The Psychopharmacology of Native American Myopathy

The Psychopharmacology of Native American Myopathy

Native American Myopathy (NAM) is a genetic disorder affecting mainly the Lumbee tribe of North Carolina. The instances of NAM in the Lumbee population are 1:5000, which is in stark comparison to the 1:50000 within the general population. Kaur, Katyal, Yelam, Kumar, Srivastava, and Govindarajan (2019) indicate only thirty-six percent of individuals born with the NAM mutation live to the age of eighteen. The mutation affects several skeletal, muscular systems, and nerve communications. Daily, many of us take for granted the ability to grasp an object, walk unassisted, and control the movement of our appendages. Though for those stricken with Native American myopathy, many never accomplish the simplest of movements or manage a sense of independence. The mutation presents with a specific set of physical defects to include cleft pallet, cleft lip, club feet, micrognathia, and malignant hyperthermia (Kaur, Katyal, Yelam, Kumar, Srivastava, and Govindarajan, 2019; Waldrop, Boue, Sites, Flanigan, and Shell, 2017). The neurological afflictions display nerve connections with a lack of CA2+ channel control where the gates are either non-functional or partially functional. The corresponding effects result in a lack of neuromuscular control or limited muscle control (Waldrop, Boue, Sites, Flanigan, and Shell, 2017). Marty and Fauré (2016) indicate the proper operation of neuromuscular action require the activation of type-1 ryanodine receptors (RyR1s). The opening of the RyR1s causes the release of calcium, which activates the process of muscle contraction. Native American Myopathy (NAM) is a variant of the STAC3 mutation within the 12th chromosome (12q 13-14) (Horstick, Linsley, Dowling, Hauser, McDonald, Ashley-Koch, and Kuwada, 2013).

The mutation, being hereditary, resides within specific family lineages (Fig1). Members of the family harboring the mutation may not present any outward sign and may only self-identify under special circumstances by which the mutation makes itself known. The starting point for the diagnosis of NAM often involves a simple surgery leading to a corresponding symptom. The term malignant hyperthermia (MH) is often the first, and at times, the last devastating symptom of an underlying genetic condition. The medication succinylcholine (neuromuscular depolarizing agent) administered as anesthesia which it’s

Stamm, D.S., Aylsworth, A.S., Stajich, J.M., Kahler, S.G., Rathmell, W.K., Speer, M.C., & Powell, C.M. (2008). Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. American journal of medical genetics. Part A, 146A 14, 1832-41.

Fig1 Examples of Native American Myopathy

Top Right-mouth agape, top right- cleft pallet, bottom left- low set ears, bottom right clubbed feet.

Stamm, D.S., Aylsworth, A.S., Stajich, J.M., Kahler, S.G., Rathmell, W.K., Speer, M.C., & Powell, C.M. (2008). Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. American journal of medical genetics. Part A, 146A 14, 1832-41.

a common effect is the relaxation of muscle via inhibiting nerve connectivity. The process in a NAM subject causes an unforeseen chain of events that often results in death if not evaluated immediately and remedied. The MH results from a combination of metabolic issues starting with excessive CA2+ release causing uncontrolled muscle contractions, which depletes adenosine triphosphate (ATP) (Fig 2). The depletion of ATP then causes the subjects system to consume oxygen excessively. The resulting use of oxygen increases the manufacturing of glucose, resulting in a rising body temp. The body now in a state of hyperthermia is only compounded by increased CO2 levels accompanying the runaway temp. The anesthesiologist can administer an AcHe inhibitor to counteract the succinylcholine in the patient’s system while attempting to stabilize the patient's temp. The symptom and reactions present the first symptom to suggest possible neurological issues associated with CA2+channels within the nerve structure, possibly signaling NAM.

Fig 2 Calcium Channel and STAC3 interaction

(.Flucher B. and Campiglio M. (2019) diagram courtesy of Science Direct, OpenSource information)

The connecting fiber, including tubules and actin, present a different challenge for identifying the mutation. Biopsy of muscle tissues can indicate a specific set of defects within the tubule and actin structures (Wong King Yuen, Campiglio, Tung, Flucher, Van Petegem, 2017). The actin and tubule structures display significant malformations indicate the presence of a mutation requiring further investigation. Visual inspection of the malformation (via microscope) within the structure indicates a lack of proper communication between actin and myosin structures (Linsley, Hsu, Groom, Yarotskyy, Lavorato, Horstick, and Kuwada, 2017). The lack of proper communication between the nerve and corresponding muscle structures inhibit the patient’s ability to properly execute excitation contractions (EC) at the motor endplate (Horstick, Linsley, Dowling, Hauser, McDonald, Ashley-Koch, and Kuwada, 2013). NAM/STAC3 mutation causes a reduction in voltage, or the lack of voltage transfer prevents the subsequent lack of muscle control between the nerve connection and the motor endplate. Wong King Yuen, Campiglio, Tung, Flucher, Van Petegem (2017) indicates that due to the rarity of neurological and physical manifestations of NAM physicians often lack experience with the mutation and unable to recognize symptoms suggesting a gene investigation for possible answerers.

The brain is also affected by changes within the communication variations associated with NAM/STAC3 mutations. The defects inhibit muscle movement via lack of proper connection within the motor cortex due to calcium channel release causing miscommunication (Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, Pecini, 2016). Most of the defects associated with NAM seem concentrated between the frontal and parietal lobes, but due to the interconnection actions within the brain, to date, the total number of regions have not been fully identified (Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira, 2017. The resulting defects result in the inability to control muscle movement and at times, a lack of muscle tone (dystonia). Patients associated with the STAC3 mutation suffer inefficient communications muscle-skeletal connections resulting in dystonia symptoms which only compounds mobility issues for the individual. The inhibited muscle activity and growth only inhibit movement more as the patient grows older. Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira (2017) explains the cleft pallet, clef lip, and lack of muscle tone inhibit speech and communication. The lack of both speech and motor skills impair the individual’s developmental growth leaving them far behind their peers (Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, Pecini, 2016).

The importance of identifying a specific mutation is often as important as the defects and the symptoms. The odd combination of physical defects with NAM/STAC3, subsequent cognitive effects on the brain, and genome effects leave physician searching for answers. Cognitive effects on the brain can range from limited abstract thought to loss of executive functions (Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, Pecini, 2016).The defects can range from a facial disfigurement, low ears, and cleft pallet to the microscopic action within the nerve cells. Individuals with NAM can be a difficult differential diagnosis, and due to the rareness of such a disease, often many physicians do not explore gene identification to verify the mutation.

Currently, two specific medications are in the testing phase for the treatment of Native American myopathy. The CA2+ channeling disorder associated with NAM and other closely related muscle-skeletal issues has several treatment possibilities (Niu, Yang, Yue, Inoue, and Ben-Johny, 2018). The medications diltiazem and verapamil are currently in the testing phases as catalysts for EC support. The intent is to slow the flow of calcium, restricting the amount of calcium flowing thru channels prevent unwanted muscle contraction (Niu, Yang, Yue, Inoue, and Ben-Johny, 2018). Though research is difficult, the use of medication addressing the flow of calcium seems a step in the right direction.

Medications Associated with Native American Myopathy:

NAM being a congenital myopathy has no known cure and as such only medications to treat the symptoms of the disease are available. The mutation attacks, specifically chromosome 12q 13.3, but the corresponding effects attack specific nerve functions. They also include actin and tubules within muscle tissue, and communication with nerve gabapentin receptors, SR gated channels, and CA2+ channel release (Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira, 2017; Wong King Yuen, Campiglio, Tung, Flucher, Van Petegem, 2017). The combination of symptoms directly affects skeletal muscle systems but, also those within the connectivity of the parietal and frontal lobes of the brain. The resulting miscommunication disruptions affect cognitive abilities and higher executive functions (Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira, 2017).

The four medications associated directly with the treatment and suppression of the symptoms of Native American Myopathy have limited results. The four medications in current use are Dantrolene(half-life 8.7 hrs), Gabapentin (Horizant) (half-life 5-7 hrs), Prednisone(half-life 3-4 hrs), and Bay-K8644 (ω-Conotoxin GVIA) (half-life undisclosed). The use of dantrolene is essential as, without its use, many might not make it the testing that provides a diagnosis of NAM. Dantrolene (used as an antagonist) counteracts the onset of malignant hyperthermia (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). The medication commonly is administered in either tablet or IV form (Sun, Slavov, Schnackenberg, Ando, Greenhaw, Yang, and Beger, 2014).The medication is a derivative of Macrodantin which originated as a relaxant for urinary tract infections (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). When testing the medication, a slight modification of the chemical makeup was made resulting in testing on mice which left the animals either unable to move or extremely lethargic (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). The medication was then used as a muscle relaxant and found to inhibit CA2+ channeling. Little did the physicians fully understand the inhibitory capability and lifesaving potential of the medication (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). Side-effects and contradictions are a focal point of the medical staff as preventing harm is key to the patient. The long-term issues include liver damage/hepatitis, hypertension, and upper motor neuron disorder. Though the motor neuron issues and hypertension are important, the most significant contradiction is the hepatic issue (Sun, Slavov, Schnackenberg, Ando, Greenhaw, Yang, and Beger, 2014). Left unmonitored the possibility exists of complete liver failure compound the patient’s condition. The ethical quandary focuses on the importance of first saving life when stricken with malignant hyperthermia then diligence in monitoring liver function (Wilkinson, Portmann, Williams, 1979).

Physicians often overlook the symptoms of NAM while administering anesthesia until the situation arises as to the instance of malignant hyperthermia (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). The use of Dantrolene specifically targets a side effect of the mutation that affects EC coupling associated RYR1 which can also affect cardiac nerves (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). Side effects of Dantrolene are vomiting, muscle weakness, and drowsiness. The contradictions of the medication range from

The sarcoplasmic reticulum (SR) is responsible for allowing the calcium release and as the SR is inhibited CA2+ is unable to transfer the potential to action (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). Dantrolene specifically inhibits CA2+release which contracts muscle without warning as often a side effect of malignant hyperthermia which at times coincides with catecholaminergic polymorphic ventricular tachycardia (Choi, Koenig, and Launikonis, 2017; (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015). The cardiac event is often unforeseen and unless the anesthesiologist is fast-acting the situation often results in death. The volatile arrhythmias are often a symptom of NAM/STAC3 mutation, and if exhibiting no other symptoms of the disease, the medical team is left reeling from the circumstances. Control of nerve calcium channeling and other calcium channel modulation drugs could soon lead to isolating all symptoms associated with controlling specific EC controls (Oo, Gomez-Hurtado, Walweel, van Helden, Imtiaz, Knollmann, and Laver, 2015).

The second medication in the group Gabapentin (Horizant) works similarly to dantrolene but utilizes a different approach focused directly on RYR1 communication (Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca, 2017). Gabapentin is a GABA antagonist which originated as a medication used to control seizures. NAM for some brings with it a set of side effect mutations that can leave the patient experiencing increased levels of pain that without intervention, decrease their already diminished quality of life. The use of Horizant targets specifically the Alpha2 Delta1 thrombospondin receptor communication (Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca, 2017; Eroglu, Allen, Susman, O'Rourke, Park, Ozkan, and Barres, 2009). The use of gabapentin (Horizant) inhibits the gabapentin receptors limiting uptake resulting in an analgesic status reducing overall nerve pain for the individual. Communication Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca (2017) explains the decrease in overall pain for the patient serves to increases the quality of life for the individual.

The origin of Neurontin Gabapentin came in the use of the drug as a muscle relaxer. Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca (2017) suggests that often with myopathies that tactile and thermal hypersensitivity are difficult physical issues to overcome. Patients were found to have increased nerve sensitivity stemming from the excited transmission of the gabapentin receptors (Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca, 2017). The medication does not completely block GABA reception but instead reduces it to an acceptable level for the patient. Bannister, Qu, Navratilova, Oyarzo, Xie, King, and Porreca (2017) indicate, however, that the patient may require increases in medication as they age, or their condition begins to deteriorate. Once physicians made compensations, patients in the studies tended to have reductions in pain, but the reduction was short-lived as the patient’s condition continued to deteriorate. The contradictions of Gabapentin suggest some individuals may suffer facial weakness along with excessive muscle fatigue (Quintero, 2017). The ethical ramifications suggest prescribing the medication may affect the patient’s quality of life. The use of the medication combined with such side effects as hypoventilation, respiratory failure, and teratogenicity may subject unborn children to risks (Quintero, 2017). The physician may find medications with less possible side effects as more useful in a given situation.

Lana, Page, Kadurin, Ho, Nieto-Rostro, and Dolphin (2016) indicates the most common symptom resulting from NAM includes myalgia associated with nerve and muscle pain. The pain often experienced may result from overactive nerve connections within GABA receptors. Lana, Page, Kadurin, Ho, Nieto-Rostro, and Dolphin (2016) suggest the patients often see increased muscle swelling and hypersensitivity to heat and cold as well. The most effective medication to reduce the swelling is the corticosteroid prednisone. The use of prednisone is common in the treatment of NAM and has had very promising results (Birnkrant, Bushby, Bann, Apkon, Blackwell, Brumbaugh, and DMD Care Considerations Working Group, 2018).

The medication has shown the capability to increase movement for those who were otherwise debilitated by their condition. Prednisone provides relief by working as an anti-inflammatory by reducing the time for effective protein repair to structures aiding in effective regeneration (Quattrocelli, Salamone, Page, Warner, Demonbreun, McNally, 2017). The improved function over a lifespan may not treat the mutation directly but have been found very effective in increasing mobility and quality of life (Birnkrant, Bushby, Bann, Apkon, Blackwell, Brumbaugh, and DMD Care Considerations Working Group, 2018). Ethical concerns of the long-term use of anti-inflammatory medication center on possible contradictions of the medication which affect the patient later in life (Krasselt and Baerwald, 2016). The know contradictions of prednisone include peptic ulcers, osteoporosis, and hypertension (Krasselt and Baerwald, 2016). Hypertension and osteoporosis may be the greatest concern due to their effects over a lifetime (Krasselt and Baerwald, 2016). Considering the nature of NAM one could argue though such contradictions are possible the use of the medication as an anti-inflammatory far outweighs the risk associated with the use of the medication (Quattrocelli, Salamone, Page, Warner, Demonbreun, McNally, 2017).

The final grouping of effective treatments comes from a modified natural source. (Hao Hu, Bandyopadhyay, Olivera, Yandell (2012) indicates that nature provided the basis for of the treatment, and with a bit modification, created several new medications. BAY-K8644 (Omega Conotoxin GVIA)(Fig 3) is one such agonist.

(Fig3- BAY-K8644)

National Center for Biotechnology Information. PubChem Database. CID=73169082, https://pubchem.ncbi.nlm.nih.gov/compound/73169082 (accessed on Aug. 25, 2019)

The Conus Geographus (Fig 4) is one such species that through a stroke of luck provided one of the best aids in controlling CA2+ channel release. The modification of the venom of this small tropical fish-eating snail provided relief to thousands of myopathy suffers (Ets, Seow, and Moreland, 2016). The unlikely source has a venom that leaves its prey immobilized by flooding the system with peptides targeting CA2+channels and specifically two nicotinic receptors (Hao Hu, Bandyopadhyay, Olivera, Yandell, 2012).

Byrne, D. (2019) Geography Cone Photo(Conus geographus),www.qm.qld.gov.au

Fig 4 Conus Geographus

The venom is not paralytic in nature but instead causes a complete collapse of voltage connectivity throughout the prey’s entire body; all nerve information transfer becomes erratic (Hao Hu, Bandyopadhyay, Olivera, Yandell, 2012). The venom though deadly in its pure form went through a tedious alteration process resulting in a medication that can target stimulation of L-type voltage in nerve connections (Lee, Park, Ha, Park, Berent, Jorgensen, Ro, 2017). The resulting increases in connectivity have allowed some with dystonia associated with NAM regain movement and the use of limbs (Hao, Bandyopadhyay, Olivera, and Yandell, 2012). Bay-K8644 has had a difficult time attempting to gain use outside the experimental realm. The medication administered via IV though very useful to those with NAM has two contradictions that make it possibly not the most ethical medication given the possible long-term effects to the patient (Fan, Yu, Lan, Ou, Yang, Li, and Li, 2018). The two most common contradictions are osteoporosis and atrial fibrillation. Physicians may consider osteoporosis an acceptable risk over a lifetime. The patient could develop osteoporosis, especially in the case of a family history supporting the disease (Fan, Yu, Lan, Ou, Yang, Li, and Li, 2018). The atrial fibrillation may become life-threatening to the patient over time. The chemical nature of the compound and point of origin make synthesis difficult and mice tested in a prolonged manner showed very high instances of atrial fibrillation (Fan, Yu, Lan, Ou, Yang, Li, and Li, 2018). The use of the medication can provide relief to the patient, but the physician must monitor the patient closely (Fan, Yu, Lan, Ou, Yang, Li, and Li, 2018).

Native American Myopathy/STAC3 mutation presents a difficult set of circumstances that affect both identification and treatment. The physical aspects of the cleft pallet, cleft lip, and club feet are only a few of the debilitating physical aspects of the mutation. Calcium channel/EC issues within the body are unable to be seen with the naked eye, and physicians must rely on symptoms alone for initial identification. The onset of symptoms often initiated first by the presence of malignant hyperthermia. The initial occurrence of MH leaves physicians perplexed, and as a result many do not survive. The identification and subsequent treatment of the Stac3 mutation hinge on a quick reaction time of medical professional combine with experience. NAM is rare and as such remains unseen by many physician’s and often overlooked. Once treatment can begin the first line of defense typically engages during surgery in the form of dantrolene. The dantrolene allows the patient to survive the surgery by confronting the malignant hyperthermia. The patient is then administered prednisone and gabapentin to control symptoms and provide a better quality of life/long term relief. The future of NAM seems a bit brighter with the testing and possible inclusion of BAY-K8644 into the mix. The medication may provide long-term correction to endplate connection with the muscle fiber/ EC control and allow the patients to become more functional. Ethical factors in using medications such as BAY-K8644 play a part in causing harm to the patient while attempting a long-term symptom relief protocol. The next generations of medication have taken a different approach, and possible gene therapy may lay on the horizon and provide an end to the scourge of NAM/STAC3 mutation.

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