of  L -arginine , and 14 grams of  L -glutamine  per two servings, [ 2 ]  has been shown to improve  lean body mass  during clinical trials in individuals with AIDS and cancer, but not  rheumatoid cachexia . [ 17 ] [ 33 ] [ 34 ]  Further research involving the treatment of cancer cachexia with Juven over a period of several months is required to adequately determine treatment efficacy. [ 17 ] [ 33 ]


With an appropriate exercise program, dietary supplementation with 3 grams of HMB per day has been shown to increase exercise-induced gains in muscle size, muscle strength and power, and lean body mass, reduce exercise-induced skeletal muscle damage, [ note 3 ]  and expedite recovery from high-intensity exercise. [ sources 2 ]  Based upon limited clinical research, HMB supplementation may also improve aerobic exercise performance and increase gains in  aerobic fitness  when combined with  high-intensity interval training . [ 12 ] [ 14 ]  These effects of HMB are more pronounced in untrained individuals and athletes who perform high intensity resistance or aerobic exercise. [ 1 ] [ 12 ] [ 14 ]  In resistance-trained populations, the effects of HMB on muscle strength and lean body mass are limited. [ 37 ]  HMB affects muscle size, strength, mass, power, and recovery in part by stimulating  myofibrillar  muscle  protein synthesis  and inhibiting muscle  protein breakdown  through various mechanisms, including the activation of  mechanistic target of rapamycin complex 1  (mTORC1) and inhibition of  proteasome -mediated  proteolysis  in skeletal muscles. [ 14 ] [ 15 ]


The efficacy of HMB supplementation for reducing skeletal muscle damage from prolonged or high-intensity exercise is affected by the time that it is used relative to exercise. [ 1 ] [ 36 ]  The greatest reduction in skeletal muscle damage from a single bout of exercise has been shown to occur when  HMB-Ca  is ingested  1–2  hours prior to exercise or  HMB-FA  is ingested  30–60  minutes prior to exercise. [ 1 ]


In 2006, only about 2% of college  student athletes  in the United States used HMB as a dietary supplement. [ 19 ] [ 28 ]  As of 2017, HMB has found widespread use as an  ergogenic supplement  among athletes. [ 29 ]  As of 2018, [update]  HMB has not been banned by the  National Collegiate Athletic Association ,  World Anti-Doping Agency , or any other prominent national or international athletic organization. [ 25 ] [ 26 ] [ 27 ]


The  safety profile  of HMB in adult humans is based upon evidence from  clinical trials  in humans and  animal studies . [ 16 ] [ 18 ]  In humans, no  adverse effects  in young adults or older adults have been reported when HMB is taken in doses of 3 grams per day for up to a year. [ 16 ] [ 17 ] [ 18 ]  Studies on young adults taking 6 grams of HMB per day for up to 2 months have also reported no adverse effects. [ 17 ] [ 18 ]  Studies with supplemental HMB on young, growing rats and livestock have reported no adverse effects based upon  clinical chemistry  or observable characteristics; [ 1 ] [ 23 ]  for humans younger than 18, there is limited data on the safety of supplemental HMB. [ 1 ]  The  human equivalent dose  of HMB for the  no-observed-adverse-effect level  (NOAEL) that was identified in a rat model is approximately 0.4 g/kg of  body weight  per day. [ note 4 ] [ 18 ] [ 23 ]


Two animal studies have examined the effects of HMB supplementation in pregnant pigs on the offspring and reported no adverse effects on the fetus. [ 23 ]  No clinical testing with supplemental HMB has been conducted on pregnant women, [ 38 ]  and pregnant and lactating women are advised not to take HMB by  Metabolic Technologies, Inc. , the company that grants licenses to include HMB in dietary supplements, due to a lack of safety studies. [ 38 ]


Several components of the  signaling cascade  that mediates the HMB-induced increase in human skeletal muscle protein synthesis have been identified  in vivo . [ 14 ] [ 15 ]  Similar to HMB's  metabolic precursor ,  L -leucine , HMB has been shown to increase protein synthesis in human skeletal muscle via  phosphorylation  of the  mechanistic target of rapamycin  (mTOR) and subsequent activation of  mTORC1 Tooltip mechanistic target of rapamycin complex 1 , which leads to  protein biosynthesis  in cellular  ribosomes  via phosphorylation of mTORC1's immediate targets (i.e., the  p70S6 kinase  and the  translation  repressor protein  4EBP1 ). [ note 5 ] [ 15 ] [ 39 ] [ 41 ]  Supplementation with HMB in several non-human animal species has been shown to increase the  serum  concentration of  growth hormone  and  insulin-like growth factor 1  (IGF-1) via an unknown mechanism, in turn promoting protein synthesis through increased mTOR phosphorylation. [ 1 ] [ 16 ] [ 23 ]  Based upon limited clinical evidence in humans, supplemental HMB appears to increase the secretion of growth hormone and IGF-1 in response to resistance exercise. [ 14 ]


As of 2016 [update] , the signaling cascade that mediates the HMB-induced reduction in muscle protein breakdown has not been identified in living humans, although it is well-established that it attenuates  proteolysis  in humans  in vivo . [ 11 ] [ 15 ]  Unlike  L -leucine , HMB attenuates muscle protein breakdown in an  insulin -independent manner in humans. [ note 6 ] [ 15 ]  HMB is believed to reduce muscle protein breakdown in humans by inhibiting the  19S  and  20S  subunits of the  ubiquitin–proteasome system  in skeletal muscle and by inhibiting  apoptosis  of  skeletal muscle nuclei  via unidentified mechanisms. [ 15 ] [ 16 ] [ 41 ]


Based upon animal studies, HMB appears to be metabolized within skeletal muscle into  cholesterol , which may then be incorporated into the  muscle cell membrane , thereby enhancing membrane integrity and function. [ 34 ] [ 35 ]  The effects of HMB on muscle  protein metabolism  may help stabilize muscle cell structure. [ 23 ]  One review suggested that the observed HMB-induced reduction in the plasma concentration of muscle damage  biomarkers  (i.e., muscle enzymes such as  creatine kinase  and  lactate dehydrogenase ) in humans following intense exercise may be due to a cholesterol-mediated improvement in muscle cell membrane function. [ note 3 ] [ 23 ]


HMB has been shown to stimulate the  proliferation ,  differentiation , and  fusion  of human  myosatellite cells   in vitro , which potentially increases the regenerative capacity of skeletal muscle, by increasing the protein expression of certain  myogenic regulatory factors  (e.g.,  myoD  and  myogenin ) and gene  transcription factors  (e.g.,  MEF2 ). [ 1 ] [ 17 ] [ 42 ]  HMB-induced human myosatellite cell proliferation  in vitro  is mediated through the phosphorylation of the  mitogen-activated protein kinases   ERK1  and  ERK2 . [ 17 ] [ 23 ] [ 42 ]  HMB-induced human myosatellite differentiation and accelerated fusion of myosatellite cells into muscle tissue  in vitro  is mediated through the phosphorylation of  Akt , a  serine/threonine-specific protein kinase . [ 17 ] [ 23 ] [ 42 ]


The free acid ( HMB-FA ) and monohydrated calcium salt ( HMB-Ca ) forms of HMB have different  pharmacokinetics . [ 1 ] [ 20 ]  HMB-FA is more readily absorbed into the bloodstream and has a longer  elimination half-life  (3 hours) relative to HMB-Ca (2.5 hours). [ 1 ] [ 20 ]  Tissue uptake and utilization of HMB-FA is  25–40%  higher than for HMB-Ca. [ 1 ] [ 20 ]  The fraction of an ingested dose that is excreted in urine does not differ between the two forms. [ 1 ]


After ingestion,  HMB-Ca  is converted to  β-hydroxy β-methylbutyrate  following  dissociation  of the calcium  moiety  in the gut. [ 1 ]  When the HMB-Ca  dosage form  is ingested, the magnitude and time at which the peak plasma concentration of HMB occurs depends on the dose and concurrent food intake. [ 1 ]  Higher HMB-Ca doses increase the rate of  absorption , resulting in a peak plasma HMB level ( C max ) that is disproportionately greater than expected of a linear  dose-response relationship  and which occurs sooner relative to lower doses. [ note 7 ] [ 1 ]  Consumption of HMB-Ca with sugary substances slows the rate of HMB absorption, resulting in a lower peak plasma HMB level that occurs later. [ note 7 ] [ 1 ]


HMB is eliminated via the  kidneys , with roughly  10–40%  of an ingested dose being excreted unchanged in urine. [ 1 ] [ 3 ]  The remaining  60–90%  of the dose is retained in tissues or excreted as HMB metabolites. [ 1 ] [ 3 ]  The fraction of a given dose of HMB that is excreted unchanged in urine increases with the dose. [ note 8 ] [ 1 ]


The metabolism of HMB is catalyzed by an uncharacterized enzyme which converts it to  β-hydroxy   β-methylbutyryl-CoA  ( HMB-CoA ). [ 43 ] [ 46 ]  HMB-CoA is metabolized by either  enoyl-CoA hydratase  or another uncharacterized enzyme, producing  β-methylcrotonyl-CoA  ( MC-CoA ) or  hydroxymethylglutaryl-CoA  ( HMG-CoA ) respectively. [ 3 ] [ 46 ]   MC-CoA  is then converted by the enzyme  methylcrotonyl-CoA carboxylase  to  methylglutaconyl-CoA  ( MG-CoA ), which is subsequently converted to  HMG-CoA  by  methylglutaconyl-CoA hydratase . [ 3 ] [ 46 ] [ 47 ]   HMG-CoA  is then cleaved into  acetyl-CoA  and  acetoacetate  by  HMG-CoA  lyase  or used in the production of cholesterol via the  mevalonate pathway . [ 3 ] [ 46 ]


HMB is synthesized in the human body through the  metabolism  of  L -leucine , a  branched-chain amino acid . [ 46 ]  In healthy individuals, approximately 60% of dietary  L -leucine  is metabolized after several hours, with roughly 5% ( 2–10%  range) of dietary  L -leucine  being converted to HMB. [ 3 ] [ 16 ] [ 46 ]


The vast majority of  L -leucine  metabolism is initially catalyzed by the  branched-chain amino acid aminotransferase  enzyme, producing  α-ketoisocaproate  (α-KIC). [ 3 ] [ 46 ]  α-KIC is mostly metabolized by the  mitochondrial  enzyme  branched-chain  α-ketoacid  dehydrogenase , which converts it to  isovaleryl-CoA . [ 3 ] [ 46 ]  Isovaleryl-CoA is subsequently metabolized by  isovaleryl-CoA dehydrogenase  and converted to  MC-CoA , which is used in the synthesis of acetyl-CoA and other compounds. [ 46 ]  During  biotin deficiency , HMB can be synthesized from  MC-CoA  via  enoyl-CoA hydratase  and an unknown  thioesterase  enzyme, [ 43 ] [ 44 ] [ 48 ]  which convert  MC-CoA  into  HMB-CoA  and  HMB-CoA  into HMB respectively. [ 44 ]  A relatively small amount of α-KIC is metabolized in the  liver  by the  cytosolic  enzyme  4-hydroxyphenylpyruvate dioxygenase  (KIC dioxygenase), which converts α-KIC to HMB. [ 3 ] [ 46 ] [ 49 ]  In healthy individuals, this minor pathway – which involves the conversion of  L -leucine  to α-KIC and then HMB – is the predominant route of HMB synthesis. [ 3 ] [ 46 ]


β-Hydroxy   β-methylbutyric  acid is a  monocarboxylic   β-hydroxy acid  and  natural product  with the  molecular formula   C 5 H 10 O 3 . [ 50 ] [ 51 ]  At room temperature, pure  β-hydroxy   β-methylbutyric  acid occurs as a transparent, colorless to light yellow liquid which is soluble in water. [ 6 ] [ 52 ]   β-Hydroxy   β-methylbutyric  acid is a  weak acid  with a  p K a  of 4.4. [ 5 ]  Its  refractive index  (

 n

 25°C

 λ
 =
 589
 n
 m

 {\displaystyle {\mathit {n}}_{\text{25°C}}^{\mathrm {\lambda =589nm} }}

 ) is 1.42. [ 5 ]


β-Hydroxy   β-methylbutyric  acid is a member of the  carboxylic acid  family of  organic compounds . [ 50 ]  It is a  structural analog  of  butyric acid  with a  hydroxyl   functional group  and a  methyl   substituent  located on its  beta carbon . [ 50 ] [ 53 ]  By extension, other structural analogs include  β-hydroxybutyric  acid  and  β-methylbutyric  acid . [ 50 ] [ 53 ]


A variety of synthetic routes to  β-hydroxy   β-methylbutyric  acid have been developed. The first reported  chemical syntheses  approached HMB by oxidation of  alkene ,  vicinal   diol , and  alcohol  precursors:


Depending on the experimental conditions,  cycloaddition  of  acetone  and  ketene  produces either  β-isovalerolactone  or 4,4-dimethyloxetan-2-one, [ 59 ] [ 60 ]  both of which  hydrolyze  under basic conditions to yield the conjugate base of HMB. The  haloform reaction  provides another pathway to HMB involving the exhaustive halogenation of the methyl-ketone region of  diacetone alcohol  with  sodium hypobromite  or  sodium hypochlorite ; [ 5 ] [ 61 ] [ 62 ]  Diacetone alcohol is readily available from the  aldol condensation  of acetone. [ 61 ]  An  organometallic  approach to HMB involves the  carboxylation  of  tert -butyl alcohol  with  carbon monoxide  and  Fenton's reagent  ( hydrogen peroxide  and  ferrous iron ). [ 5 ] [ 63 ]  Alternatively, HMB can be prepared through  microbial oxidation  of  β-methylbutyric  acid by the fungus  Galactomyces reessii . [ 64 ]


The concentration of naturally produced HMB has been measured in several human  body fluids  using  nuclear magnetic resonance spectroscopy ,  liquid chromatography–mass spectrometry , and  gas chromatography–mass spectrometry  methods. [ 65 ] [ 50 ]  In the blood plasma and  cerebrospinal fluid  (CSF) of healthy adults, the average  molar concentration  of HMB has been measured at 4.0  micromolar  (μM). [ 50 ]  The average concentration of HMB in the  intramuscular fluid  of healthy men of ages  21–23  has been measured at 7.0 μM. [ 15 ]  In the urine of healthy individuals of any age, the excreted urinary concentration of HMB has been measured in a range of  0–68   micromoles  per millimole (μmol/mmol) of  creatinine . [ 50 ]  In the breast milk of healthy lactating women, HMB and  L -leucine  have been measured in ranges of  42–164  μg/L and  2.1–88.5  mg/L. [ 65 ]  In comparison, HMB has been detected and measured in the milk of healthy cows at a concentration of  <20–29  μg/L. [ 66 ]  This concentration is far too low to be an adequate dietary source of HMB for obtaining pharmacologically active concentrations of the compound in blood plasma. [ 66 ]


In a study where participants consumed 2.42 grams of pure  HMB-FA  while fasting, the average plasma HMB concentration increased from a basal level of 5.1  μM  to 408 μM after 30 minutes. [ 15 ]  At 150 minutes post-ingestion, the average plasma HMB concentration among participants was 275 μM. [ 15 ]


Abnormal HMB concentrations in urine and blood plasma have been noted in several disease states where it may serve as a  diagnostic biomarker , particularly in the case of  metabolic disorders . [ 50 ]  The following table lists some of these disorders along with the associated HMB concentrations detected in urine or blood plasma. [ 50 ]


The first reported  chemical synthesis  of HMB was published in 1877 by the Russian chemists Michael and  Alexander Zaytsev . [ 54 ]  HMB was isolated from the bark of  Erythrophleum couminga  (a Madagascan tree) in 1941 by  Leopold Ružička . [ 67 ]  The earliest reported isolation of HMB as a human  metabolite  was by Tanaka and coworkers in 1968 from a patient with  isovaleric acidemia . [ 68 ] [ 69 ]


The effects of HMB on human skeletal muscle were first discovered by Steven L. Nissen at  Iowa State University  in the  mid-1990s . [ 8 ] [ 24 ]  Nissen founded a company called  Metabolic Technologies, Inc.  (MTI) around the time of his discovery, which later acquired six HMB-related  patents  that the company has used to license the right to manufacture and incorporate HMB into dietary supplements. [ 24 ] [ 70 ] [ 71 ]  When it first became available commercially in the late 1990s, HMB was marketed solely as an exercise supplement to help athletes and bodybuilders build muscle. [ 70 ]  MTI subsequently developed two HMB-containing products, Juven and Revigor, to which  Abbott Nutrition  obtained the market rights in 2003 and 2008 respectively. [ 8 ] [ 70 ]  Since then, Abbott has marketed Juven as a medical food and the Revigor brand of HMB as an active ingredient in food products (e.g., certain formulations of Ensure) and other medical foods (e.g., certain formulations of Juven). [ 8 ] [ 21 ] [ 70 ]


Hypertonia  is a term sometimes used synonymously with  spasticity  and  rigidity  in the literature surrounding damage to the  central nervous system , namely  upper motor neuron lesions . [ 1 ]  Impaired ability of damaged  motor neurons  to regulate descending pathways gives rise to disordered  spinal reflexes , increased excitability of  muscle spindles , and decreased  synaptic  inhibition. [ 2 ]  These consequences result in abnormally increased  muscle tone  of symptomatic muscles. [ 3 ]  Some authors suggest that the current definition for spasticity, the velocity-dependent over-activity of the  stretch reflex , is not sufficient as it fails to take into account patients exhibiting increased muscle tone in the absence of stretch reflex over-activity. They instead suggest that " reversible hypertonia " is more appropriate and represents a treatable condition that is responsive to various therapy modalities like drug or physical therapy. [ 4 ]


Symptoms associated with central nervous systems disorders are classified into positive and negative categories. Positive symptoms include those that increase muscle activity through hyper-excitability of the stretch reflex (i.e., rigidity and spasticity) where negative symptoms include those of insufficient muscle activity (i.e.  weakness ) and reduced motor function. [ 5 ]  Often the two classifications are thought to be separate entities of a disorder; however, some authors propose that they may be closely related. [ 6 ]


Hypertonia is caused by  upper motor neuron lesions  which may result from injury, disease, or conditions that involve damage to the central nervous system.  The lack of or decrease in upper motor neuron function leads to loss of inhibition with resultant hyperactivity of  lower motor neurons .  Different patterns of muscle weakness or hyperactivity can occur based on the location of the lesion, causing a multitude of neurological symptoms, including  spasticity ,  rigidity , or  dystonia . [ 3 ]


Spastic hypertonia involves uncontrollable  muscle spasms , stiffening or straightening out of muscles, shock-like contractions of all or part of a group of muscles, and abnormal  muscle tone . It is seen in disorders such as  cerebral palsy ,  stroke , and  spinal cord injury .  Rigidity is a severe state of hypertonia where muscle resistance occurs throughout the entire range of motion of the affected joint independent of velocity. It is frequently associated with lesions of the  basal ganglia . Individuals with rigidity present with stiffness, decreased range of motion and loss of motor control. Rigidity is a nonselective increase in the tone of agonist and antagonist without velocity dependence, and the increased tone remains uniform throughout the range of movement. On the contrary, spasticity is a velocity-dependent increase in tone resulting from the hyper excitability of stretch reflexes. [ 7 ]  It primarily involves the antigravity muscles – flexors of the upper limb and extensors of the lower limb. During the passive stretch, a brief “free interval” is appreciated in spasticity but not in rigidity because the resting muscle is electromyographically silent in spasticity. In contrast, in rigidity, the resting muscle shows firing. [ 8 ]   Dystonic  hypertonia refers to muscle resistance to passive stretching (in which a therapist gently stretches the inactive contracted muscle to a comfortable length at very low speeds of movement) and a tendency of a limb to return to a fixed involuntary (and sometimes abnormal) posture following movement. [ citation needed ]


Therapeutic interventions are best individualized to particular patients. [ citation needed ]  Basic principles of treatment for hypertonia are to avoid noxious stimuli and provide frequent range of motion exercise. [ citation needed ]


Physiotherapy  has been shown to be effective in controlling hypertonia through the use of stretching aimed to reduce  motor neuron  excitability. [ 9 ]  The aim of a physical therapy session could be to inhibit excessive tone as far as possible, give the patient a sensation of normal position and movement, and to facilitate normal movement patterns. While static stretch has been the classical means to increase range of motion,  PNF stretching  has been used in many clinical settings to effectively reduce muscle spasticity. [ 10 ]


Icing and other  topical anesthetics  may decrease the reflexive activity for short period of time in order to facilitate motor function.  Inhibitory pressure (applying firm pressure over muscle tendon) and promoting body heat retention and rhythmic rotation (slow repeated rotation of affected body part to stimulate relaxation) [ 11 ]  have also been proposed as potential methods to decrease hypertonia.  Aside from static stretch casting, splinting techniques are extremely valuable to extend joint range of motion lost to hypertonicity. [ 12 ]   A more unconventional method for limiting tone is to deploy quick repeated passive movements to an involved joint in cyclical fashion; this has also been demonstrated to show results on persons without physical disabilities. [ 9 ]  For a more permanent state of improvement, exercise and patient education is imperative. [ 11 ]   Isokinetic , [ 13 ] [ 14 ] [ 15 ] [ 16 ]   aerobic , [ 17 ] [ 18 ] [ 19 ]  and  strength training [ 20 ] [ 21 ] [ 22 ] [ 23 ]  exercises should be performed as prescribed by a physiotherapist, and stressful situations that may cause increased tone should be minimized or avoided. [ 11 ]


Baclofen ,  diazepam  and  dantrolene  remain the three most commonly used pharmacologic agents in the treatment of spastic hypertonia. Baclofen is generally the drug of choice for spinal cord types of spasticity, while sodium dantrolene is the only agent which acts directly on muscle tissue.  Tizanidine  is also available.  Phenytoin  with  chlorpromazine  may be potentially useful if sedation does not limit their use.  Ketazolam , not yet available in the United States, [ needs update ]  may be a significant addition to the pharmacologic set of options.  Intrathecal  administration of antispastic medications allows for high concentrations of drug near the site of action, which limits side effects. [ 12 ]


Inclusion body myositis  ( IBM ) ( / m aɪ oʊ ˈ s aɪ t ɪ s / ) (sometimes called  sporadic inclusion body myositis ,  sIBM ) is the most common  inflammatory muscle disease  in older adults. [ 2 ] [ failed verification ]  The disease is characterized by slowly progressive weakness and wasting of both proximal muscles (located on or close to the  torso ) and distal muscles (close to hands or feet), most apparent in the  finger   flexors  and  knee   extensors . [ 3 ]  IBM is often confused with an entirely different class of diseases, called  hereditary inclusion body myopathies  (hIBM). [ 4 ] [ 5 ]  The "M" in hIBM is an abbreviation for "myopathy" while the "M" in IBM is for "myositis". [ 6 ]  In IBM, two processes appear to occur in the muscles in parallel, one autoimmune and the other degenerative. Inflammation is evident from the invasion of muscle fibers by  immune cells . Degeneration is characterized by the appearance of  holes , deposits of  abnormal proteins , and filamentous inclusions in the muscle fibers. [ 7 ]  sIBM is a rare disease, with a prevalence ranging from 1 to 71 individuals per million. [ 8 ] [ 9 ]


Weakness comes on slowly (over months to years) in an asymmetric manner and progresses steadily, leading to severe weakness and wasting of arm and leg muscles. IBM is more common in men than women. [ 10 ]  Patients may become unable to perform  activities of daily living  and most require assistive devices within 5 to 10 years of symptom onset. [ 11 ]  sIBM does not significantly affect  life expectancy , [ 1 ]  although death related to  malnutrition  and  respiratory  failure can occur. [ 12 ]  The risk of serious injury due to falls is increased. [ 1 ]  There is no effective treatment for the disease as of 2019. [ 1 ]


IBM  stands for "inclusion body  myositis:  not "inclusion body  myopathy. " [ 6 ]  The 'inclusion body' refers to a histological finding of rimmed vacuoles in muscle tissue. [ 6 ]  However, IBM does not refer to the collection of diseases that feature these inclusion bodies. It refers to a specific disease entity. [ 6 ]


Multiple genetic diseases that feature inclusion bodies have been grouped into " hereditary  inclusion body  myopathies  (hIBM)." [ 6 ]   Myopathy  is used because inflammation is not a prominent finding. There is inconsistency in what individual disease entities fall under the category of hIBM. [ 6 ]  The term " sporadic  inclusion body  myositis " (sIBM) was introduced as a way to refer to IBM to avoid confusion with hIBM. [ 6 ]  However, one author discourages use of sIBM, as it implies that IBM and hIBM differ only in inheritance; they actually have unrelated mechanisms and manifestations of disease. [ 6 ]


sIBM causes progressive muscle weakness. [ 1 ]  How sIBM affects individuals is variable, including the age of onset (which generally varies from the forties upwards) and rate of progression. Because of this variability, there is no "textbook case". [ 13 ]


Common early symptoms include frequent tripping and falling and difficulty going up stairs.  Foot drop  in one or both feet can occur. [ 14 ]  Part of the cause for this dysfunction is the early involvement of the  quadriceps  muscles. [ 1 ]  Weakness of the  tibialis anterior muscle  is responsible for foot drop. Another common early symptom is trouble manipulating the fingers, such as difficulty with tasks such as turning doorknobs or gripping keys. Weakness of finger flexion and ankle dorsiflexion occurs early. [ 1 ]  sIBM also preferentially affects the  wrist flexors ,  biceps , and  triceps . [ 1 ]


During the course of the illness, the patient's mobility is progressively restricted as it becomes difficult to bend down, reach for things, and walk quickly. Many patients say they have balance problems and fall easily, as the muscles cannot compensate for an off-balanced posture. Because sIBM makes the leg muscles weak and unstable, patients are very vulnerable to serious injury from tripping or falling down. Although pain has not been traditionally part of the "textbook" description, many patients report severe muscle pain, especially in the thighs. [ citation needed ]


Progressive difficulty swallowing ( dysphagia ) is present in 40 to 85% of IBM cases and often leads to death from  aspiration pneumonia . [ 15 ]


IBM can also result in diminished capacity for aerobic exercise. This decline is most likely a consequence of the sedentary lifestyle leading to disuse  muscle atrophy  that is often associated with the symptoms of IBM (i.e. progressive muscle weakness, decreased mobility, and increased level of fatigue). Therefore, one focus of treatment should be the improvement of aerobic capacity. [ 16 ]


Patients with sIBM usually eventually need to resort to a cane or a walker and in most cases, a wheelchair eventually becomes a necessity.


"The progressive course of s-IBM leads slowly to severe disability. Finger functions can become very impaired, such as manipulating pens, keys, buttons, and zippers, pulling handles, and firmly grasping handshakes. Arising from a chair becomes difficult. Walking becomes more precarious. Sudden falls, sometimes resulting in major injury to the skull or other bones, can occur, even from walking on minimally irregular ground or from other minor imbalances outside or in the home, due to weakness of quadriceps and gluteus muscles depriving the patient of automatic posture maintenance. A foot-drop can increase the likelihood of tripping.  Dysphagia  can occur, usually caused by upper esophageal constriction that often can be symptomatically improved, for several months to years, by bougie dilation per a GI or ENT physician. Respiratory muscle weakness can sometimes eventuate." [ 17 ]


The cause of IBM is unknown. IBM likely results from the interaction of a number of genetic and environmental factors. [ 18 ]


There are two major theories about how sIBM is caused. One hypothesis suggests that the inflammation-immune reaction, caused by an unknown trigger – likely an undiscovered virus or an autoimmune disorder – is the primary cause of sIBM and that the degeneration of muscle fibers and protein abnormalities are secondary features. [ 19 ]  Despite the arguments "in favor of an adaptive immune response in sIBM, a purely autoimmune hypothesis for sIBM is untenable because of the disease's resistance to most immunotherapy." [ 20 ]


The second school of thought advocates the theory that sIBM is a degenerative disorder related to aging of the muscle fibers and that abnormal, potentially pathogenic protein accumulations in myofibrils play a key causative role in sIBM (apparently before the immune system comes into play). This hypothesis emphasizes the abnormal intracellular accumulation of many proteins, protein aggregation and misfolding,  proteosome  inhibition, and  endoplasmic reticulum  (ER) stress. [ 17 ]


One review discusses the "limitations in the beta-amyloid-mediated theory of IBM myofiber injury." [ 21 ]


Dalakas (2006) suggested that a chain of events causes IBM – some sort of virus, likely a  retrovirus , triggers the cloning of  T cells . These T cells appear to be driven by specific  antigens  to invade muscle fibers. In people with sIBM, the muscle cells display "flags" telling the immune system that they are infected or damaged (the muscles ubiquitously express MHC class I antigens) and this immune process leads to the death of muscle cells. The chronic stimulation of these antigens also causes stress inside the muscle cell in the  endoplasmic reticulum  (ER) and this ER stress may be enough to cause a self-sustaining T cell response (even after a virus has dissipated). In addition, this ER stress may cause the misfolding of protein. The ER is in charge of processing and folding molecules carrying antigens. In IBM, muscle fibers are overloaded with these  major histocompatibility complex  (MHC) molecules that carry the antigen protein pieces, leading to more ER stress and more protein misfolding. [ 19 ]


A self-sustaining T cell response would make sIBM a type of autoimmune disorder. When studied carefully, it has not been possible to detect an ongoing viral infection in the muscles. One theory is that a chronic viral infection might be the initial triggering factor setting IBM in motion. There have been a handful of IBM cases – approximately 15 – that have shown clear evidence of a virus called  HTLV-1 . The HTLV-1 virus can cause  leukemia , but in most cases lies dormant and most people end up being lifelong carriers of the virus. One review says that the best evidence points towards a connection with some type of retrovirus and that a retroviral infection combined with immune recognition of the retrovirus is enough to trigger the inflammation process. [ 19 ]


sIBM is not inherited and is not passed on to the children of IBM patients. There are genetic features that do not directly cause IBM but that appear to predispose a person to getting IBM – having this particular combination of genes increases one's susceptibility to getting IBM. Some 67% of IBM patients have a particular combination of  human leukocyte antigen  genes in a section of the 8.1 ancestral haplotype in the center of the MHC class II region. sIBM is not passed on from generation to generation, although the susceptibility region of genes may be. [ 19 ]


There are also several rare forms of hereditary inclusion body myopathy that are linked to specific genetic defects and that are passed on from generation to generation. Since these forms do not show features of muscle inflammation, they are classified as myopathies rather than forms of myositis. Because they do not display inflammation as a primary symptom, they may in fact be similar, but different diseases to sporadic inclusion body myositis. There are several different types, each inherited in different ways. See  hereditary inclusion body myopathy . [ 24 ]


A 2007 review concluded there is no indication that the genes responsible for the familial or hereditary conditions are involved in sIBM. [ 25 ]


Elevated  creatine kinase  (CK) levels in the blood (at most ~10 times normal) are typical in sIBM but affected individuals can also present with normal CK levels.  Electromyography  (EMG) studies display variable abnormalities such as increased insertional activity, [ 26 ]  increased spontaneous activity (fibrillation potentials and sharp waves), [ 1 ]  and large/broad or short/narrow motor unit potentials. [ 1 ]  On EMG, recruitment patterns can be reduced or increased. Findings can vary even within the same muscle of an affected individual. [ 1 ]  Muscle biopsy may display several common findings including inflammatory cells invading muscle cells, vacuolar degeneration, and  inclusion bodies  of aggregations of multiple proteins. [ 27 ]  sIBM is a challenge to the pathologist and even with a biopsy, diagnosis can be ambiguous. [ 28 ]


A diagnosis of inclusion body myositis was historically dependent on muscle biopsy results. Antibodies to cytoplasmic 5'-nucleotidase (cN1A;  NT5C1A ) have been strongly associated with the condition. [ 1 ]  However, other inflammatory conditions, such as lupus, can have a positive anti-NT5C1A. [ 1 ]  As of 2019, it remains to be established whether a positive anti-NT5C1A antibody test can make muscle biopsy unneeded. [ 1 ]


Muscle imaging can help establish the pattern of muscle involvement and selection of a biopsy site. [ 1 ]


IBM is often initially misdiagnosed as  polymyositis . A course of  prednisone  is typically completed with no improvement and eventually, sIBM is confirmed. sIBM weakness comes on over months or years and progresses steadily, whereas polymyositis has an onset of weeks or months.  Muscular dystrophy  (e.g.,  limb girdle muscular dystrophy ) must be considered as well. [ citation needed ]  sIBM can be mistaken for physical deconditioning. [ 1 ]


Hereditary myopathies can mimic sIBM, both in signs and symptoms and in the appearance of muscle biopsies. A small percentage of those initially diagnosed with sIBM are later found to have pathogenic mutations in the genes  VCP  and  SQSTM1 , which are known to cause hIBM. [ 1 ]


IBM has a distinctive pattern of muscle involvement that distinguishes it among inflammatory myopathies. [ 6 ]  Characteristic of IBM is weakness of finger flexion, knee extension, and ankle dorsiflexion. [ 6 ]  Other inflammatory myopathies cause a proximal muscle weakness pattern, such as weakness of hip flexion, abduction, and extension, as well as shoulder abduction. [ 6 ]  IBM and other inflammatory myopathies both cause bicep/tricep weakness. [ 6 ]


There is no standard course of treatment to slow or stop the progression of the disease as of 2019. [ 1 ]  sIBM patients do not reliably respond to  anti-inflammatory ,  immunosuppressant , or   immunomodulatory medications . [ 31 ]  Most of disease management is  supportive care . [ 1 ]  Prevention of falls is an important consideration. [ 1 ]  There is no consensus on  exercise guidelines ; however, physical therapy is recommended to teach the patient a home exercise program, to teach how to compensate during mobility-gait training with an assistive device, transfers and bed mobility. [ 32 ]  An exercise regimen preferentially minimizes a patient's risk of injury and corresponds to the patient's goals. [ 1 ] [ 33 ]


When sIBM was originally described, the major feature noted was muscle inflammation. Two other disorders were also known to display muscle inflammation, and sIBM was classified along with them. They are  dermatomyositis  (DM) and  polymyositis  (PM) and all three illnesses were called  idiopathic  (of unknown origin) myositis or inflammatory myopathies. [ 34 ]


It appears that sIBM and polymyositis share some features, especially the initial sequence of immune system activation, however, polymyositis comes on over weeks or months, does not display the subsequent muscle degeneration and protein abnormalities as seen in IBM, and as well, polymyositis tends to respond well to treatments, IBM does not. IBM is often confused with (misdiagnosed as) polymyositis. Polymyositis that does not respond to treatment is likely IBM. [ 35 ]


Dermatomyositis  shares a number of similar physical symptoms and histopathological traits as polymyositis, but exhibits a skin rash not seen in polymyositis or sIBM. It may have different root causes unrelated to either polymyositis or sIBM. [ 36 ]


Mutations in  valosin-containing protein  (VCP) cause  multisystem proteinopathy  (MSP), which can present (among others) as a rare form of inclusion body myopathy. [ 37 ]


Prevalence of disease in a rigorous  meta-analysis  in 2017 was 46 patients per million. [ 6 ]  The earliest published prevalence was in 2000 and put at 5 per million. [ 6 ]  A 2017 study in Ireland reported 112 per million. [ 6 ]  It is not believed that the disease prevalence is increasing with time, but rather diagnostics and reporting are improving. [ 6 ]


Estimates of the mean age of onset range from 61 to 68 years old. [ 6 ]


In the biographical drama film  Father Stu , the protagonist, a boxer-turned-Catholic priest, has sIBM. [ 38 ] [ 39 ]


Musician  Peter Frampton  was diagnosed with the disease in 2019.


Kocher–Debré–Semelaigne syndrome  ( KDSS ) is  hypothyroidism  in infancy or childhood characterised by lower extremity or generalized muscular hypertrophy ( Herculean appearance [ 1 ] ),  myxoedema ,  short stature , and  cognitive impairment . [ 2 ]


The syndrome is named after  Emil Theodor Kocher ,  Robert Debré  and Georges Semelaigne. Also known as Debré–Semelaigne syndrome or cretinism-muscular hypertrophy, hypothyroid myopathy, hypothyroidism-large muscle syndrome, hypothyreotic muscular hypertrophy in children, infantile myxoedema-muscular hypertrophy, myopathy-myxoedema syndrome, myxoedema-muscular hypertrophy syndrome, myxoedema-myotonic dystrophy syndrome.


The adult-onset form of this syndrome is  Hoffmann syndrome . [ 3 ]  Some sources claim that two of the differentiating symptoms between KDSS and Hoffmann syndrome is that Hoffmann syndrome lacks painful spasms and pseudomyotonia; [ 1 ] [ 4 ]  however, this claim is in conflict with other sources that list these symptoms as also being present in Hoffmann syndrome. [ 5 ] [ 6 ] [ 7 ] [ 8 ]


The age at which a child presents with KDSS may vary from new born to as late as 11 years of age. [ 9 ]  This disease is very rare as only less than 10% of children with hypothyroid myopathy develops this condition. [ citation needed ]  Along with features of  hypothyroidism  (such as lethargy, slow heart rate, cold intolerance, dry skin, and hoarse voice) the main additional feature is muscle hypertrophy. It can happen in any muscle of the limbs, but commonly affects the calf muscles, giving the typical Herculean appearance. [ 9 ]


Other features are pseudo myotonia ,  myokymia , slow tendon reflex, slowed muscle contractions and relaxations, muscle stiffness, proximal muscle weakness and myopathy. The severity of these symptoms are determined by the period of hypothyroidism and the degree of deficiency of thyroid hormones. [ 10 ]  It may also include  macroglossia . [ 11 ]


EMG is either normal or may show myopathic low amplitude and short duration motor unit action potentials (MUAPS). [ 12 ]  The enzymes creatine kinase is elevated usually.


The assumed cause of muscle hypertrophy in KDSS is an abnormal metabolism of carbohydrates leading to increased glycogen accumulation and increased  mucopolysaccharide  deposits in the muscles. [ 13 ]  Yet another speculation is an excess intra cellular calcium due to ineffective reuptake into the sarcoplasmic reticulum, which causes a sustained contraction and thereby hypertrophy. [ 14 ]


In hypothyroidism the fast twitch muscle fiber is converted to slow twitch fiber, causing the slower reflex or hung up reflex. This may occur as a result of reduction in muscle mitochondrial oxidative capacity and beta-adrenergic receptors, as well as the induction of an insulin-resistant state, due to decrease in thyroid hormones. [ 15 ]


The causes for muscle weakness is said to be decrease in muscle  carnitine , decreased muscle oxidation, expression of a slower  ATPase  in myosin chain and decreased transport across the cell membrane. [ 16 ] [ 17 ]


The rigidity associated with congenital hypothyroidism may be due to abnormal development of basal ganglia. [ 18 ]


Thyroid metabolism can be disrupted secondary to a primary disease. A common  comorbidity  of the  metabolic myopathy  McArdle disease (Glycogen storage disease type V) is hypothyroidism. [ 23 ] [ 24 ]  It is also a comorbidity of late-onset Pompe disease (Glycogen storage disease type II). [ 25 ] [ 26 ]  As both hyper- and hypothyroidism disrupts muscle glycogen metabolism, it is important to keep in mind differential diagnoses and their comorbidities when trying to determine whether signs and symptoms are either  primary or secondary disease . [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ]


The muscle hypertrophy and other symptoms are reversible on treatment with  levothyroxine . [ 32 ]


Laminopathies  ( lamino-  +  -pathy ) are a group of rare  genetic disorders  caused by  mutations  in genes encoding proteins of the  nuclear lamina .  Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals. Laminopathies are a group of degenerative diseases, other disorders associated with  inner nuclear membrane proteins  are known as  nuclear envelopathies . [ 2 ]


Laminopathies and other nuclear envelopathies have a large variety of clinical symptoms including skeletal and/or cardiac  muscular dystrophy ,  lipodystrophy  and  diabetes ,  dysplasia , dermo- or  neuropathy ,  leukodystrophy , and  progeria  (premature aging). Most of these symptoms develop after birth, typically during childhood or adolescence. Some laminopathies however may lead to an early death, and mutations of lamin B1 ( LMNB1  gene) may be lethal before or at birth. [ 3 ]


Patients with classical laminopathy have mutations in the gene coding for  lamin  A/C ( LMNA  gene). [ citation needed ]


Mutations in the gene coding for  lamin B2  (LMNB2 gene) have been linked to Barraquer-Simons syndrome [ 4 ]  and duplication in the gene coding for lamin B1 (LMNB1 gene) cause autosomal dominant leukodystrophy. [ 5 ]


Mutations implicated in other nuclear envelopathies were found in genes coding for lamin-binding proteins such as  lamin B receptor  (LBR gene), [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ]   emerin  (EMD gene) and  LEM domain-containing protein 3  (LEMD3 gene) and prelamin A-processing enzymes such as the  zinc metalloproteinase STE24  (ZMPSTE24 gene).


Mutations causing laminopathies include  recessive  as well as  dominant   alleles  with rare  de novo  mutations creating dominant alleles that do not allow their carriers to reproduce before death. [ citation needed ]


The nuclear envelopathy with the highest frequency in human populations is  Emery–Dreifuss muscular dystrophy  caused by an  X-linked  mutation in the EMD gene coding for emerin and affecting an estimated 1 in 100,000 people. [ citation needed ]


Lamins are  intermediate filament  proteins that form the  nuclear lamina  scaffold underneath the  nuclear envelope  in animal cells. They are attached to the nuclear envelope membrane via farnesyl anchors and interaction with  inner nuclear membrane proteins  such as lamin B receptor and emerin. The nuclear lamina appears to be an adaptation to mobility in animals as sessile organisms such as  plants  or  fungi  do not have lamins [ 11 ]  and the symptoms of many laminopathies include  muscle  defects. Mutations in these genes might lead to defects in filament assembly and/or attachment to the nuclear envelope and thus jeopardize nuclear envelope stability in physically stressed tissues such as  muscle fibers ,  bone ,  skin  and  connective tissue . [ 12 ]


Messenger RNA  produced from the LMNA gene undergoes  alternative splicing  and is  translated  into lamins A and C. Lamin A undergoes  farnesylation  to attach a membrane anchor to the protein. This version of the protein is also referred to as prelamin A. Farnesylated prelamin A is further  processed  into mature lamin A by a  metalloproteinase  removing the last 15  amino acids  and its farnesylated  cysteine . This allows lamin A to dissociate from the nuclear envelope membrane and fulfill nuclear functions. Mutations causing laminopathies interfere with these processes on different levels. [ citation needed ]


Missense mutations  in the lamin A/C rod and tail domains are the cause for a wide array of genetic disorders, suggesting that lamin A/C protein contains distinct functional domains that are essential for the maintenance and integrity of different cell lineages. Interaction between lamin A and the nuclear envelope protein emerin appears to be crucial in muscle cells, with certain mutations in lamin mimicking mutations in emerin and causing  Emery–Dreifuss muscular dystrophy . Different mutations lead to dominant-negative and recessive alleles. Mutations in the lamin rod domain leading to mislocalization of both lamin A and emerin occur in patients with  autosomal dominant  forms of muscular dystrophy and cardiomyopathy. [ citation needed ]


Most lamin B mutations appear to be lethal with mutations in lamin B1 causing death at birth in mice. [ 3 ]  In 2006, lamin B2 missense mutations were identified in patients with acquired partial lipodystrophy. [ 13 ]


The most common mutation in the lamin A/C is the homozygous Arg527His (arginine replaced by histidine at position 527) substitution in
exon 9 of the LMNA gene [ 14 ]
Other known mutations are Ala529Val and Arg527His/Val440Met. [ 15 ]  Additionally, some mutations such as Arg527Cys, Lys542Asn, Arg471Cys, Thr528Met/Met540Thr, and Arg471Cys/Arg527Cys, Arg527Leu
result in  mandibuloacral dysplasia  with  progeria -like features. [ 16 ]


Mutations causing  progeria  are defective in  splicing  LMNA mRNA, therefore producing abnormal lamin A protein, also known as  progerin . The mutations activate a cryptic splice site within  exon  11 of the gene, thereby causing the deletion of the processing site on prelamin A. [ 17 ]  This results in an accumulation of progerin that is unable to mature into lamin A, leading to misshapen nuclei. Missplicing also leads to the complete or partial loss of exon 11 and results in a truncated prelamin A protein in the neonatal lethal  tight skin contracture syndrome . [ 18 ]


Since the metalloproteinase STE24 is required to process prelamin A into mature lamin A, mutations in this gene abolishing  protease  activity cause defects similar to laminopathies caused by prelamin A with truncated processing sites. Symptoms in patients with ZMPSTE24 mutation range from mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy to infant-lethal  restrictive dermopathy . [ citation needed ]


In the case of  autosomal dominant  leukodystrophy, the disease is associated with a duplication of the lamin B gene LMNB1. The exact  dosage  of lamin B in cells appears to be crucial for nuclear integrity as increased expression of lamin B causes a degenerative phenotype in  fruit flies  and leads to abnormal nuclear morphology. [ 19 ]


Antibodies against lamins are detected in the sera of some individuals with  autoimmune diseases . [ 20 ]


A-type  lamins  promote genetic stability by maintaining the levels of proteins that have key roles in DNA double-strand break repair during the processes of  non-homologous end joining  and  homologous recombination . [ 21 ]   Mutations in lamin A (LMNA) cause Hutchinson–Gilford  progeria  syndrome, a dramatic form of premature aging. [ 17 ]   Mouse cells deficient for maturation of prelamin A show increased DNA damage and  chromosome aberrations  and are more sensitive to DNA damaging agents. [ 22 ]   The inability to adequately repair DNA damages when A-type lamins are defective is likely responsible for some of the aspects of premature aging. [ citation needed ]


Currently, there is no cure for laminopathies and treatment is largely symptomatic and supportive.  Physical therapy  and/or corrective  orthopedic surgery  may be helpful for patients with muscular dystrophies. Laminopathies affecting  heart muscle  may cause  heart failure  requiring treatment with medications including  ACE inhibitors ,  beta blockers  and  aldosterone antagonists , while the  abnormal heart rhythms  that frequently occur in these patients may require a  pacemaker  or  implantable defibrillator . [ 40 ]  Treatment for neuropathies may include medication for  seizures  and  spasticity . [ citation needed ]


The recent progress in uncovering the molecular mechanisms of toxic progerin formation in laminopathies leading to premature aging has opened up the potential for the development of targeted treatment. The farnesylation of prelamin A and its pathological form progerin is carried out by the enzyme  farnesyl transferase .  Farnesyl transferase inhibitors  (FTIs) can be used effectively to reduce symptoms in two mouse model systems for progeria and to revert the abnormal nuclear morphology in progeroid cell cultures. Two oral FTIs,  lonafarnib  and  tipifarnib , are already in use as anti-tumor medication in humans and may become avenues of treatment for children with laminopathic progeria. Nitrogen-containing bisphosphate drugs used in the treatment of  osteoporosis  reduce  farnesyldiphosphate  production and thus prelamin A farnesylation. Testing of these drugs may prove them to be useful in treating progeria as well. The use of  antisense   oligonucleotides  to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs. [ 41 ] [ 42 ]


Ankyrin :  Long QT syndrome 4


Macrophagic myofasciitis  ( MMF ) is a  histopathological  finding involving inflammatory  microphage  formations with aluminium-containing crystal  inclusions  and associated microscopic muscle  necrosis  in  biopsy  samples of the  deltoid muscle . Based on the presence of aluminium and the common practice of administering vaccines into the deltoid, it has been proposed that the abnormalities are a result of immunisation with aluminium  adjuvant -containing vaccines. The findings were observed in a minority of persons being evaluated for "diffuse myalgias, arthralgias or muscle weakness" who underwent deltoid muscle biopsies. The individuals had a history of receiving aluminium-containing vaccines, administered months to several years prior to observation of MMF histopathology, however this link is tenuous and unsustainable.  [ 1 ] [ 2 ]


It has been subsequently proposed that macrophagic myofasciitis is in fact a systemic disorder where various diseases develop in association and as consequence of vaccination with aluminium-containing vaccines in susceptible individuals, however, the  World Health Organization  has concluded that "[t]here is no evidence to suggest that MMF is a specific illness", and that "[t]he current evidence neither establishes nor excludes a generalized disorder affecting other organs." [ 1 ] [ 2 ]


MMF was first described in 1998 by a consortium of French myopathologists as an emerging condition of unknown cause characterised by a defining lesion observed upon muscle biopsy. MMF was identified in patients affected by myalgia and fatigue. MMF was judged a consequence of a switch to  intramuscular injection  and the deltoid muscle being the preferred site of both vaccine injection and biopsy in France (while other sites were preferred for biopsy in other countries) and the commencement of  HBV vaccination  in French adults. Similar lesions could be detected in babies and children upon biopsy of the quadriceps as this is the site of vaccine administration in this group. MMF could also be experimentally reproduced in animals, with regression over time. It has been proposed that in a small portion of the population, vaccination results in persistence of aluminium-compound particles in macrophages in association with myalgia, fatigue, and cognitive dysfunction. A MMF disorder has been compared to  autoimmune/inflammatory syndrome induced by adjuvants . [ 3 ] [ 4 ]  A case-controlled study in France found those with MMF were more likely to have received aluminium-containing vaccines. MMF was also associated with fatigue “and related functional limitations", with fatigue more common in the beginning of the malady that led to the biopsy. However, neither  myalgia ,  arthralgia , nor any other symptoms or risk factors were identified as specific to those with MMF. [ 2 ]


Many of those with MMF had previously been treated for  malaria  with  chloroquine  or  hydroxychloroquine . [ 5 ]


As of 2009, with few exceptions, MMF had only been reported in France. [ 1 ]


Malignant hyperthermia  ( MH ) is a type of severe reaction that occurs in response to particular medications used during  general anesthesia , among those who are susceptible. [ 1 ]  Symptoms include  muscle rigidity ,  fever , and a  fast heart rate . [ 1 ]  Complications can include  muscle breakdown  and  high blood potassium . [ 1 ] [ 2 ]  Most people who are susceptible to MH are generally unaffected when not exposed to triggering agents. [ 3 ]


Exposure to triggering agents (certain  volatile anesthetic agents  or  succinylcholine ) can lead to the development of MH in those who are susceptible. [ 1 ] [ 3 ]  Susceptibility can occur due to at least six  genetic mutations , with the most common one being of the  RYR1  gene. [ 1 ]  These genetic variations are often inherited in an  autosomal dominant  manner. [ 1 ]  The condition may also occur as a new mutation or be associated with a number of inherited muscle diseases, such as  central core disease . [ 1 ] [ 4 ]


In susceptible individuals, the medications induce the release of stored  calcium ions  within  muscle cells . [ 1 ]  The resulting increase in calcium concentrations within the cells cause the  muscle fibers  to contract. [ 1 ]  This generates excessive heat and results in  metabolic acidosis . [ 1 ]  Diagnosis is based on symptoms in the appropriate situation. [ 2 ]  Family members may be tested to see if they are susceptible by  muscle biopsy  or  genetic testing . [ 4 ]


Treatment is with  dantrolene  and rapid cooling along with other  supportive measures . [ 2 ] [ 4 ]  The avoidance of potential triggers is recommended in susceptible people. [ 2 ]  The condition affects one in 5,000 to 50,000 cases where people are given anesthetic gases. [ 1 ]  Males are more often affected than females. [ 3 ]  The risk of death with proper treatment is about 5% while without it is around 75%. [ 3 ]  While cases that appear similar to MH have been documented since the early 20th century, the condition was only formally recognized in 1960. [ 3 ]


The typical signs of malignant  hyperthermia  are due to a  hypercatabolic  state, which presents as  a very high temperature ,  an increased heart rate  and  abnormally rapid breathing , increased  carbon dioxide production , increased oxygen consumption, mixed  acidosis ,  rigid muscles , and  rhabdomyolysis . [ 5 ]  These signs can develop any time during the administration of the anesthetic triggering agents. Rarely, signs may develop up to 40 minutes after the end of anaesthesia. [ 6 ]


Malignant hyperthermia is a disorder that can be considered a gene–environment interaction. In most people with malignant hyperthermia susceptibility, they have few or no symptoms unless they are exposed to a triggering agent. The most common triggering agents are volatile anesthetic gases, such as  halothane ,  sevoflurane ,  desflurane ,  isoflurane ,  enflurane  or the depolarizing muscle relaxants  suxamethonium  and  decamethonium  used primarily in general anesthesia. [ 5 ]  In rare cases, the biological stresses of physical exercise or heat may be the trigger. [ 5 ] [ 7 ]  In fact, malignant hyperthermia susceptibility (MHS), predisposed by mutations in the skeletal muscle calcium release channel (RYR1), is one of the most severe heat-related illnesses. The MHS-associated heat susceptibilities predominantly affect children and metabolically active young adults, often leading to life- threatening hypermetabolic responses to heat. [ 8 ]


Other anesthetic drugs do not trigger malignant hyperthermia. Some examples of drugs that don't cause MH include local anesthetics ( lidocaine ,  bupivacaine ,  mepivacaine ), opiates ( morphine ,  fentanyl ),  ketamine ,  barbiturates ,  nitrous oxide ,  propofol ,  etomidate , and  benzodiazepines . The nondepolarizing muscle relaxants  pancuronium ,  cisatracurium ,  atracurium ,  mivacurium ,  vecuronium  and  rocuronium  also do not cause MH. [ citation needed ]


There is mounting evidence that some individuals with malignant hyperthermia susceptibility may develop MH with exercise and/or on exposure to hot environments. [ 9 ]


Malignant hyperthermia's inheritance is  autosomal dominant  with variable penetrance. [ 5 ]  The defect is typically located on the long arm of  chromosome 19  (19q13.2 [ 10 ] ) involving the  ryanodine receptor . [ 5 ]  More than 25 different mutations in this gene are linked with malignant hyperthermia. [ 5 ]  These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and  Ca 2+ . MH3 is located in the transmembrane forming C-terminus. This region is important for allowing  Ca 2+  passage through the protein following opening. [ citation needed ]


Chromosome 7q and chromosome 17 have also been implicated.  It has also been postulated that MH and  central core disease  may be allelic and thus can be co-inherited. [ citation needed ]


In a large proportion (50–70%) of cases, the propensity for malignant hyperthermia is due to a  mutation  of the  ryanodine receptor  (type 1), located on the  sarcoplasmic reticulum  (SR), the  organelle  within  skeletal muscle  cells that stores  calcium . [ 11 ] [ 12 ]  RYR1 opens in response to conformational changes in the L-type  calcium channels  following membrane depolarisation, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing  Ca 2+  concentrations: the A-site and the I-site. The A-site is a high  affinity   Ca 2+  binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing.  Caffeine , halothane, and other triggering agents act by drastically increasing the affinity of the A-site for  Ca 2+  and concomitantly decreasing the affinity of the I-site in mutant proteins.  Mg 2+  also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for  Mg 2+  at either one of these sites is greatly reduced. The result of these alterations is greatly increased  Ca 2+  release due to a lowered activation and heightened deactivation threshold. [ 13 ] [ 14 ]  The process of sequestering this excess  Ca 2+  consumes large amounts of  adenosine triphosphate  (ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including  potassium ,  myoglobin ,  creatine ,  phosphate  and  creatine kinase . [ citation needed ]


The other known causative gene for MH is  CACNA1S , which encodes an  L-type   voltage-gated calcium channel  α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086. [ 15 ] [ 16 ]  This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in human embryonic kidney ( HEK 293 )  cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5–10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic  Ca 2+  concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular  Ca 2+ , and, thereby, muscle excitability. [ 17 ]


Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified. [ 18 ]


Research into malignant hyperthermia was limited until the discovery of " porcine stress syndrome " (PSS) in  Danish Landrace  and other  pig  breeds selected for muscling, a condition in which stressed pigs develop  "pale, soft, exudative" flesh  (a manifestation of the effects of malignant hyperthermia) rendering their meat less marketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently, susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use  halothane  cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market.  This also reduced the use of breeding stock carrying the genes for PSS.  The condition in swine is also due to a defect in ryanodine receptors. [ 19 ]


Gillard  et al.  discovered the causative mutation in humans only after similar mutations had first been described in pigs. [ 11 ]