The Importance of Rare Disease Research Through a Bain Syndrome Case Study

Written by: Anna Jonczyk

Edited by: Kate Falla, Rachel Smith, Lauren Chiriboga

Illustrated by: Gabe de la Cruz

Physicians have been captivated by the characteristics, progression, underlying mechanisms, and puzzling aspects of rare disorders for centuries [1]. Rare disorders often provide unique perspectives on human physiology and biomedical sciences, and major scientific advancements from investigations on rare disorders often grant scientists a greater understanding of common diseases. However, the satisfaction of successfully diagnosing a patient with a rare disorder is swiftly diminished with the realization that comprehending and addressing the patient’s condition is limited by the difficulties of researching the disease [1]. 

Depending on the location and organization, the definition of a rare disorder varies. In the United States, a “rare” disease is one with fewer than 60 affected people per 100,000 individuals, or a 0.06% prevalence [2, 3]. For the European Union, the cutoff for “rarity” is 50 affected people per 100,000 individuals, a 0.05% prevalence. Yet, the World Health Organization states that a rare disorder has less than 65 per 100,000 people, a 0.065% prevalence [2, 3]. Regardless of location, rare disorders, also known as “orphan” diseases, are classified by their low incidence rates.

One such classified rare disorder is Bain Syndrome, which only affects approximately 100 individuals globally to date [4]. The syndrome was discovered by Dr. Jennifer Bain and colleagues at New York-Presbyterian/Columbia University Irving Medical Center when 6 unrelated females presented with developmental delay (DD), seizures, autism, and intellectual disability (ID) [5]. The syndrome is due to a de novo missense mutation, which is a spontaneous non-inherited alteration in the DNA sequence, causing a change from one amino acid to another, resulting in a toxic function to the subsequent protein [4, 6]. The mutation occurs in the HNRNPH2 gene on the X-chromosome, most commonly at the R206W location: the 206th amino acid position is changed from an arginine to a tryptophan [7]. It is hypothesized that the most severe case of the syndrome occurs when the mutation happens in the nuclear localization signal, the sequence responsible for shuttling the protein from the cytoplasm into the nucleus [7, 8]. With as little as one change in the amino acid sequence, the syndrome has serious side effects, including muscular dystrophy, which is the weakness and loss of muscle mass, intellectual disabilities, craniofacial abnormalities, which are deformities in the head and facial bones, as well as clubfoot, which is a deformity that causes the feet to be twisted out of shape [7, 9, 10]. Without enough cases and varying levels of severity amongst people diagnosed with Bain Syndrome, there are no formal clinical diagnostic criteria for the disorder [4].  

Bain Syndrome is an exemplary rare disease for which there is no cure, resulting in people diagnosed with the syndrome having a reduced quality of life even upon detection [4]. They must rely on life-long physical and mental palliative care, treating each symptom separately [4]. An interview with the mother of Cady, a ten-year-old girl with Bain Syndrome, reveals her daughter has grown up without saying a word [11]. Bain Syndrome is a debilitating and chronic rare disease and based on the story of Cady’s family and the stories of other patients with rare diseases, most families of people with rare diseases likely dedicate significant portions of their time, money, and resources to provide twenty-four-hour care to their loved one [12]. Unfortunately, the lack of prevalence is a hindering factor for access to research into improving treatments and quality of care for patients diagnosed with rare diseases, including Bain Syndrome. 

Most pharmaceutical companies use the number of patients — the “rarity” of the disease — as the primary reason to acquire funding for research related to the disease [13]. This approach to funding disease research is based on a utilitarian ethical view, which supports cost-effectiveness. From this point of view, pharmaceutical companies direct their funding to more common diseases to bring as many health benefits as possible for the entire population, essentially with the perspective of funders maximizing the number of patients treated per dollar. The drugs for rare diseases — called orphan drugs — have small potential markets due to the miniscule number of target patients. As such, large pharmaceutical companies have poor incentives to invest in such drugs [13]. But even with prevalence as the motivating factor, is it ethical to leave people with rare diseases untreated? 

Even more so, in the way that prevalence restricts funding for rare disease research, looking at numbers may also illuminate why “rarity” can’t be the reason for the neglect of these diseases. Leaving rare diseases untreated means we would leave 300 million people worldwide without treatment, with 25-30 million people in America alone being left without a remedy [14]. The lack of economic incentive to invest in these orphan drugs ultimately leads to the neglect of millions of people diagnosed with life-threatening rare diseases, who collectively create a large portion of the population [13]. 

In order to account for the millions of people with rare diseases currently without treatment, the way in which funding is distributed must change. The equal claims view, in opposition to the utilitarian view, argues that all patients have the same right to gain societal assistance, and this right cannot be ignored due to cost [13]. Instead of prevalence, severity must be the priority for funding allocation, to provide effective means to treat those who need it most [13]. Organizations, such as the International Rare Diseases Research Consortium Funders Constituent Committee and the Undiagnosed Disease Network (UDN), have adopted this view and believe that severity of the disease should be enough incentive for researchers to receive funding [15-17]. 

Policy on orphan drugs also aims to change how funding is distributed by changing the metric that determines allocation of funds from prevalence of a condition to its severity. The United States passed the Orphan Drug Act in 1983 to encourage sponsors to develop drugs that can treat, prevent, or aid in the diagnosis of rare diseases [1, 18]. The incentives include orphan product development grants, seven-year marketing exclusivity once approved by the Food and Drug Administration (FDA), and tax credits equal to 50% of qualified clinical testing expenses [1]. This measure has served crucial to increasing funding for rare diseases, creating over 300 orphan products over the span of three decades compared to 10 drugs in the decade prior to the policy change [1]. 

As gratifying as these changes are, 94% of rare diseases still lack an approved treatment [16].  Treatments for Bain Syndrome are slowly developing as patient numbers increase. As of July 2023, mice models that downregulate, or decrease expression of, the mutated HNRNPH2 gene, while upregulating, or increasing the expression of, the HNRPH1 gene, which is an analog that genetically compensates for the loss of the HNRNPH2 gene, may serve as preclinical models for drug testing [19].

The work to provide people with rare disease treatment cannot stop. Even with the adoption of the Orphan Drug Act, subsequent problems arise from making the drugs affordable to the patient. With manufacturing costs and a small patient pool, the orphan drugs have an extremely high cost per patient, and insurance does not cover many of these costs [20]. For people diagnosed with chronic rare diseases who may be unable to make the decision to take the drug, how can others make such a life-altering decision for them [11]? Cady’s mother shares the view that the possibility of a drug for Bain Syndrome is both relieving and frightening, as these powerful drugs may have the unbelievable ability to cure aspects of her condition but may also introduce other risky side effects that exacerbate the problem. Regardless, she finds the very possibility of a drug that treats Bain Syndrome for Cady motivating [11]. 

In large part, activism has been a contributor to bringing attention to the situation of people with rare diseases, resulting in policy changes like the Orphan Drug Act [21]. Activist organizations continue to fundraise for rare diseases without treatment or for the patients who can’t afford the approved cures. For example, the French Foundation for Rare Diseases deliberately expanded its patient pool to research both the patient and the caregivers, allowing researchers in social and human sciences to work together to better understand the social, familial, and individual consequences of rare diseases [22].

Similarly, the HNRNP Family foundation works with people who contain mutations in all genes within the same family as the gene affected by Bain Syndrome, notably HNRPU, HNRNPH2, HNRNPH1, SYNCRIP/HNRNPQ, HNRPC, and HNRNPR genes [23]. This foundation serves to create a community of those affected by rare HNRNP diseases, providing them with a larger supportive group. It also schedules symposiums and events that raise awareness for the public and provides a location where people with HNRNP-related disorders may come for clinical assessment including blood and skin biopsies. Collecting physical samples and assessing their development through clinical and behavioral studies provides information about these patients over a long period of time, which is crucial for disease characterization and drug development [23]. 

The awareness required for rare diseases is far from realized. Though implemented policy changes have served integral to developments in treatments, there are still several hurdles that patients with rare diseases and their families must overcome. While activism is important for raising funds and awareness, the necessity for families to dedicate resources and time to gaining money for their loved ones’ treatments and research fundamentally demonstrates how much improvement is needed. Someone diagnosed with a rare disorder no longer perceives the rarity of their condition that they and their loved ones live with daily. Though society may still classify diseases through the lens of prevalence, there is much more to the disease that must be taken into consideration for research funding, therapeutic development, and drug distribution. 

References

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[2] Crain, E. (2023, February 28). What is a rare disease? Johnson and Johnson. https://www.jnj.com/health-and-wellness/what-is-a-rare-disease

[3] Abozaid, G. M., Kerr, K., McKnight, A., & Al-Omar, H. A. (2022). Criteria to define rare diseases and orphan drugs: a systematic review protocol. BMJ open, 12(7), e062126. https://doi.org/10.1136/bmjopen-2022-062126

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[9] Boston Children’s Hospital. (n.d.) What is a craniofacial anomaly? https://www.childrenshospital.org/conditions/craniofacial-anomalies

[10] Boston Children’s Hospital. (n.d.). What is clubfoot? https://www.childrenshospital.org/conditions/clubfoot

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