BACKGROUND AND PURPOSE:

• Women who carry a permutation in the Fragile-X gene (FMR1) are at risk for
  • Fragile X–associated primary ovarian insufficiency (FXPOI) | Affects approximately 20 to 30% carriers
  • Fragile X–associated tremor–ataxia syndrome (FXTAS): Affects approximately 6 to 15% carriers
  • More information on Fragile X premutation available in ‘Related ObG Topics’ below
• Recent evidence suggests other health-related risks beyond these two disorders
• Allen et al. (Genetics in Medicine, 2020) examined whether there are other medical issues among women with an FMR1 permutation

METHODS:

• Participants identified from
  • Previous study on Fragile X | Scientific conferences | Collaborations with other research groups | Additional affected family members
  • Eligibility was based on FMR1 permutation carrier status, age, and sex
  • FXPOI diagnosis: Menopause <40 years (excluding iatrogenic causes such as oophorectomy)
  • A blood or saliva sample was collected from each participant
  • Each participant also completed a reproductive and health history questionnaire, which included
    • General demographics (e.g., age at interview, date of birth, race/ethnicity)
    • Lifestyle factors that might affect overall health (e.g., smoking, body mass index [BMI])
    • Reproductive history (e.g., menstrual history, reason for cessation of menses, pregnancy history)
    • General medical history

RESULTS:

• 355 carrier women
• 22 health conditions were reported by ≥10% of participants
• The following were reported >30% of participants
  • Anxiety
  • Depression
  • Migraine and tension headaches
• Only peripheral neuropathy was associated with repeat size
• The number of comorbid conditions was significantly associated with body mass index (BMI) and history of smoking, but not age
• Women with FXPOI had earlier age at onset for anxiety and osteoporosis vs those without FXPOI (p = 0.001)
• The authors identified eight clusters of women who reported similar patterns of comorbid conditions
  • Clusters: (1) minimal health problems (2) headaches (3) sleep problems (4) mental health problems, (5) FXPOI with minimal health problems (6) FXPOI with mental health problems (7) FXPOI with complex profiles (8) FXTAS
  • Largest cluster: Minimal health problems
  • 63% fell into three categories primarily defined by the presence of only a few conditions
    • Minimal health problems | Headaches | FXPOI with minimal health problems clusters
  • A single cluster defined women with symptoms of FXTAS and no FXPOI

CONCLUSION:

• Most women who are FMR1 permutation carriers appear to have minimal comorbid conditions
• Authors expected other comorbid conditions to be associated with FXPOI but the converse was true
• Women with symptoms of FXTAS appear not to overlap with women who have FXPOI symptoms

Learn More – Primary Sources:

Clustering of comorbid conditions among women who carry an FMR1 premutation

Related ObG Topics:

Prenatal & Preconception Carrier Screening for Fragile X: Clinical and Genetic Essentials

Intellectual Disability Defined

Infertility Evaluation: Who, When and How