Mutation Origins in Native American Myopathy: Proposal

Specific Aims

The origin of specific cellular malformations or subsequent mutations often becomes the battleground when seeking root causes for debilitating diseases. The variation that produces Native American myopathy is a devastating diagnosis for those afflicted. Waldrop, Boue, Sites, Flanigan, and Shell, (2017) indicates the origin of NAM (Native American Myopathy) is challenging to decipher and may require more in-depth investigation. Waldrop, Boue, Sites, Flanigan, and Shell (2017) present the case of a 24-month-old child referred for evaluation. The symptoms of NAM are without question and suggest specific muscle, cognitive, and congenital disabilities as part of the diagnosis. The defects present as hypotonia, micrognathism, club feet, diminished cognitive ability, and cleft pallet. The general population does not exhibit the combination of errors at the same rate, such as cleft pallet (Mangold, Böhmer, Ishorst, Hoebel, Gültepe, Schuenke, and Ludwig, 2016). Those with NAM/STAC3 mutation are four to five times more likely to exhibit numerous defects than those with only cleft pallet (Mangold, Böhmer, Ishorst, Hoebel, Gültepe, Schuenke, and Ludwig, 2016). Neurological issues indicate Stac3 gene mutation resulting in N-terminal difficulties, low nucleophile reactions lowering connectivity to nerve and muscle tissues (Waldrop, Boue, Sites, Flanigan, and Shell, 2017). The identification of the mutation via muscle biopsy provides nerve and connectivity information. While attempting to perform the muscle biopsy, the final issue specific to NAM during surgery became apparent (Waldrop, Boue, Sites, Flanigan, and Shell, 2017). Once anesthesia was administered the child began to exhibit signs of malignant hyperthermia, though the muscle biopsy was vital in the final diagnosis malignant hyperthermia is a tell-tale sign of the mutation (Waldrop, Boue, Sites, Flanigan, and Shell, 2017). Given the debilitating effects and suffering involved presents in a triad of difficulty, including physical, psychological, and cognitive, the need for finding the origin of the mutation is imperative.

Working in conjunction with medical professionals in a longitudinal study will indicate families of interest who exhibited the gene mutation. The use of qualitative data and genetic histories are essential to the research. The cataloging of surveys and neurological abnormalities provide a system of organizing contributing factors of NAM. Following research completion, all data capture, cataloging, and verification will then require presentation to the Comanche Tribal Council for approval. The data will then be transferred to the NIH for publication to aid in the identification of the mutation’s origins and possible gene therapies to prevent the variation in the future. The specific aim of the proposal is to isolate the cognitive disabilities caused by the NAM/STAC3 mutation within the Comanche Tribe of Oklahoma to address possible connections to environmental factors that influence the gene mutation.

Background

Ravenscroft, Laing, and Bönnemann (2015) explain that NAM, as well as many congenital myopathies, are part of significant gene mutations experienced in the human genome. The disease is hereditary and often found anchored within specific families which onset is precursory by a secondary issue. Kaur, Katyal, Yelam, Kumar, Srivastava, Govindarajan, (2019) suggest family members carrying the mutation though presenting few physical signs of stac3 mutation may suffer malignant hyperthermia as a result of the mutation. These individuals have also been known to produce offspring bearing several of the physical defects of NAM/Stac3 mutation. There are many developmental defects associated with the specific of NAM but, for the research, the focus will focus specifically on the significant areas conspiring to result in NAM. The effects of the mutation, malignant hyperthermia, hypotonia, neurological issues, cognitive disruptions, and possible environmental causes such as water, air, and soil contamination which may all contribute to increases in NAM/STAC3 in a specific physical location.

First and foremost, the discussion must begin with the instances of NAM/STAC3 mutation and the presence via hereditary and individual family genetic lines. McDonald (2012) suggests the need for inclusion of family history and extensive background information before beginning any diagnosis. The collection of family histories indicates not only the prevalence of specific diseases but also the frequency, location, and possible influences affecting a particular mutation. McDonald (2012) explains that once the research attains all vital information regarding family history, the second avenue if likely is to examine each family member suffering from congenital myopathies. The data given in such cases may direct the physician into a specific area of testing. McDonald (2012) initiates a battery of testing, beginning with RNA testing in an attempt to find increased toxicity levels. McDonald (2012) proposes toxicity levels to be found higher than average a battery of physical and cognitive tests begin on all subjects. The tests have a twofold need in the case of a family with multiple individuals suffering from the mutation (McDonald, 2012). The first is to find at what depth the mutation is affecting each generation (McDonald, 2012). The second is to see the progressive nature of the mutation and local factors that may influence the variations in question (McDonald, 2012). NAM has several contributing factors and levels of condition, once better understood, the physician could suggest a means of treatment. Following the foundation of a mutation brings about a better understanding of how a disease affects the individual both initially and throughout their lives (McDonald, 2012).

Beginning with the first factor, an emphasis on the specific outcomes of the NAM/Stac3 mutation is the foundation of understanding the disease and the effects within specific kinship groups. Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira, (2017) indicate the modification the gene pairs suffer derelict change resulting in a variant within the STAC3 Gene leads to the mutation. The mutation results in a protein that becomes disabled, resulting in several defects associated with proper tissue growth and connectivity within the neuromuscular system. The underlying issues affect several regions of including the motor cortex, which regulates planning and voluntary muscle movement, for example — the area where much of the concentrated malformations lie within the parietal lobe (posterior precentral gyrus). Telegrafi, Webb, Robbins, Speck-Martins, FitzPatrick, Fleming, and Sobreira, (2017) goes on to indicate that though the STAC3 mutation is associated with NAM, several muscle-skeletal afflictions also fall into the category due to overlapping symptoms including Moebius Syndrome and Carey-Fineman-Ziter Syndrome.

The issue of hyperthermia plays a significant role in the identification of NAM/STAC3. Waldrop, Boue, Sites, Flanigan, and Shell (2017) indicates while diagnosing a 24-month-old for possible NAM mutation and unforeseen event aided in the diagnosis. The child was given anesthesia before the surgery beginning when complication began, which prevented the initial biopsy from taking place (Waldrop, Boue, Sites, Flanigan, and Shell, 2017). The child suffered malignant hyperthermia almost immediately after the physician-administered anesthesia. The critical part of such a reaction comes in the form of relaxants that cause the blood to flood with oxygen and lack of nerve connectivity result in the bodies inability to regulate temperature (Kaur, Katyal, Yelam, Kumar, Srivastava, and Govindarajan, 2019; Waldrop, Boue, Sites, Flanigan, and Shell, 2017). The symptoms display a significant warning sign of those suffering from NAM or gene mutation without specific physical symptoms. Those presenting such symptoms are tested via biopsy immediately. The test is to check the actin within nerve cells to verify malformations.

Wong King Yuen, Campiglio, Tung, Flucher, and Van Petegem (2017) explains the malformations of actin effect nerve connectivity and indicate the presence of STAC3 mutation. These mutations are also visible via the titan and lack of a bridge to myosin. The other area of malformation is the gated calcium channels that are deformed, and lack correct operation not allow calcium to enter during the reception of action potential. The actin cells require the discharge of calcium ions, which would enable the release of potential to the muscle tissue. The result is movement of the muscle in a normally functioning patient (Wong King Yuen, Campiglio, Tung, Flucher, and Van Petegem, 2017; Horstick, Linsley, Dowling, Hauser, McDonald, Ashley-Koch, and Kuwada, 2013). However, those with the STAC3 mutation having malformations within the connective structure either present inconsistent transfer of information or no information transfer (Wong King Yuen, Campiglio, Tung, Flucher, and Van Petegem, 2017; Marty, and Fauré, 2016). The resulting connectivity issues to the muscle tissue often result in indications of hypotonia in the patient. When children are born with NAM/STAC3 mutation, there is a presentation of non-resistance to arm and leg movement testing (Wong King Yuen, Campiglio, Tung, Flucher, and Van Petegem, 2017; Waldrop, Boue, Sites, Flanigan, and Shell, 2017). Currently, there is no gene therapy, nor is the origin of the mutation known. The heart of the debilitation and the most destructive result of the STAC3 variant comes in the form of cognitive dysfunction.

Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, and Pecini (2016) suggest the neuropsychological profiles of individuals with NAM/STAC3 mutation fall into a vast realm of cognitive disabilities. The first and most prevalent with neuromuscular issues is the loss of problem-solving ability and the use of higher executive functions. The secondary areas of interest fall toward those of obsessive-compulsive disorders, ADHA, and those on the autism spectrum. Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, and Pecini (2016) illustrates the underlying neuromuscular connections in the brain as the source of impairment especially those suffering from congenital myopathies such as NAM/STAC3 mutation. Astrea, Battini, Lenzi, Frosini, Bonetti, Moretti, and Pecini (2016) also found that those infants born with congenital myopathies suffer extensive cerebellum deformities and widespread white matter malformation. Such extensive abnormality directly affects the connectivity and set pathways by which the brain not only contains memory but also trickles into difficulties within skeletal muscle functions. Bönnemann, Wang, Quijano-Roy, Deconinck, Bertini, Ferreiro, and Members of International Standard of Care Committee for Congenital Muscular Dystrophies (2014) indicate the presence of Type II lissencephaly (Cobblestone Lissencephaly) in patients with congenital myopathies (p.7). The presence noted defects in both full-term and aborted fetuses during the research. The excessive migration of neurons in the brain during brain formation leads to a cobblestone style effect along with the subarachnoid space. The malformations have been known to cause cognitive issues such as development learning difficulties, mental retardation, and lack of higher executive functions. The diagnostic test performed at birth include analysis of the contraction of knee and elbow joints along with club feet, and seizure may also be present during initial examination (Bönnemann, Wang, Quijano-Roy, Deconinck, Bertini, Ferreiro, and Members of International Standard of Care Committee for Congenital Muscular Dystrophies, 2014).

Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas (2018) explain cognitive dysfunction associated with the neuromuscular disease as a trend that tends to be increasing within the human population. Dowling, Lawlor, and Dirksen (2014) also indicate the increase in neuromuscular mutations associated with T-tubule and excitation difficulties associated with actin malformations Niu, Yang, Yue, Inoue, and Ben-Johny, 2018; Wong King Yuen, Campiglio, Tung, Flucher, and Van Petegem (2017). The ever-growing list has became classified into the group triadpathies, which encompasses several neuromuscular diseases. Each disease even though neuromuscular in nature compound difficulties for the quality of life for a patient due to a wide range of cognitive challenges. Linsley, Hsu, Groom, Yarotskyy, Lavorato, Horstick, and Kuwada (2017) purposes that although not all mutations are presenting in STAC3 mutation, all the variations are associated with protein inactivity associated with nerve connectivity and at times nerve formation. Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas (2018) explain that the malformations resulting cognitive difficulties affect each patient differently which emphasizes the need for broader research broaden in scope. Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas (2018) elucidates the need for further investigation due to our lack of deep understanding of the connection between several neuromuscular diseases. The diseases have begun grouping into three specific areas of interest, each with their particular cognitive difficulties (Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas, 2018). The areas of interest include motor neuron diseases, muscular dystrophy, and hereditary disease associated with inhibiting protein function (STAC3) mutations (Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas, 2018). Each of the diseases/mutations hold cognitive malfunctions associated with cognitive functions with the prefrontal cortex affecting executive function(Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas, 2018). Diagnostic testing, along with MRI showed malformations in the prefrontal cortex of patients resulting like their cognitive impairment (Orsini, Carolina, Ferreira, de Assis, Magalhães, Teixeira, and de Freitas, 2018).

Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan (2012) suggests the myopathies are well known the lack of understanding regarding care is an area in need of more in-depth consideration. Though the cognitive effects are widely recognized little is understood as to the origin of the mutation and the environmental factors that may influence the variation (Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan, 2012). The care being of at time negligent status has caused a significant turn toward providing physicians and caregivers with the means of better understanding the depth of the patient’s difficulties (Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan, 2012). Most patients suffer from various forms of cognitive problems lacking in less knowledge of their conditions as well as severe muscle dystonia only compounding the issues (Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan, 2012). The caregivers and physicians attend seminars which aid in understanding the mutation, the effects on the body, and at times the resulting extreme cognitive impairment (Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan, 2012). The idea is to present caregiver and physicians with the tools to better sever the patient and increase the patient’s quality of life where possible. Impairments tend to increase with age, which increases the need for therapies to reduce suffering throughout the patient’s lifespan (Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan, 2012). Though Wang, Dowling, North, Schroth, Sejersen, Shapiro, and Yuan (2012) do not consider the origin of the mutation and focus on care, there is a sense of urgency in locating the source of the STAC3 variation and the resulting myopathy NAM.

Significance

The research within the proposal will begin by first identifying individuals/family lines connected to local Native American tribes. The exceptional circumstances require the permission of local tribal councils and access to reservation medical locations and possible residents. The intent is to discover the depth of cognitive difficulties with those suffering the mutation. The research will then select a group of families and compare symptoms and underlying cognitive aspects that tend to afflict all those with the mutation. The study will use elements of polling, survey, and interviews to identify individuals with cases of NAM. The individuals cataloged then are described only by letter and number combination to protect the identity of both the family and the individual. The use of such a coding system will minimalize the risk to those coming forward to provide information. The research will keep all identities confidential unless the participant states otherwise. The research will organize research into cognitive difficulties and investigate the scope of those difficulties. The study will then be presented to the tribal medical facility and used to develop treatment plans for patients to increase the quality of life. Researchers will offer all participants with letters explaining the procedures of the research, the intent of the study, and letters of informed consent. Copies of all notes and consent forms will be collected and kept securely for four years, then destroyed.

There will be a section regarding future research added as a means to present a direction to investigate the origin of the mutation. Environmental causes regarding the modification have little research, especially regarding NAM and Native American reservation. Researchers may collect water, air, and soil samples in conjunction with the current study as a means of ruling out other toxins that may result in cognitive difficulty (Bönnemann, Wang, Quijano-Roy, Deconinck, Bertini, Ferreiro, and Members of International Standard of Care Committee for Congenital Muscular Dystrophies, 2014). All testing will be done by a third-party source at Oklahoma State University, which is a neutral site and far from the reservation areas. A secondary are that will be used in describing future research is the area of Gnome research and Myoediting (Zhang, Long, Bassel-Duby, and Olson, 2018). There have been several advances in the areas of gene editing which could provide a useful means to stop the mutation in future generations resulting in the end of variation and subsequent cognitive disabilities (Zhang, Long, Bassel-Duby, and Olson, 2018).

Purposed Study

Research Question

What is the cognitive effect associated with the NAM/STAC3 mutation within the Native American population?

Hypothesis

The effects of Native American Myopathy are well documented, however, whether clusters of cognitive impairment exist has not been well researched (Bönnemann, Wang, Quijano-Roy, Deconinck, Bertini, Ferreiro, and Members of International Standard of Care Committee for Congenital Muscular Dystrophies, 2014). Prior research focused on the existence of cognitive delays, but little attention provided toward specific patterns of cognitive difficulties. This research will attempt to fill the gap in prior research, documenting specific patterns of cognitive difficulty for those with NAM/STAC3 variation. Medical professionals have carried out many studies associated with the NAM/STAC3 mutation though little has been done to isolate specific cognitive disabilities. The research will focus on identifying particular cognitive effects caused by mutations and their connection to precise regions of the brain. The final step will be to cross-reference those findings with Native American tribes in other location exhibiting the NAM/STAC3 mutation. Compiling a group of cognitive dysfunctions and comparing them to other known factors which influence mutation. The elements will then be used to identify only those cognitive disabilities that are associated with NAM/STAC3 mutation. The necessity of regrouping the cognitive defects is to focus primarily on only those defects which present in all subjects. The isolation will provide focus toward specific disabilities and not a wide-ranging group of defects.

Research question two

Does the NAM/STAC3 mutation present in a specific physical location on the reservation?

Hypothesis

The grouping of defects associated with cellular mutation often is isolated to specific areas or regions due to environmental influences. Gene mutations on the level of NAM/STAC3 often present as subject to outside influences responsible for the cellular modifications (Bönnemann, Wang, Quijano-Roy, Deconinck, Bertini, Ferreiro, and Members of International Standard of Care Committee for Congenital Muscular Dystrophies, 2014). When compiling data of specific families, the researcher will analyze all data for possible anomalies and defect correlations. The intent is to identify potential connections between particular locations on the reservation and those exhibiting the NAM/STAC3 mutation. Data is then used to extrapolate a cross-reference list with the number and physical location of those with cognitive disabilities. Once the list is cross-referenced, families will be identified for visual inspection of the premises to verify if any openly visible contagion points may be responsible for the possible mutation.

Research question 3 (future research)

What is the possible unseen environmental factor associated with NAM/STAC3 mutation in the air, soil, and water?

Hypothesis

The justification for environmental research hinges on the need for not only identifying the cognitive difficulties but also possible causes for those defects. Conducting inspections of environmental issues may shed light on possible causes of the mutation. Little academic material exists connecting NAM to possible environmental cases; as such, the collection of data would provide a direction for further research. Environmental contamination is a common source of gene mutation among organism’s living within all ecosystems on the earth (Dandage, Pandey, Jayaraj, Rai, Berger, and Chakraborty, 2018). Though factors of mutation are well known to exist in current environments, the break-over level of exposure is not known, which results in specific variations. Dandage, Pandey, Jayaraj, Rai, Berger, and Chakraborty (2018). The research will (if possible) remove air, water, and soil samples from the locations with the most prevalent cognitive dysfunctions. The samples identified are then examined for anomalies and potential items that may influence mutation at the cellular level. Individual interest items will include those that are known to have mutation influence over nerve cell structures and Ca+2 channel gates. Were specific information and anomalies located all data will be provided to the tribal council immediately for further action?

Note: As of 7/26/19 it was found that an artillery test range operates just outside the reservation and the use of depleted uranium shells is common in this location.

Methodology

The research will focus on the cognitive effects associated with the NAM/STAC3 mutation. The origin and impact of the mutation indicate the possibility of specific family groups carrying the variation from one generation to the next. The study conducted on the Comanche Reservation of Oklahoma is a foundation study examining the way NAM/STAC3 mutation affects a specific population. Though a plethora of information about the NAM/STAC3 mutation exists, not many research studies have focused on groupings of those with mutations. The third issue is that of kinship groupings, which also have not been widely studied to indicate both the path and extent of the mutation infiltration. The final consideration of the study will consider future studies to include possible environmental causes (water, air, and soil) for the mutation. A trip to the are proved fruitful finding at the SW corner of the reservation is an artillery test range for depleted uranium shells which if the allowed to leech into the groundwater may provide a pathway for possible environmental contamination.

Study Design

The design of the study will conduct in-depth research into the cognitive effects of NAM/STAC3 mutation of residents. The first aspect of the study is first to contact local health officials who are to provide records of individuals exhibiting signs of NAM. Local physicians have accumulated data and a list of name and address of individuals wishing to share their stories regarding the defects associated with NAM. The researcher will present a letter of informed consent to all participants stating the nature of the study, along with the use of data description. The form will also list boxes regarding the level of approval to include the use of recording and camera equipment if they wish. All participants will then fill out surveys containing questions associated with the disease and a list of defects known to exist in the family. The research will verify all defects via medical information and catalog via color code and numbed a severity list. The geneticist on staff will analyze providing reports identifying specific families and lists of specific genetic defects. The research will cross-reference findings with listed cognitive difficulties; the findings then are assessed for patterns connecting genetic and cognitive defects. The use of a letter, number, and color-coding system will indicate the family groups or individuals’ effects by the mutations. The color code of (red=5+),(yellow=3-5), and (green=1-3) will describe the severity of the mutation commonality in a specific group.

Researchers will then cross-reference the list of severity to actual physical addresses searching for commonality. During this time, a second list will compile all cognitive defects with there own severity levels. The interviews conducted will visually verify faults along with evaluations of cognitive ability. The flaws are then compared to the physical address location, searching for defect patterns. The final stage of data collected will require coding of all transcribed interviews searching for commonality. The researcher then compares commonalities within the family histories and possible generational mutative or congenital disability issues. The information once collected will be compiled and first presented to the tribal council for publication approval. The tribal council and I will negotiate any areas of dispute regarding publication. Once all conflicts are corrected finding will be assembled into a presentation and delivered at the National APA convention.

Participants

First and foremost, the researcher will explain that at any time the participant becomes uncomfortable with the study, the participant may terminate involvement. The control group will consist of 10 individuals of average cognitive ability, and a selection of forty individuals in total from each of the color codes (symbolizing defects) of severity. Thirty-three percent of each designation for a total of forty. Testing conducted will utilize a combination of a modified version of a Criteria Cognitive Aptitude Test (CCAT), IQ, and chronological puzzle tests. Average scores will compare participants in the control group and those with NAM/STAC3 mutation. The researcher examines the participant's physical residents with the lowest scores and the highest number of defects, plus environmental factors patterns. All environmental testing or samples of water, air, and soil will require written consent of the participant. Local authorities on the reservation will receive reports of any examination resulting in chemical abnormalities. The researcher will then pay all participants after the study and presentation of the information to the tribal council. Upon completion of the presentation to the tribal council, all participants will receive a copy of the survey. The research then advises all applicants that all physical information regarding interviews, recordings, and surveys will be scanned securely to the psychology department archives at Ashford University marked for educational use only. All physical contents will then be held securely for four years and destroyed.

Budget Justification

The budget will cover 12 months in total of research conducted on the Comanche reservation near Elgin/Lawton Oklahoma. Prorated salaries list as a percentage of yearly wages for the PI (principal investigator) and graduate student. The process will include data collection, surveys, interviews, and medical information analysis. The graduate student pay will reflect assistance in conducting research, transcribing interviews, and finalization of information before the presentation. Large equipment purchases will include a video camera for possible interviews with families. Oklahoma State University will conduct environmental testing of air, water, and soil searching for chemical abnormalities for twelve-hundred dollars. The miscellaneous items also include a digital recorder and supplies provide the means for transcribing interviews. The research allows seventy-five dollars to each of the fifty participants in the study. The use of a personal vehicle will provide transportation for the graduate student and myself to and from the reservation. While staying at the reservation, the use of a home is offered at a fee of zero dollars as the Comanche Tribal council is providing the residence. No payments will be charged for access to medical histories via the Indian hospital at the location. Local physicians are more than willing to provide information leading to the research of NAM and finding possible links to the mutation.

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