Cardiac to Dental Problems Can Be Early Signal of Fragile X

Physical health is also affected by fragile X syndrome, with problems evident in the heart, digestive system, respiratory tract and even the teeth years before the cause of patients’ intellectual difficulties might be pinpointed, scientists report.

Their study, “Artificial intelligence–assisted phenotype discovery of fragile X syndrome in a population-based sample,” was published in the journal Genetics in Medicine.

Fragile X syndrome is a leading cause of inherited intellectual disability, but presents no obvious signs at birth. One result is delays in diagnosis and gaps in medical services — a “diagnostic odyssey” for confirmatory genetic testing that often “takes 18 to 24 months after parents express concerns,” placing considerable stress on families.

While often considered a neurological disorder, several clinical studies have reported health issues affecting other systems in people with fragile X, although their frequently is not well documented.

Collecting patient data that could improve diagnosis and care is challenging in the case of rare disorders like fragile X. Rare disease registries such as the Fragile X Online Registry With Accessible Research Database (FORWARD registry) can be helpful, but the difficulties of traveling with more severe patients may limit to families with better resources those attending the specialty clinics in this registry, and its data lacks people without this disease to serve as a control group for comparison.

Researchers at the University of Wisconsin-Madison sought to fill in these gaps by using an artificial intelligence (AI) approach called machine learning to analyze the records of a large population — over 1 million people — that included several dozen individuals diagnosed with fragile X.

Machine learning refers to computer algorithms that can refine their own ability to recognize patterns based on large amounts of data and a set of analytical rules. Machine learning is often used to better understand how to predict likely outcomes from a given dataset.

Researchers identified 55 cases of fragile X (11 females and 44 males) and included 5,500 age- and sex-matched controls for comparison. Some in the control group (28 people) had conditions affecting their development, such as Down syndrome, Edwards syndrome, Marfan syndrome, Klinefelter syndrome, gonadal dysgenesis, and Prader–Willi syndrome.

Because they were interested in less-known conditions possibly linked to fragile X, the investigators excluded known co-occurring conditions (comorbidities), like those of mental health, neurology, or congenital anomalies, from their analysis.

Fragile X syndrome associated with a wide range of health conditions that tended to occur more frequently and earlier in patients than among the healthy controls. These included problems in the circulatory, endocrine, digestive, dental, and genitourinary [reproductive and urinary] systems, in addition to mental and neurological disorders marking the syndrome.

People with fragile X, for example, were on average more than twice as often to be treated for heart valve disorders (25.4 times vs 12.5) as were controls, and were generally diagnosed with these cardiac problems at much younger ages (median age of 26 vs. 52).

Digestive conditions more associated with fragile X included intestinal obstruction, indigestion, and irritable bowel syndrome, also diagnosed at younger ages than the general population. A variety of dental and gum issues were found in 43.64% of fragile X cases, compared with 11.93% of controls.

People with fragile X also experienced higher rates of mental and neurological disorders than did controls. These included autism, developmental delays, speech disturbances, seizures, and schizophrenia.

The algorithm successfully distinguished fragile X cases from controls — determined based on patients’ diagnostic codes (ICD codes used to signify a diagnosis) — over the five years prior to their disorder’s diagnosis and “without relying on any genetic or familial data,” the researchers wrote.

More specifically, individuals with fragile X were diagnosed with intellectual disability, anxiety disorder, ADHD, depression, acute upper respiratory infections, acute sore throats, unspecified disorders of the teeth and gums, abnormal development, and unspecified middle ear problems for at least five years before they were diagnosed with fragile X.

“Thus,” the researchers wrote, “our predictive model is able to accelerate identification of these underdiagnosed cases in the population.”

A study limitation was a lack of diversity: most people in this study identified as Caucasian, despite its large numbers of patient records.

Nonetheless, the researchers considered their approach to be a valid means of improving public health by speeding a fragile X diagnosis.

“Understanding the complicated health profile of [fragile X syndrome],” they concluded, “and its implications for the health and well-being of patients and their families will improve current clinical practice and the quality of life of these individuals.”