|
balance problems or ataxia are
more difficult to treat . 15
FRAGILE X- ASSOCIATED PRIMARY OVARIAN INSUFFICIENCY
FEMALES with an FXS premutation
can develop primary ovarian insufficiency in adulthood . This presents with menstrual irregularities , reduced fertility and premature menopause before the age of 40 . 16 Symptoms and signs associated with fragile X-associated primary ovarian insufficiency ( FXPOI ) appear in box 4 . 16
The condition occurs in 20 % of
|
B Welleschik / CC BY-SA 3.0 / bit . ly / 47lVYZN |
Box 5 . Barriers and facilitators impacting the long-term care of women with FXPOI
• Barriers : — Lack of point of care .* — Lack of provider familiarity with the condition .* — Strained family / partner relationship . — Focus on health of other family members . — Lack of diagnosis disclosure from family members .
• Facilitators : — Education on reproductive options .* — Research participation . — FXPOI-aware providers of care in reproductive endocrinology and infertility , obstetrics and gynaecology , and primary care .* — Hormone replacement therapy .* — Therapy or counselling .
|
||||||
women who carry a premutation allele compared with 1 % in the general population . Most women learn they are |
* Factors more commonly discussed by participants . Source : Poteet B et al 2023 16 |
|||||||
premutation carriers because of a family |
||||||||
|
history of FXS , but an estimated 15 % of women are diagnosed because of symptoms of FXPOI . 16
Hormonal replacement is recom-
|
Figure 7 . Acute otitis media . |
individuals who are concerned about weight gain with SSRIs . Bupropion can assist with the inattention of ADHD but is contraindicated in those with sei- |
regulating the circadian rhythm . It allows the child to fall asleep more quickly and increases their night sleep duration . Melatonin is usually well |
||||
|
mended for those with FXPOI , and SSRIs and psychological counselling are indicated when depression or anxiety are present .
The barriers and facilitators impacting the long-term care of women with FXPOI are listed in box 5 .
TREATMENT
THERE is currently no cure for FXS . Early identification and targeted intervention and support are required to allow an individual to attain their potential . Genetic counselling is the cornerstone of prevention , as it empowers families to make informed decisions regarding family planning .
Multimodality therapy is recommended for children with FXS . This includes non-pharmacological interventions from a range of providers , including speech and language therapists , occupational- and physiother-
|
A
Figure 8 . This 7-yearold boy with fragile X syndrome demonstrates a broad forehead ( A ) and a high arched palate ( B ). However , he does not have a long face or prominent ears . He is a high-functioning individual with mosaicism .
B
|
Rajaratnam A et al . F1000Res 2017 / CC BY 4.0 / bit . ly / 44RTrEZ |
zures or a propensity for seizures . Possible side effects include xerostomia , restlessness and insomnia . 8
ADHD Stimulants ( methylphenidate and ( lis ) dexamphetamine ) are the firstline pharmacological treatment for ADHD . 8 These drugs are typically trialled in children older than six years but may be considered at a younger age in special circumstances and when prescribed by a specialist . These stimulants appear to be effective in about 70 % of those with symptoms of ADHD and are effective at similar doses as in the general population and those with FXS . 8 Not all children respond to stimulants , and some may experience increased anxiety , mood lability , and aggression ; discontinue the medication in these children . 8
The alpha-2 adrenergic receptor agonists clonidine ( 2-3 times a day )
|
tolerated with minimal side effects , but day-time drowsiness and nausea have been reported in some individuals . 8 Slow-release melatonin is a more expensive alternative .
SEIZURES Most seizures are well controlled on one anticonvulsant drug only . Levetiracetam and oxcarbazepine are first line treatment for seizures . In generalised seizures , lamotrigine and valproic acid are often used . 8
Targeted treatments
METFORMIN This targeted treatment has the potential to reverse the neurobiological abnormalities in FXS . It can reduce the upregulation of the mTOR and MEK-ERK signalling pathways in FXS . 1 Metformin has been shown to improve behaviour and language in children and adults with FXS . 16-18
|
|||
apists , psychologists , social workers |
and guanfacine ( once daily ) are sec- |
||||||
and special education teachers . Phar- |
ond-line and may be useful for symp- |
CANNABIDIOL |
|||||
macological interventions are war- |
toms of ADHD in children older than |
Cannabidiol ( CBD ) is an exogenous |
|||||
ranted to treat specific symptoms . 3 , 8 Formal assessment and diagnosis are helpful to enable children to receive the necessary services and targeted |
six years in whom other stimulants are not effective or tolerated . These drugs are safe and effective in children of 4-5 years of age where stimulants |
phytocannabinoid that has the potential to improve anxiety , sleep issues and cognitive deficits in FXS . 13 Endocannabinoid deficiencies have been |
|||||
interventions , with treatment specific to their medical and behavioural issues . |
may not be indicated . Clonidine is useful in lower doses during the day time to address predominantly impulsive |
demonstrated in individuals with FXS , prompting the use of this product . 13 An ongoing controlled trial of topical CBD- |
|||||
Goal setting and progress should |
and aggressive behaviours . Clonidine |
ZYN002 ( that contains no psychoactive |
|||||
focus on education and empower- |
may be used in a higher dose in the |
component such as tetrahydrocannab- |
|||||
ment and always be in collaboration |
evening for children who have sleep |
inol ) in children with FXS has to date |
|||||
with affected individuals and / or par- |
difficulties . 8 |
demonstrated significant efficacy for |
|||||
ents and integrated into their daily |
anxiety and other behavioural prob- |
||||||
living . |
IRRITABILITY , AGITATION , |
lems , including irritability in those |
|||||
|
Non-pharmacological therapy
Speech therapy and occupational
therapy ( OT ) are commonly used in children with FXS to address delays in communication and motor ( fine and gross ) movements , with OT also important in improving sensory integration difficulties . Psychological intervention , especially behavioural therapy , can enhance social interaction and assist parents to manage and understand challenging behaviours
|
Box 4 . Symptoms and signs associated with FXPOI
• Menstrual dysfunction , early menopause and infertility .
• Anxiety , major depressive disorder , sleep disturbances .
• Thyroid dysfunction .
• Cardiovascular morbidity .
• Neuropathy , fibromyalgia .
|
treat ADHD , anxiety , aggression and sleep problems in FXS ( see table 1 ). Always use medication in conjunction with non-pharmacological strategies , which build skills in the social and emotional environment .
ANXIETY This is seen in most children and adults with FXS and is often the most
|
AGGRESSION AND SELF-INJURY It is vital to understand the drivers for these behaviours , which may be anxiety , ADHD , pain , medical , psychosocial or environmental . Medications should target the specific driver ; that is , stimulants for the ADHD , SSRI for the anxiety or if the stress is caused by interference of a specific routine or ritual , or removal of an environmental precipitator such as headphones for noise reduction . Implement behavioural interventions before or with the initiation of a medication trial . Helpful med- |
with an FMR1 gene that is fully methylated ( more than 90 % methylation ). 4 , 8
Genetic counselling and reproductive carrier screening
Genetic carrier screening will assist in
determining the risk of having a child with a genetic condition . Genetic carrier screening is increasingly available and may be performed before pregnancy or in the early stages of pregnancy . The Fragile X Association of Australia recommends carrier test-
|
|||
such as tantrums , aggression behav- |
challenging for parents . SSRIs are usu- |
ications for refractory symptoms may |
ing for fragile X syndrome for those |
||||
|
iour and anxiety , which are common in FXS .
Exercise has been found to be beneficial in those with FXS and
|
neurotypical children enjoy but may require some support and accommodations in order to do so . |
ally the first-line treatment for anxiety . 9 Sertraline has been shown to be effective in treating the anxiety in FXS and has a beneficial effect on language |
include atypical antipsychotics such as risperidone or aripiprazole . 8 Aripiprazole is less likely to cause weight gain and therefore may be favoured over |
listed in box 6 .
CASE STUDIES
CASE STUDY ONE
|
|||
associated ASD and / or ADHD . Interventions such as music therapy may improve communication skills |
A schematic presentation of non-pharmacological interventions for fragile X syndrome appears in |
and motor development and receptiveness . 8 Sertraline can be used in children from a young age and may be most |
risperidone . 8
SLEEP DISORDERS
|
JACK , aged three years and six months , is brought to the GP by his parents , who are concerned about |
|||
and self-expression and are enjoyable , social activities . 8 Children with FXS will enjoy and benefit from all the leisure and sports activities that |
figure 10 .
Pharmacological therapy
Drug therapy is commonly used to
|
beneficial in the early years . 7 , 8
Bupropion , an antidepressant , can be used to treat symptoms of both depression and anxiety , especially in
|
These are common in FXS and treatment options include melatonin and clonidine . Melatonin is the primary drug of choice and works by |
his developmental delay and some behavioural issues . His gross motor development is generally delayed , and he was walking at 23 months . |