5.22 High Frequency of Neuropsychiatric Disorders and a Need for Treatment in Patients with FXAND Linked to FMR1 Gene Premutation Carriers

Fragile X messenger ribonucleoprotein 1 (FMR1) gene premutation (PM, “carrier”) is linked to a higher frequency of anxiety, depression, ADHD, and other forms of fragile X–associated neuropsychiatric disorders (FXAND), and frequently requires both psychotropic drugs and nondrug therapies. We examined for frequencies of FXAND and types of the treatments in a clinically ascertained cohort of 17 patients with PM (55-199 CGGs) from the Fragile X Clinic at Kennedy Krieger Institute/Johns Hopkins medical institutions. The carrier status was determined by FMR1 DNA test. The vast majority of patients were from the pediatrics population (13/17, 76.5%; median age 12.0 years old; 8/13, 61.5% males). The study was approved by the Johns Hopkins Hospital’s IRB. All patients in the cohort had FXAND. Anxiety and ADHD diagnoses were equally the most common (12/17, 70.6%), followed by learning and reading disabilities (9, 52.9%) mostly in pediatrics, depression mostly in adults (5, 29.4%), ASD (3, 17.7%; all ≥ 100 CGGs), and language disorders (3, 17.6%), respectively. The study’s cohort mean number of CGG repeats was 82.50 ± 20.71 (range: 56-113). The FMR1 gene protein (FMRP) level was 15.54 ± 10.84 pg/ng (range: 6.05-32.02) in 5 (29.4%) of those patients. The vast majority (12, 70.6%) of patients were on at least 1 psychotropic drug, with SSRI being the most prescribed (8, 47.1%). Nondrug treatment was also common (7, 41.2%) driven by pediatric patients aged 3 to 15 years old (23.5% had both speech and language therapy and occupational therapy, respectively), behavioral therapy (17.6%), and applied behavior analysis (ABA; 5.9%, one boy aged 13 years with ASD). A clinical cohort of FMR1 gene carrier patients, both sexes, had an extremely high frequency of FXANDs: all had at least 1, 65% had 1 or 2, and 35% had 3 or 4 FXANDs driven by anxiety and ADHD in 70% of the pediatric cases; males were slightly more affected. Depression was found in the adults. The vast majority of them (71%) received psychotropic drug treatment driven by SSRIs, and 41% of them also had nondrug treatments driven by the pediatric population. The study contributes to the call for a screening, early diagnosis, and treatment of the FMR1 gene and PM-associated FXANDs and to educate multispecialty clinicians in that regard, which may also facilitate such a system-based interdisciplinary effort.