It is hypothesized that many problems involving foot pain and ankle pain stem from the structure or malalignment of the foot. It has been shown that foot functionality is hereditary and that certain foot types put individuals at greater risk of developing musculoskeletal pain in the lower limb. Since a child’s foot is simply a miniature of the adult foot, many structural abnormalities are present at birth increasing the risk of pain in the individual’s lifetime. This implies that the foot type is the precursor to many painful conditions and is an important avenue for podiatric intervention. Understanding the hereditary factors that cause various foot types is important for the development of this intervention. However, the link between hereditary factors and foot and ankle pain is not well understood, and it is uncertain whether foot pain originated from that foot type or whether individuals with painful feet develop certain habits or choose occupation and footwear that lead to the foot pain. It is important, however, to prevent the development of these painful conditions.
Foot pain and ankle pain have been shown to be highly prevalent in adults and even more so in individuals of advanced age. In a study of 208 men and 197 women over the age of 60, it was found that 80% had reported some form of disabling foot pain. 1 in 4 adults over the age of 45 were found to have this problem, which in another survey was reported to be more prevalent than rheumatoid arthritis and gout in adults 35 years or older. Foot pain has also been shown to impair the ability to perform activities of daily living. This is particularly important as it has been suggested that the onset of functional limitations is often the initial phase in the disablement process and a contributor to the loss of independent living. As foot pain is so common and has profound effects on the elderly, it is important that we understand how this happens and the best methods to prevent and treat it.
Background on foot pain and ankle pain
Foot pain and ankle pain are common conditions experienced by elderly people. A study in 2012 stated that 1 in 4 older people reported having foot pain on most days. This is significant as foot pain and dysfunction are considered to be a major public health issue and are key barriers to successful aging. The inability to perform daily activities while not experiencing pain greatly impairs quality of life. Pain and functional limitations in the lower extremities are also predictors of falls in the elderly. The annual prevalence of falls in the elderly is 30% and it is estimated that 10-15% of falls result in severe injury. Pain-related fear of falling and lesser confidence in the ability to perform daily activities of living are mediators of the relationship between foot pain and falls in the elderly. Lesser confidence in the ability to perform daily activities of living because of foot pain has also been shown to be associated with greater difficulty in independence maintenance in elderly people. As hereditary factors may contribute to the development of foot and ankle pain in elderly people, understanding whether there is a link or not between genetic predispositions and foot and ankle pain is of importance. This may lead to the identification of at-risk populations and specific factors which are influenced by heredity that can be targets for preventive interventions.
Importance of understanding genetic predispositions
In order to understand the best way to move research on foot and ankle pain from the old to the new genetics, it is first necessary to understand the nature of genetic causation and the ways in which genetic information can be applied to improve health. An overview of genetic concepts and their relevance to research on foot and ankle pain is provided in Table 1. Terminology in genetic epidemiology is to be found in a recent article by Valdes and Spector.
Advances in genetic science and biotechnology have resulted in a gradual but decisive shift from research on genetic causes of illness to research on utilizing genetic information to predict, prevent, and treat illness, a transformation described as a shift from the “old” to the “new” genetics. A recent article by Drs. Rich and Valdes provides an excellent example of research on the old genetics through a systematic review of the literature on the heritability of spinal disorders and associated symptoms. Published research on the heritability of musculoskeletal conditions, including a limited body of our own work, represents the “old” genetics, while the elucidation of specific genetic causes and pathways, and eventually the application of this knowledge to prevent and treat these conditions, will represent the “new” genetics. This shift in genetic research has clear implications for research on foot and ankle pain, where an understanding of genetic predispositions may have the potential to inform precision medicine and new preventative strategies.
Information regarding the significance of recognizing genetic vulnerabilities is scattered throughout the literature on musculoskeletal disorders and on the subject of clinical genetics. The development of hereditary epidemiology has underlined the significance of considering primary and auxiliary genetic factors as causes of illness. The disparities between research on genetic influences on illness and research on how to apply that knowledge have been highlighted in the US National Institute of Health’s Report of the Task Force on Genetics Research and the subsequent “Second Genetics Task Force Report,” both of which recommend increasing scientific inquiry into how genetic information can be used to improve health. Though it is widely recognized that the final intention of most genetic research is to enhance health and prevent illness, the best method for achieving this objective through genetic research is not self-evident.
Hereditary Factors and Foot Pain
The specific genetic factors involved are likely to be more clearly defined in research using large populations of people from a homogeneous genetic background, such as the current work being done on Icelandic populations. This research involves the study of genetic markers and specific gene sequencing in large populations of people with a specific condition compared to those without the condition. This type of work may ultimately define individuals at risk of developing a particular condition based on their genetic makeup, and allow for targeted prevention strategies.
A logical starting point in understanding genetic predisposition to disease is the study of familial aggregation of specific conditions. This approach has been used extensively in disorders such as diabetes and hypertension, and involves comparing the prevalence of a specific condition in a large group of people with a known family history of that disease to a similar group without the disease. If the condition is found to be more prevalent in the group with the positive family history, then it is likely that genetic factors contribute to the development of that condition.
Despite the significant burden of foot pain, very little is known about the etiological processes involved. Foot pain is known to arise from a wide range of etiologies, including acute trauma, overuse injury, surgery, as well as systemic and neurological causes. One area that has received virtually no attention is the possibility that genetic factors play a role in the development of foot pain. The human genome has now been sequenced, and this offers a new opportunity to understand the genetic contribution to many common conditions. A greater understanding of the genetic contribution to foot pain may eventually lead to multifaceted prevention and treatment strategies.
Genetic causes of foot pain
There are two primary methods used to study the influence of genetic factors in human disease. The most common is to estimate the heritability of the disease or disorder. Heritability is a population-based statistic that provides an estimate of the total genetic and environmental influence on the liability of developing a disease. The second method is to identify the specific genes that are responsible for the disease state. These genes can be identified by producing a genetic map of the human genome and performing genetic linkage studies using microsatellite markers, or by using the newer method of assaying single nucleotide polymorphisms with microarray technology. At present, there are few studies that have estimated the heritability of foot pain, and no studies have attempted to identify specific genes that may be involved. It is likely that heritability estimates and gene identification for foot pain will become a focus for research in the future.
Most of the foot and ankle pain literature has focused on the effects of environmental factors such as occupation, obesity, footwear, and physical activity. However, these variables account for only some of the observed variance in musculoskeletal pain. It is becoming increasingly evident that there are complex genetic and environmental interactions that can influence an individual’s susceptibility to developing specific musculoskeletal pain disorders.
Common foot conditions influenced by genetics
It was concluded from the investigated generations that certain foot and ankle conditions showed strong linkage across generations and thus suggests a hereditary influence. These conditions include hallux valgus, a common and complex deformity of the foot, and the incidence of overlapping and osteoarthritis were both higher between participants and at least one offspring. A further recognized finding was that six percent of the occurrence of adult acquired flat foot was transmitted from parents to adult children. These are just several examples of various conditions with findings to show hereditary contribution.
This section opens with a discussion of an investigation that aimed to determine how specific foot and ankle conditions cluster within families to understand possible hereditary links. This was done using data from the Framingham Foot study undertaken by Massachusetts General Hospital and Boston University School of Public Health. Information from participants in this study and their children, which totaled four generations provided participants were in generation three or four, was used. General recruitment into the Framingham study required that participants were living in proximity to Boston.
Impact of hereditary factors on foot pain severity
Reported data also reveals that some conditions demonstrate greater hereditary contribution than others. Estermann found that out of 233 cases of pes planus, 150 had a positive family history. Of those with a family history, 47 were considered strongly positive and rapidly progressive, whereas there were only two cases of the strongly positive type in those without a family history. This demonstrates that there are differing types of pes planus which may have varying degrees of hereditary influence. Estermann suggested that a familial pes planus was a specific disease entity that required differential treatment.
In their systematic review, Roddy et al. state that one way to determine whether a disorder is influenced by hereditary factors is through investigating the severity of the disease over time. They theorize that if the severity of the disease is influenced by heredity, then a younger age of onset and increasing severity in each generation would signify a genetic contribution. Since podiatric conditions can often be subclinical and are also influenced by environmental factors, it can be difficult to determine whether a condition is strongly influenced by heredity. However, there are family histories and case studies reported in the literature that strongly support the theory that certain foot disorders are influenced by heredity. For example, Charcot-Marie Tooth disease (CMT) is the most common cause of hereditary neuropathy. It has been reported that CMT patients who have an affected parent have an earlier onset and faster progression of the disease. Osteochondral dysplasia is a common condition in the pediatric foot that also has earlier onset in successive generations. Coxa vara and genu varum have been shown to have a greater severity in patients who have an affected parent.
Hereditary Factors and Ankle Pain
High arched feet can cause problems due to the reduced ability to absorb shock during weight bearing. This can lead to increased stress on the ankle joint and potentially result in injury. The most common inherited condition associated with ankle pain is hemophilia. This is a group of inherited genetic disorders that impair the body’s ability to control blood clotting. A joint bleed (more specifically described as a hemarthrosis) is the most common site of bleeding in people with hemophilia and if it occurs in the ankle, it can result in severe pain and permanent damage to the joint.
Posterior tibial tendon dysfunction is a condition that affects the tendon that helps to support the arch of the foot. It is most common in women over 40 and is a cause of acquired flat foot deformity. It has been suggested that this condition may have a genetic predisposition to its development.
Ankle deformities such as flat foot or high arched foot are often inherited and can be a source of lifelong pain and disability. Flat feet are a common condition and usually only a few people will actually have symptoms. However, a large study of US army recruits found that people with symptomatic flat feet were twice as likely to develop injury in comparison to those with asymptomatic flat feet.
Genetic factors and their role in ankle pain are well defined and researched. In a study to investigate the heritability of ankle and foot symptoms, the authors concluded that “an important role of inherited factors in the severity of early and mid-life foot symptoms.” It is known that having a family history of gout is an important risk factor for developing gout. Polymorphisms in the gene encoding interleukin-1 also increase the risk of developing gout, as well as influencing the age of onset of the condition.
Genetic factors contributing to ankle pain
Collagen is the most abundant protein in the human body and is the substance that provides the infrastructure of the complex tissues found in joints. It is a well-accepted fact that alterations to collagen metabolism brought about by genetic mutations can lead to structural abnormalities in tissue, increased vulnerability to tissue damage, and subsequent development of painful conditions in the joint affected. A prime example of this in the context of ankle pain is identifying an abnormal allele of the collagen 11 gene being a predisposing factor for the development of osteochondral dissecans in the knee. Though this is not related to the ankle, it provides clear evidence that genetic changes to collagen metabolism can result in debilitating joint conditions. With specific reference to the ankle, individuals with an inherited syndrome known as Ehlers-Danlos type 2 were found to frequently suffer ankle pain given that the syndrome affected their ankle joint’s ability to achieve stability while walking. The Ehlers-Danlos syndromes are a group of rare genetic disorders that affect connective tissues, often resulting in joints being hypermobile and having an increased propensity for dislocation and chronic musculoskeletal pain. This can be related to yet another study which found that variations to the gene which codes for the alpha 2 macroglobulin protein led to an increased risk of developing ankle osteoarthritis. The individuals in the study having this genetic variation were no doubt predisposed to the condition as the protein is known to have anti-catabolic properties in preventing degenerative joint diseases.
Genetic factors contributing to ankle pain may potentially cover a wide area. From a standpoint of understanding the interactions of biochemical processes in the body, alterations to the physical structure of any complex tissue within a joint and any variations to the ways in which the body is able to repair damage done to tissues can all be seen as potential factors influenced by genetics.
Inherited conditions associated with ankle pain
An important consideration in HLA associated conditions is that not all individuals who possess the gene in question will develop the arthritic condition, indicating that there is a gene-environment interaction and supporting the theory that arthritis is not purely genetic in nature.
In the case of the former, the individual has a 50:50 chance of passing the abnormal gene to their offspring. HLA (human leukocyte antigen) is a gene complex, the products of which are involved with presenting protein fragments to the immune system. Specific HLA gene types have been shown to be associated with the development of arthritic conditions. For example, the HLA-DR4 gene is associated with rheumatoid arthritis, and an individual possessing this gene has a greater risk of developing rheumatoid arthritis if they encounter certain environmental factors.
Patients who experience symptoms of arthritis at an early age and have a family history of a specific type of arthritis are potentially suffering from an inherited condition. Inherited conditions, although relatively rare in comparison to acquired injuries and arthritic conditions, can result in significant damage to the joint. These conditions may result from a single gene abnormality, leading to the expression of a faulty protein, or a more complex interaction of several genes and the environment.
Role of genetic predispositions in ankle injury risk
High TRA injuries (e.g., ankle sprains incurred during vigorous sports) are more likely to be similar to specific environmental acts in the causation of a chronic disease. In this instance, it is more probable that genetic factors have altered the TRA of the individual, then the specific environmental act can be considered the AT (causal act) with the injury being an AAA (acute adverse event) – an ankle sprain during non-professional sports or other low TRA injuries are to be considered alongside chronic diseases and possible to contrast the two in terms of differing predisposing genetic factors. This distinction between various TRA to ankle injuries and differentiation from specific chronic diseases is important but requires a thorough understanding of the specific injury types and their mechanisms.
The deduction from the belief that a person’s genetic status can affect their risk of an ankle injury is that various genetically moderated factors alter the probability of incurring the injury upon exposure to environmental factors. This concept is parallel to the multifactorial causation model for chronic diseases, whereby the disease is seen as an outcome of the complex interplay between genetic and environmental factors. An ankle injury is an obvious acute outcome rather than a chronic disease, but methodologically it is useful to consider causal factors as risk assessments (TRA) leading to the injury act or behavior. This TRA model provides a framework for which genetic research into ankle injuries can be based and helps distinguish between different mechanisms by which a person can incur an ankle injury.
Upon recognizing that genetics are often an overlooked risk factor for musculoskeletal injuries, a few important questions arise: Does the likelihood of incurring the injury depend on the type of ankle injury? Should ankles classified with genetic predisposition be considered as a specific subgroup of patients with lower absolute injury risk?
Managing Foot and Ankle Pain with Genetic Predispositions
Certain changes to your lifestyle can help alleviate your foot pain symptoms. For example, weight loss is the best lifestyle change to decrease pain in the feet. A weight loss of five pounds can translate into a 20-pound force reduction on the knee. Weight loss can decrease the progression of foot deformities and wearing shoes with arch supports and cushioning, and avoiding barefoot walking may help reduce pain. Individuals with toe deformities may find it more comfortable to wear sandals or slippers around the house. A switch to an alternate exercise routine that reduces high impact movement will also help alleviate pain symptoms. For example, swimming or biking is easier on the feet than running or walking. Altering work activities may also be in order. Those accustomed to prolonged standing or work on hard surfaces should seek to find an alternate position with more opportunity for sitting and less impact on the feet. These lifestyle changes are not easy and may take considerable time to come to full fruition, but can significantly impact foot pain symptoms.
Genetic testing for foot and ankle pain management
Although the current evidence supports the existence of genetic predispositions to foot and ankle pain, direct and structured research is required to fully understand the magnitude and potential impact of genetic profiling on foot and ankle pain management. Currently, no studies exist in the utilization of genetic testing in the management of foot and ankle pain. However, in an era where the aura of prediction and prevention from disease is highly esteemed, genetic testing may become an integral part of management for many chronic diseases, including those which affect the musculoskeletal system. As the Human Genome Project has been completed and the knowledge of gene sequencing becomes more widespread, it is likely that patients will seek knowledge about genetic contributions to their musculoskeletal ailments. This, in turn, will require healthcare providers to become knowledgeable about the potential interaction and effects of genetic predispositions on musculoskeletal disorders and to assist patients in understanding their genetic and environmental contributors to disease. In the future, it is envisaged that a combination of family history and genetic tests may be used to classify specific foot and ankle conditions, which have a strong genetic predisposition, into respective risk categories. This may then lead to primary and secondary prevention strategies aimed at reducing environmental risk factors for the condition and minimizing the impact of the condition on the patient’s quality of life.
Lifestyle modifications to alleviate pain symptoms
Lifestyle modifications have been suggested to alleviate pain symptoms in various forms of musculoskeletal conditions. These include efforts to lose weight, occupational changes, and orthotic modifications. Lifestyle changes are generally more suitable for genetic conditions where the problem has developed over time, instead of traumatic injuries. Weight loss has been widely suggested for conditions of the foot and ankle, as lower limb joint pain is exacerbated with increased loads. A suggested method to lose weight is by adopting a low-fat plant-based diet, whereas the Dietary Approaches to Stop Hypertension (DASH) diet has been shown to prevent the development of gout. Both diets prevent the development of arthritic conditions, which can be advantageous to an individual with genetic predispositions to foot and ankle pain. The Mediterranean diet, on the other hand, has been recommended for rheumatoid arthritis sufferers due to its anti-inflammatory nature on the body. However, a review has shown that there is only weak to moderate evidence to suggest weight loss can alleviate symptoms of pes planus and its associated conditions. Occupational changes to avoid hard, concrete floors have been suggested for individuals with pes planus who experience significant pain due to its aggravating nature on the condition. This can be a difficult change to make and will impact some individuals financially. In cases where individuals are not able to reduce or modify the stresses to their lower limb, it may be difficult to relieve pain symptoms with these methods.
Treatment options tailored to genetic predispositions
O’Reilly et al have recommended a framework for ideal CMT clinical trials, which involves a stepwise process of improving understanding of pathophysiology, validating clinical outcome measures, and then testing different drugs in randomized controlled trials. This is no simple task given the genetic heterogeneity and slowly progressive nature of CMT, but a successful trial of tailored medications would be a huge step forward in the management of this inherited neuropathy.
In the field of Charcot-Marie-Tooth disease, there are various drug treatments to alleviate symptoms, which have been suggested based on our understanding of the specific pathophysiology in each type of CMT. It is well recognized that CMT Type 1A is characterized by abnormally high myelin protein production due to a PMP22 gene duplication, and that this disease process may be correctable. Various studies on animal models have shown that ascorbic acid may improve nerve conduction velocity by reducing myelin abnormalities, and that controlled trials on human patients are warranted. Other drug treatments for CMT1A have included a trial of progesterone to regulate PMP22 gene expression, and a study on the tyrosine kinase inhibitor imatinib mesylate to reduce Schwann cell proliferation. These are encouraging early studies which may, in time, yield treatments to halt CMT1A disease progression. The ascorbic acid trial is especially promising as it is a widely available supplement with minimal side effects. This is similar to progesterone use in HNPP. Sixteen patients have been recruited, and HNPP mouse models have provided evidence that progesterone may normalize myelin formation by inhibiting the overactive kinase cdk2. However, it is best to not try to change too much at once. The case of carbamazepine in CMT Type 1B has shown the potential for symptom exacerbation with incorrect medication. This seems more likely in the frequently mistaken diagnosis of HSP or CMT2, as symptoms are compared and drug trials for neurodegenerative diseases have already been attempted. An example is the PRISEM HSP study, which unintentionally recruited CMT patients for a trial of neurotrophic factors. Thus, it’s evident that careful consideration is needed in choosing treatments relevant to the specific disease.
Lefeber et al compared the efficacy of three different classes of analgesic drugs on neuropathic pain in HSN Type 1 with cerebral atrophy. They demonstrated that the opioid tramadol, the antiepileptic pregabalin, and the tricyclic antidepressant amitriptyline were all effective in reducing pain intensity, but that amitriptyline was also associated with more severe side effects. These findings are generalizable to other forms of peripheral neuropathy, and thus it is likely that pain in HSN could be addressed by similar pharmacological means. However, it is important to take into consideration the findings of a study on cost-effectiveness and quality of life in diabetic neuropathy, which demonstrated that tricyclic drugs gave the best quality of life years at the lowest cost, suggesting that it is the best treatment option in many cases. This is significant to HSN; while an expensive medication such as pregabalin may be effective in reducing pain, it could exacerbate the problem of postural dizziness by further lowering blood pressure. High-quality research like this must be replicated in HSN to ensure that the most appropriate medications are used to treat specific symptoms. This could involve further studies on the effects of different drugs on pain and autonomic function.
A treatment approach that has been suggested for those with hereditary sensory neuropathy is the use of pharmacological agents to either alleviate specific symptoms, such as neuropathic pain or postural dizziness, or to rectify the underlying pathophysiology. It is hoped that in the future it may be possible to use gene therapy or other techniques to correct the specific genetic abnormality, thus curing the disease. However, it will be a number of years before this becomes a reality. In the meantime, some of the drug treatments that are being investigated in clinical trials may be of benefit to those with hereditary sensory neuropathy.
