The diagnostic odyssey: The search for answers for rare diseases

Rare diseases affect between 300 and 400 million people worldwide – more than cancer and AIDS combined [1, 2], but despite this, many people face a diagnostic odyssey, with an average wait of 4 to 6 years for a diagnosis [1, 3]. In this article, we will look at how rare diseases are diagnosed and why it takes so long.

What is a rare disease?

The definition of a rare disease varies around the world, but in the EU, it is defined as a disease affecting no more than 1 in 2,000 people [4], while in the USA, a disease is called rare if fewer than 200,000 Americans are affected by it at any time [5].

Although each rare disease affects only a small number of people, it is estimated that there are between 6,000 and 7,000 rare diseases [4 ,5]. This means that regardless of the small number of people affected by each disease, the global impact of rare diseases is huge, with up to 5.9% of the global population affected [2], which is between 300 and 400 million people worldwide [1, 2].

Read more about rare diseases in our blog article Rare diseases revealed: explaining, understanding, and raising awareness on rare disease day.

Why diagnosing rare diseases is so difficult

The following factors complicate rare disease diagnosis [3, 6, 7, 8]:

• The number of rare diseases
• Diversity and variability of symptoms among patients with the same condition
• Syndromes/diseases with overlapping symptoms, and some symptoms that are relatively common
• Rare diseases often affect multiple organs and body systems
• Each organ or system is often looked at in isolation by a specialist on a particular body part
• Delays getting referrals to specialists and long waiting times for appointments
• Lack of communication between specialists
• Limited medical awareness and knowledge

The diagnostic odyssey: a long and frustrating journey

Diagnosis of rare diseases is challenging in part due to the diversity and variability of symptoms among diseases and patients as well as the overlap between diseases. An accurate diagnosis often takes between 4 and 6 years [1, 3] and the journey is referred to as a diagnostic odyssey [3].

Patients and their caregivers often find themselves caught in a cycle of referrals and visits to specialists, sometimes in various geographical locations, to have their symptoms considered in isolation rather than as part of a complete clinical picture. As a result, patients may receive several wrong diagnoses, and try numerous ineffective or inappropriate treatments, on their way to a final diagnosis [3].

This diagnostic odyssey is a stressful time for a patient and his or her family, as no diagnosis often means no treatment or support. Around 70% of rare diseases start in childhood [4], and one in two of those diagnosed with a rare disease is a child [1]; therefore, entire families bear the burden, and caregivers often struggle physically, emotionally, and financially while seeking answers. Patients, caregivers, and families may feel disappointed and let down by the medical system and that they are alone and isolated, adding to the stress and anxiety of the situation. Furthermore, without treatment, a disease may progress, and symptoms worsen. Parents may feel they are failing their child, particularly in education and social opportunities [3, 8].

The importance of diagnosis

Receiving a diagnosis can be a relief. A diagnosis can empower patients and their families, give access to support groups and specialists, and guide treatment plans and family planning decisions [3].

How are rare diseases diagnosed?

At some point in the diagnostic journey, a patient will usually be referred to a genetic specialist, and because up to 80% of rare diseases have a genetic cause [1], genetic testing can result in a diagnosis.

Genetic testing

A genetic test identifies the harmful or pathogenic variants (mutations) in genes or chromosomes that are known to be responsible for causing disease and can provide a diagnosis. They require a biological sample (blood, saliva or cheek swab) that is sent to a laboratory where the DNA is extracted for analysis. The method used to analyze the DNA depends on whether there is a suspected diagnosis, a clear pattern of symptoms, a known or unknown genetic cause, and whether chromosomal changes or gene variants should be detected.

Molecular testing methods detect changes to the DNA and can identify single nucleotide changes, variants in single genes, multiple genes, or throughout the entire DNA. Sanger sequencing is used to analyze variants in single genes while next generation sequencing (NGS) can analyze variants in multiple genes. Whole exome sequencing (WES) is an NGS approach used to analyze the protein-coding regions (exons) of all human genes, while whole genome sequencing analyzes the entire genome including exons and non-coding regions. Trio WES (child plus both biological parents) increases the likelihood of finding the genetic cause of diseases with complex and non-specific symptoms and can reduce the time to diagnosis.

Cytogenetic testing methods (karyotyping, fluorescence in situ hybridization) are used to analyze changes in chromosome number or structure.

Biomarker testing

This identifies and measures unique biological markers (biomarkers) in tissue, blood or body fluid samples to detect a disease, confirm a diagnosis, identify a disease subtype, assess treatment success, or make a prognosis [9, 10]. Often used to plan cancer treatment [10], liquid biopsy offers a deep investigation of a tumor’s genetic alterations and immunotherapy biomarkers.

Biomarker testing also has a role in the diagnosis of rare diseases, e.g., lysosomal storage disorders, such as Gaucher and Fabry disease [11], and there is much ongoing research into the use of biomarkers including gene expression, metabolites, inflammatory markers, and proteins, to measure endpoints in drug development trials for rare diseases [12].

The role of technology in rare disease diagnosis

AI-Powered Diagnostics and Machine Learning

Innovative technology has the potential to revolutionize diagnosis, including that of rare diseases. AI and machine learning can analyze medical images, detect subtle abnormalities, and differentiate between positive and negative results—sometimes beyond human capability. It can process a large amount of data very quickly, and detect patterns or trends, leading to more accurate and faster diagnoses [13]. Read more about the role of AI in healthcare.

Telehealth

Telehealth is the use of technologies such as computers and mobile phones to access health care services remotely. One application of this is the use of virtual consultations enabling patients to access medical specialists at other locations, thus bypassing geographical limitations and reducing travel and referral times [14].

Local and global expert networks

Health care providers can also make use of technology to consult with each other virtually and share knowledge, thus improving all round patient care [14]. This idea is further expanded by the RARE-X research program, which provides a collaborative platform for collecting, sharing and analyzing, data among researchers and drug developers, doctors, and patients with the aim of progressing rare disease knowledge and treatments [15]. Other research programs such as Undiagnosed Diseases Network [16] and Care4Rare [17] bring together researchers, healthcare providers, and patients in the search for diagnostic answers.

Online patient support communities

Patients can use platforms like PatientsLikeMe to record data on their health conditions and connect with other patients to empower them on their journey to better treatment and support. The platform was originally launched for patients with amyotrophic lateral sclerosis (ALS) and although not limited to rare diseases (currently over 2,800 conditions are covered by the community), it is a good example of how technology can bring people in the same position together [18]. Online communities have a global reach that can benefit and maximize support for patients and their caregivers [19].

Patient advocates can form their own disease-specific advocacy or support group. These can be extremely powerful and can contribute in many ways, including providing research funding or input for clinical trials, connecting people with healthcare providers or other patients, as well as educating and motivating the medical and scientific community, and raising awareness [19].

How patients, families and caregivers can advocate for a diagnosis

Throughout the long journey towards a diagnosis, patients and their families and caregivers can practice advocacy and make a significant difference [19]. Key strategies that patients and families can use to push for answers include

• Keeping detailed records to provide healthcare providers with a comprehensive picture.
• Asking questions and continue asking or searching until the questions are answered.
• Joining patient advocacy groups and online communities for emotional support and access to valuable resources.

Why might there be no diagnosis?

Sometimes, despite years of tests and referrals, a diagnosis remains elusive, and up to 50% of patients with a rare disease in Europe remain undiagnosed, adding to the emotional burden faced by patients and their families [20]. Reasons for a lack of diagnosis can include [3]:

• A genetic variant is detected for the first time in combination with the symptoms.
• A variant of unknown clinical significance is detected.
• Genetic testing has targeted the wrong genes.

How are rare diseases treated?

Medications used for the treatment of rare diseases are called orphan drugs, and although legislation is in place in many countries to support their development, only around 5% of rare diseases currently have an approved treatment [21, 22]. Unfortunately, due to the cost and length of time involved in developing drugs and the limited market for a rare disease treatment, these drugs are unlikely to offer significant financial rewards. This means that in many cases, a diagnosis does not lead to effective treatment.

Read more in Understanding orphan drugs: Definitions, examples, and legislative support for the treatment of rare diseases.

Conclusion

Receiving a rare disease diagnosis provides both patients and their families information about the disease and its prognosis and treatment, as well as guiding future family planning decisions and providing access to support groups. However, despite technological advances and an expanding knowledge and understanding of rare diseases, as many as 50% of rare disease patients do not have a diagnosis. Key factors in a diagnosis delay include appointment waiting time and geographical location or access to specialists. With this in mind, the increasing use of technology and online communities to make specialists and information more accessible, offers hope to rare disease patients that as advancements continue, answers may become more accessible, accurate and faster.

Rare Disease Day is a global awareness day held annually on the last day of February to raise awareness of all rare diseases. Raising awareness and education, together with patient advocacy and support for rare disease research are all important to help drive progress forward and improve outcomes for those living with rare conditions.

AI Disclaimer: This outline for this article was written with the help of AI.

References

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