Overview

Fragile X-associated disorders are caused by mutations in the FMR1 gene, located on the X chromosome. The most notable of these conditions is Fragile X Syndrome (FXS), which occurs in individuals carrying the full mutation of FMR1. But, did you know that individuals carrying the premutation of the FMR1 gene can also develop these disorders? That’s the case for fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). 

Disorders associated with FMR1 premutation

It is estimated that approximately 1 in every 130 to 250 people assigned female at birth (AFAB) and 1 in 500 to 800 people assigned male at birth (AMAB) carry the premutation version of FMR1, and are thus at risk of developing fragile-X associated disorders, such as FXTAS and FXPOI.¹

For this reason, genetic testing of the FMR1 gene is recommended for individuals being considered for these diagnoses, or with a family history of FXS. Genetic testing is also important to identify the number of CGG repeats present in FMR1 premutation carriers because the severity of associated disorders increases with the number of repeats. 

FXTAS

FXTAS is a neurodegenerative condition that can affect individuals AFAB and those AMAB, who are carrying the premutation of FMR1, although it is much more common in the latter. It is estimated that FXTAS affects 16% of individuals AFAB carrying the premutation and 40% of individuals AMAB carrying the premutation.²

Signs and symptoms

FXTAS is an adult-onset disorder, more commonly diagnosed in premutation carriers over 50 years of age. It was first identified in 2001 after scientists noticed a pattern of grandfathers of children diagnosed with FXS that presented tremors, ataxia (balance issues), and slowly progressive neurodegenerative disorders.³ 

The main signs and symptoms of FXTAS include:

• Intention tremor, which is a shakiness of the hands that occurs during a purposeful action, such as reaching for something, buttoning a shirt, using utensils, etc
• Ataxia, which includes balance problems, falling over, needing the support of a cane or walker to walk, and a wide gait
• Magnetic Resonance Imaging (MRI) scans indicating white matter lesions in middle cerebellar peduncles

Minor symptoms of FXTAS, which are observed less frequently, include:

• Parkinsonism (tremors while resting)
• Association with the onset of other neurological diseases, such as Parkinson’s disease and Alzheimer’s disease
• MRI scans suggesting generalised brain atrophy
• Intranuclear inclusions (accumulation of protein aggregates) in brain and nerve cells 

A key feature of FXTAS in people AMAB is that the chance of exhibiting the key symptoms of the condition increases with age. It is estimated that this risk can increase from 17 % at ages 50 to 59 to 75 % at age 80 or more.⁴

The symptoms described above are more frequent and severe in people AMAB. They may also experience symptoms, such as: 

• Fibromyalgia
• Hypothyroidism
• Seizures
• A higher risk of developing anxiety and depression 

Management and treatment

Medications

Unfortunately, there’s no known cure for FXTAS, and treatment is largely aimed at reducing symptoms and improving life quality. These include:^1,5

• Treatment for tremors, such as beta-blockers, primidone, and topiramate
• Treatment for Parkinsonism, such as carbidopa/levodopa
• Treatment for ataxia, such as riluzole and amantadine (although the effect of these has not been specifically studied in FXTAS)
• Treatment for psychiatric symptoms (i.e., anxiety and depression), such as sertraline or escitalopram

Other interventions

Besides medication, other interventions aimed at improving life quality for individuals with FXTAS may include:⁵

• Genetic counselling 
• Psychological counselling 
• Physical therapy for ataxia, muscle strengthening, and gait training
• Speech and occupational therapy

Other lifestyle changes can have a positive impact both emotionally and physically. Examples of this are avoiding smoking, drinking, and consuming illicit substances, and exercising daily. The latter can also help with weight loss, which can benefit patients experiencing chronic pain, especially in the back or following back surgery.⁵ It is also important to consider the effect of an FXTAS diagnosis on the patient’s family and carers, thus family support services and counselling are encouraged. 

FXPOI

FXPOI is a fragile X-associated condition observed in individuals with ovaries carrying the FMR1 premutation. It is important to note that, although people AFAB can develop primary ovarian insufficiency (POI) for other reasons, this condition is observed more frequently in people AFAB who are premutation carriers.

It is estimated that 1 to 1.9 % of people AFAB under the age of 40 in the general population will experience POI, while 10 to 20 % of people AFAB with the FMR1 premutation will develop FXPOI. The premutation in FMR1 is the main single-gene cause of POI.⁶

Signs and symptoms

As the name suggests, the main symptom associated with FXPOI is ovarian insufficiency. The ovaries are reproductive organs, usually present in people AFAB, which contain egg cells. During the menstrual cycle, one of the ovaries releases an egg to be fertilised, which can lead to pregnancy if fertilisation is successful.

The ovaries are responsible for producing hormones that affect a person’s fertility. As menopause approaches in people AFAB, around age 45, the ovaries naturally reduce their function. In FXPOI, this decrease in the ovaries’ function is observed before menopause and can affect the patient’s capacity to get pregnant. 

Therefore, the main signs and symptoms of FXPOI are:

• Irregular or absent periods for more than 4 months, under the age of 40
• Infertility or reduced fertility
• Symptoms also observed during menopause, like vaginal dryness and hot flushes
• Levels of follicle-stimulating hormone (FSH) similar to those observed in menopause
• Primary ovarian insufficiency, which is when the ovaries stop working before age 40

These symptoms are shared by other conditions that cause POI. Even if a patient is a known FMR1 premutation carrier, other possibilities should be explored besides FXPOI, such as:

• Pregnancy
• Polycystic ovarian syndrome (PCOS)
• Thyroid disorders

In addition, patients with FXPOI are at increased risk of developing other conditions, such as:^6,7

• Anxiety
• Depression
• Osteoporosis and cardiovascular diseases, associated with the early onset of menopause 

Management and treatment

Unfortunately, there is no dedicated treatment to restore the normal ovarian function of patients with FXPOI. However, some measures can be taken to improve the emotional and physical well-being of individuals with FXPOI. These include: 

• Psychological counselling, as well as medication for anxiety and depression
• Hormone replacement therapy, to decrease bone mass reduction due to early menopause
• Ingestion of calcium and vitamin D supplements to assist in maintaining healthy bone density
• If total infertility is confirmed, exploring other possibilities for parenthood, including in vitro fertilisation (IVF) 

Importantly, individuals with FXPOI may still be able to conceive naturally, and thus appropriate contraceptive strategies should be implemented to avoid an unwanted pregnancy. Specifically, barrier methods and other non-hormonal methods should be preferred over hormonal methods, such as the contraceptive oral pill, since the latter might not be as effective due to the hormonal changes typical of FXPOI.⁸

Summary

Fragile X-associated disorders, such as FXTAS and FXPOI, are conditions caused by the premutation of the FMR1 gene, located on the X chromosome.

The key facts about FXTAS are:

• It is more common in people AMAB over 50 years of age
• Main symptoms include tremors, balance issues (ataxia), and specific alterations in MRI scans
• Medication is available to treat symptoms, although no specific therapy for FXTAS is available yet
• FXTAS patients may benefit from psychological counselling and physical and speech therapy

The key facts about FXPOI are:

• It affects approximately 10 to 20 % of people AFAB carrying the FMR1 premutation
• Major symptoms include irregular or absent periods, infertility or reduced fertility, and early onset of menopause
• FXPOI patients are also at increased risk of osteoporosis and cardiovascular diseases
• There’s no specific treatment available for FXPOI, but patients may benefit from hormonal replacement therapy and calcium and vitamin D supplementation
• Individuals diagnosed with FXPOI should not assume complete infertility and should implement family planning measures appropriately
• If complete infertility is experienced, there are other options for individuals seeking to conceive, such as IVF

FAQs

What is the life expectancy of someone with FXTAS?

Based on preliminary studies, the life expectancy of someone with FXTAS ranges from 5 to 25 years after diagnosis.⁹

What is the difference between Parkinson's and FXTAS?

Both conditions share tremors as main symptoms - however, FXTAS presents mostly as intentional tremors, while Parkinson’s presents mainly as resting tremors. Patients with FXTAS may also present Parkinsonism, which is a generic term used to describe a group of symptoms including tremors, slowness of movement, and muscle stiffness. Furthermore, it is known that the cause of FXTAS is the premutation in the FMR1 gene, while the exact cause of Parkinson’s disease has yet to be determined.

How do you treat FXPOI?

Many of the symptoms of FXPOI are related to the early onset of menopause. There are many effective treatments available for menopause symptoms, including hormonal replacement therapy. It is also beneficial to include supplements targeting bone density, such as vitamin D and calcium, since the early onset of menopause could lead to decreased maximum bone mass and thus, increased risk of osteoporosis if untreated.

How is FXPOI diagnosed?

Three main signs need to be observed:

• The patient is a Fragile-X premutation carrier (determined by genetic testing)
• Irregular or absent period for more than 4 months
• Serum FSH levels similar to those observed in menopause (determined by blood tests)