Newswise — Rare Disease Day is observed on February 28 each year, or February 29th on leap years — the rarest day on the calendar. It is a day dedicated to raising awareness about rare diseases and advocating for health equity to ensure all people living with rare diseases have access to diagnosis and therapies.
According to a 2021 study published by the U.S. Government Accountability Office, there are approximately 7,000-8,000 recognized rare diseases that affect around 30 million people in the United States. Thousands more are yet unnamed. Erin Conboy, MD, associate professor and Francesco Vetrini, PhD, assistant professor in the Department of Medical and Molecular Genetics, serve as co-directors of the Undiagnosed Rare Disease Clinic at the Indiana University School of Medicine. Launched in 2020, the clinic aims to diagnose ultra rare genetic disorders and help families living with unknown diseases.
Question: What is the purpose of the rare disease clinic and why is it such an important resource?
Conboy: We provide answers in the form of a genetic diagnosis to patients and their families who are struggling with the uncertainty of an undiagnosed rare disease. Our patients have often gone through a long diagnostic odyssey: multiple evaluations, no underlying disorder identified, high index of suspicion for an underlying genetic disorder, and genetic testing has been unrevealing.
Q: How does the clinic stay up to date with the latest research and advancements in the treatment of rare disease?
Vetrini: We use a multidisciplinary approach that integrates clinical genetics, molecular diagnostics and cutting-edge research. URDC collaborates with national and international groups, including the Undiagnosed Diseases Network and other rare disease initiatives. Our major strength lies in the fact that every case is unique, and we employ a patient-centered approach. Another key strength is the commitment to follow the patient over the years and periodically reevaluate clinical and genomic data, looking for new insights that could lead to a definitive diagnosis.
Q: What are some of the biggest challenges faced to diagnosing, discovering and treating novel rare diseases in patients?
Conboy: The challenge is deciding if we have enough evidence to establish the gene-disease relationship and then diagnose the patient. Sometimes evidence is too preliminary, and then we struggle to find more evidence and additional affected patients. We cannot make a diagnosis because our gut says so, but we need to support these educated hunches with data.
Q: What aspects of the clinic’s approach or environment do you believe make the biggest difference for families facing the challenges of rare disease diagnoses?
Vetrini: As the knowledge about variants and genes evolves and improves overtime, we keep reanalyzing periodically the data of the patients looking for new clues leading, eventually, to definitive answers. This continuous approach ensures that families benefit from the latest advancements in genetics, increasing the likelihood of identifying the underlying cause of their condition over time.
Conboy: We express to the patients that we care about them, want to do everything we can to help them and provide them with a diagnosis that will hopefully improve their life, their medical care and health.
Q: Can you share some cases you’ve solved and how the clinic supported these patients and families through the diagnosis and treatment process?
Case 1: A 14-year-old female with a complex medical history including cataracts, poor feeding as an infant, low muscle tone, delayed developmental milestones, painful skin and mouth lesions, a hernia that required surgery and hair loss was enrolled in URDC in 2021. The patient’s family enrolled her in the URDC at IU School of Medicine because a prior molecular diagnosis had not been reached. Following advanced genetic analysis, URDC diagnosed this patient with a disorder linked to the MBTPS1 gene, ending the diagnostic odyssey in this family. Of note, we have begun high-dose vitamin B2 treatment, and her hair has begun to grow back, and her skin inflammation and hyperkeratosis is starting to improve. Read about Aly Edmonson’s journey to diagnosis.
Case 2: A 15-year-old male presented with a history of retinal dystrophy, cone dysfunction with normal dark-adapted response on electroretinogram, congenital nystagmus (involuntary eye movements), farsightedness and astigmatism diagnosed at 3 months of age. We enrolled the patient in URDC in November 2021 and identified a single pathogenic variant in the CNGB3 gene. Subsequently, research-based genomic selection analysis by the URDC team identified a second disease-causing variant in the CNGB3 gene causing achromatopsia in this patient. Hence, due to definitive clinical diagnosis, the patient has been eligible for enrollment in clinical trials for gene therapy of CNGB3 achromatopsia. Read about Evan Mowery’s journey to diagnosis.
