As a psychiatrist studying fragile X syndrome -- an inherited form of intellectual disability, autism, and behavioral disturbance -- I've spoken with patients and parents from California to Calcutta, and one theme always repeats itself: the path to diagnosis of a rare disease is never easy.
Despite their designation as "rare," rare diseases are not a rare problem. While families contending with rare diseases (defined in the U.S. as conditions affecting fewer than 200,000 people) may feel isolated, in total there are about living with rare diseases globally; there's even a designated World Rare Disease Day (February 28 this year). As of rare diseases are genetic, they tend to be diagnosed in young children. Accordingly, parents often spend years trying to get a proper diagnosis for their children. "Big data" -- vast quantities of health information, collected anonymously from electronic medical records and crunched by sophisticated statistical software -- may help speed the process.
But what about other types of information? Fragile X disorders provide physicians and researchers a primer for recognition of rare diseases using only an open mind, compassion, and a willingness to learn from families. The "small data" that emerges when doctors listen to patients and parents is critical for research.
Fragile X syndrome was first described in 1943 by doctors who visited and photographed affected children and spent time with their mothers. Without access to DNA technology or large databases, they depended on their observations to figure out how the condition could be passed from mothers to children: on the X chromosome. As in other X-linked diseases, like hemophilia, parents of fragile X kids were believed to be unaffected carriers.
That began to change in 1987, when fragile X researchers held a conference that was among the first of its kind in the rare disease community. Researchers and families came together. Scientists lectured, and families attended workshops. One workshop was on family planning for women who already had a child with fragile X syndrome. The researchers presumed that many women would wish to avoid having another affected child.
To their surprise, one mother after another spoke up and announced that she could no longer have children, having gone through early menopause. Genetic counselor Amy Cronister, MS, was at the workshop. Cronister told me, "You have to remember, back in the '80s, before we were so overwhelmed with genetic information, what we really had to offer was important psychological support for fragile X families...it was intimate and exhausting. We'd sit in the hallways, the families would absorb, and the clinicians would listen." Scientists at the conference recognized the importance of this unexpected cohort of women with early menopause; it was a previously unrecognized consequence of being an "unaffected" carrier of fragile X syndrome. Thus FXPOI -- fragile X-associated primary ovarian insufficiency -- came to for the first time.
A similar story surrounds the discovery of FXTAS, or fragile X-associated tremor/ataxia syndrome, a movement and cognitive disorder that affects aging carriers of the gene for fragile X syndrome. Behavioral pediatrician Randi Hagerman, MD, and genetic counselor Louise Gane, MS, were unusually devoted to their patients and their patients' families. As a result of this empathy, the moms of children with fragile X syndrome confided they were also worried about their own fathers. Their fathers, once competent family men, were increasingly impulsive, showed poor judgment, and fell frequently. In fact, this scenario recurred so often that when Hagerman finally proposed looking into it in the late 1990s, Gane snapped, "Duh!" FXTAS is likely to be the only late-onset neurodegenerative disease discovered by special-needs pediatric clinicians.
Of course, "big data" does have its uses, even in the fragile X world. For example, a recently published examined the de-identified medical records of 3.8 million patients in Wisconsin, and showed that fragile X syndrome is dramatically under-diagnosed. Mining electronic medical records can call attention to a problem nobody knew existed.
But for diagnosis and even discovery of rare genetic diseases, there is nothing like the "small data" one encounters when listening to mothers, and nothing like the kindness and empathy of seasoned clinicians to create the conditions in which mothers feel safe and heard.
Rare diseases are by definition uncommon, but a powerful connection between patient and doctor doesn't have to be. Doctors who wish to advance the cause of patients with rare diseases must remember that attentive care and compassion don't just help patients -- they serve science too.
is a clinical instructor in psychiatry at NYU Grossman School of Medicine and the author of the forthcoming book, , available in May 2022 from Columbia University Press.