Fragile X syndrome: Part 2

This Update is the second in a two-part series and focuses on the assessment and management of fragile X. It is by Dr Jonathan Cohen, MBBS, FACTM, FRACGP, MastFamMed; Dr Alison D Archibald, PhD, GDipGenetCouns and A/Prof Sylvia A Metcalfe PhD, BSc (Hons), and A/Prof Sylvia A Metcalfe, PhD, BSc (Hons).

Dr Jonathan Cohen, MBBS, FACTM, FRACGP, MastFamMed
Dr Cohen is Medical Director, Fragile X Alliance Clinic; Adjunct Senior Research Fellow, Centre for Developmental Disability Health Victoria; Department of General Practice, Monash University; Honorary Research Fellow, Murdoch Childrens Research Institute, Victoria.

Dr Alison D Archibald, PhD, GDipGenetCouns
Dr Archibald is from the Murdoch Childrens Research Institute; and the Department of Paediatrics, The University of Melbourne, Victoria.

A/Prof Sylvia A Metcalfe, PhD, BSc (Hons)
Professor Metcalfe is from the Murdoch Childrens Research Institute; and the Department of Paediatrics, The University of Melbourne.

INTRODUCTION
DIAGNOSIS of fragile X syndrome (FXS) allows implementation of effective treatment and management strategies for individuals and their families regardless of age, but these are more effective if started early.

While there is currently no cure for the underlying genetic mutation, specific treatment and management strategies are of great benefit to individuals and their families. Management rests on implementation of behavioural and educational strategies in conjunction with appropriate pharmacotherapy.

Several medications have been shown to be helpful in managing the associated behavioural disorders commonly seen with FXS, such as anxiety disorders, ADHD, epilepsy, enuresis and encopresis, aggression and self- injury.

Management is multidisciplinary, and it is important to both involve and follow up with the family on a regular basis to provide support and ensure the appropriate strategies are being implemented (see Table 1).

TABLE 1: CARE PLAN SUMMARY

• For DNA testing to confirm FXS status: genetic counselling for information and cascade testing of relevant family members; grief and supportive counselling for family
• Hearing assessment with audiologist
• Vision assessment with optometrist/ophthalmologist
• Assessment for orthotics podiatrist
• Trial SSRI for anxiety: start with a low dose and report back to GP in one week or earlier, if needed
• Speech and language therapist
• Educational psychologist: assess for IQ, ADHD and autism spectrum disorder, behaviour management strategies
• Occupational therapist including sensory issues
• Developmental paediatrician
• Centrelink for help with funding, home support, etc
• Information on FXS: to join Fragile X Alliance and Fragile X Association of Australia
• Multidisciplinary assessment at Fragile X Association clinic

GENETIC COUNSELLING
As this is an inherited condition, it is likely to impact multiple family members, so it is important for the GP to identify all those at risk with genetic testing. This especially applies to females of child-bearing age, who will need to know their carrier status if they want to have any choice in whether or not to have an affected child.

Knowledge of carrier status offers the full spectrum of reproductive options, including the choice of becoming pregnant, testing of the fetus for FXS, and the option of termination. There is also a range of assisted reproduction techniques including egg or embryo donation and pre-implantation genetic embryo testing using DNA techniques before implantation into
the uterus.

ASSESSMENT
Initial assessment
It is therapeutic for the family and carer that they be listened to carefully, as they may have been struggling with the many challenges associated with looking after an individual with FXS for a long time.

It is important to specifically look for the typical phenotypic features of FXS when taking medical and family history and initially examining the child.  As it is common for the mother to be the carrier, it is important to ensure another family member attends the consultation.

Providing a clear explanation of the reasons for behavioural presentations can be helpful for the family and/or carer, as this removes the fear of previously misunderstood behaviour, and provides a basis for more appropriate management in the home, school and at work or day placement.

Educational assessment
The main presenting concerns for families regarding their children centre on educational approaches, which are best managed by a combination of a speech and language therapist, occupational therapist, psychologist and a special education teacher.

While most younger children will be able to attend a mainstream school, if there is  an understanding teacher and the appropriate support from the school, few mainstream secondary schools provide the necessary educational modifications, necessitating transfer to a special developmental school in most cases.

Higher-functioning individuals with FXS may be able to transition into the various TAFE options on offer which include workplace experience in areas such as hospitality, horticulture, aged care and retail.

Physical assessment
There is a high incidence of both hearing and vision problems in FXS, which add to the difficulties experienced by people with intellectual difficulties, so appropriate referral is critical. Referral to an optometrist and audiologist familiar with neurodevelopmental issues in developmental disability is often more helpful functionally, and they are able to refer directly to ophthalmologists and ENT surgeons for surgical intervention, if necessary.

Strabismus can often be managed with eye exercises and spectacles provided therapy is implemented early enough, with the aim of achieving binocular vision.

Recurrent Eustachian tube blockage responds well to grommet tube insertion and allows earlier restoration of normal hearing.

PHARMACOLOGICAL TREATMENT OF CLINICAL FEATURES
Anxiety
SSRIs such as sertraline, fluoxetine, citalopram, escitalopram or fluvoxamine can be extremely effective in managing the anxiety disorders that occur in most individuals with the full mutation and a subgroup with the pre-mutation. These medications help block the uptake of serotonin from synapses in the locus coeruleus, increasing the individual’s ability to remain calm when confronted by perceived threatening situations. It is axiomatic that medications are used to treat the disorder as defined by DSM-IV, not the behaviour per se.

Paradoxical arousal or activation occurs in up to 20% of those prescribed fluoxetine, so this medication should be avoided when there is hyperactivity, hyper-arousal, restlessness or agitation. However, it can be helpful for treatment of those who are extremely shy, socially avoidant, or diagnosed with social anxiety disorder or selective mutism.

SNRIs such as venlafaxine or desvenlafaxine are also helpful in ameliorating symptoms of anxiety, as well as concentration and attention. This tends to be a class effect, so a trial of one or two medications from this class is often worthwhile. If behaviour worsens in the absence of an antecedent cause, then another medication should be trialled.

Benzodiazepines such as diazepam are generally unhelpful in FXS as they can disinhibit and so worsen the underlying problems. Buspirone is an exception to this, and midazolam can be helpful for procedures such as dental visits.

Tricyclic antidepressants and the older antipsychotics are contraindicated due to their side-effect profiles, including a range of cardiovascular and neurological effects such as sedation, which worsens pre-existing cognitive problems.

ADHD
ADHD occurs more frequently in FXS and management is very much the same as with individuals with or without intellectual disability. Behaviour management strategies and educational modifications are synergistic with medications.

The psychostimulants methylphenidate and dexamphetamine enhance dopamine and noradrenalin neurotransmitter function, and help individuals focus on the task at hand. These medications can be helpful for people older than five years to better manage attention, concentration, impulsivity, restlessness, handwriting, and also to improve social function. Both short- and long-acting versions are available in Australia and may need to be used in combination. Current prescribing requirements mandate that an assessment tool such as the DSM-IV ADHD criteria checklist or Conners’ rating scale be used to assess and monitor progress.

Regular follow-up is required, including monitoring for side-effects, which are generally mild and tolerable and may include a reduction in appetite and sleep and, rarely, cardiovascular effects.

Clonidine is an alpha-adrenergic receptor agonist used for the treatment of hypertension, but which may be especially helpful for children older than five years. It has been used effectively for the treatment of hyperactivity and sleep disorders in FXS as well as in older individuals by itself or in conjunction with SSRIs. Side-effects include hypotension, so the lowest effective dose is used generally at night before bed, and ECGs are recommended to monitor for arrhythmias.

Seizures
Anticonvulsant medications are generally very effective in FXS, with carbamazepine and valproate being equally effective as monotherapy and well tolerated by most.

If seizures are not controlled, most other currently available anticonvulsants can be trialled, bearing in mind their potential side-effects. Phenytoin, phenobarbital and gabapentin are generally avoided due to their potential for unwanted side-effects in this group.

Mood instability and aggression
In addition to the anticonvulsants above, the atypical antipsychotics such as risperidone, olanzepine, quetiapine and aripiprazole may be helpful in alleviating what can be very dramatic behavioural problems.

Many individuals with FXS will meet the criteria for either bipolar mood disorder or autism spectrum disorder, and so can be prescribed these medications on the PBS. Risperidone (starting with low-dose 1 mg bd and increasing as needed) is effective in both young children with autism spectrum disorder and also adults with severely challenging behaviour.

Olanzepine and aripiprazole have a wide range of action in managing many of the emotional and behavioural problems seen in FXS including anxiety, agitation, aggression and mood stability; however, a supervised diet needs to be implemented to avoid significant weight gain.

Enuresis and encopresis
While management of these conditions is the same as in the general community; the problems may extend to a later age associated with developmental delay.

Behaviour management techniques such as alarm blankets can be very helpful. Medications such as imipramine and desmopressin are also helpful, but require careful ongoing monitoring.

Sleep disorders
Sleep disorders are common and will usually respond to behavioural management techniques, which have been shown to be effective. Clonidine can be used at night, with the added benefit of helping manage anxiety and hyperactivity. Melatonin can be helpful in FXS and has no known or apparent side-effects.

MANAGEMENT OF ADULTSPreventive careA number of medical conditions are often missed in the developmentally disabled population and FXS is no exception (see Table 2).TABLE 2: 

TABLE 2: OFTEN MISSED MEDICAL CONDITIONS IN FRAGILE X PATIENTS

• Neurological: Epilepsy – tonic-clonic seizures, complex-partial seizures
• Gastrointestinal: Constipation, reflux oesophagitis
• Urogenital:
  
  • Female – polycystic ovaries, FXPOI, vesicoureteric reflux, renal abnormalities
  • Male – undescended testes, hypospadias, vesicoureteric reflux, renal abnormalities

• Orthopaedic: Pes planus, hyperextensible joints, scoliosis, asymmetrical leg length
• ENT: Recurrent otitis media, hearing loss
• Dental: Caries, gingivitis, root abscess
• Ophthalmological: Strabismus, visual perception defects
• Nutrition: Obesity, under-nutrition
• Dermatological: Dry skin, eczema, striae
• CVS: Mitral valve prolapse, aortic root dissection/rupture
• Psychiatric: Anxiety, low self-esteem, schizophrenia, depression, ADHD

Adult issues
Few adult males will be able to form relationships with females and, in general, their social contacts tend to be limited to their immediate family, carers and therapists. Many will be able to work in areas such as hospitality, horticulture, cleaning and occasionally retail, with some in sheltered workshops or taking part in supervised
day programs.

Adult females are much more likely to live a relatively normal life; however, some will be severely affected. Counselling for sexuality issues needs to be offered, with the aim of ensuring females can manage their periods and are taught the skills to be able to decline unwanted advances and to be safe.

While some paediatricians continue to see affected individuals into adulthood, this is not common. Apart from a handful of specialist adult disability units, management generally falls to local GPs, most of whom are generally not trained in this area.

In addition, community resources, when present, are generally extremely poor. Many problems have been identified surrounding inappropriate accommodation for individuals such as the existing community residential units, where a cluster of people with behavioural problems share a unit under guidance of well-meaning but often untrained carers. Preferred alternative housing such as cluster units are rarely available and consequent to behavioural outbreaks, some residents may be transferred to forensic facilities.

Appropriate support in the workplace and in day programs may be less than satisfactory, and numerous cases of all forms of abuse have been well documented. Well-intentioned social change in the past few decades has brought with it confusion about allowing an intellectually disabled individual independence, which includes allowing undesired activities and behaviours.

For example, it is questionable as to whether an individual with a chronological age of 40 but a developmental age of four should be allowed to smoke cigarettes or eat whatever they like. Needless to say, much of this is completely out of the hands of the average GP.

In the absence of a caring family member, many adults with FXS are completely dependent on the goodwill and abilities of the carers who supervise their activities on a daily basis.

FUNDING
The Better Start program under FaHCSIA offers funding for early intervention for children younger than six years. The Department of Education provides some funding for school-age children with intellectual disability or severe disabilities.

For children and adults, there are a number of Medicare item numbers that may act as an incentive to provide a care plan including annual health assessments, medication reviews, case conferences and care plans. Private health extras insurance covers some allied health services.

Centrelink case managers and local hospital-based social workers can help identify funding sources, and there are a number of private and religious-based associations that can also offer
some help.

NEW DEVELOPMENTS AND FUTURE DIRECTIONS IN RESEARCH
New medications
Animal knockout models have contributed to the understanding of the neurobiological abnormalities in FXS, and a number of promising medications targeting synapses involved with regulation of emotions and learning are currently in various stages of development.

FMRP is an mRNA-binding protein normally needed for synaptic protein inhibition. The lowered levels seen in FXS result in up-regulation of several synaptic proteins, including metabotropic glutamate receptor activated pathways (GluR1 and mGluR5).

Inhibition of mGluR5 would therefore, in theory, inhibit these pathways and contribute to alleviating many of the core symptoms seen in FXS including anxiety, arousal and aggression.

A stage II multicentre DBRCT trial of an mGluR5 inhibitor in FXS AFQ056
is currently underway, with several other medications in various stages of development or at trial, including other mGluR5-negative modulators, arbaclofen, mino­cycline, lithium and ampakines.

The aim of developing these and newer medications is to reverse the synapse modifications with repair of the pathways needed for normal emotional and intellectual function in individuals affected by FXS and other disorders such as autism.

TABLE 3: MULTIDISCIPLINARY TEAM

• Audiologist/ENT
• Optometrist/ophthalmologist
• Speech and language therapist
• Occupational therapy/physiotherapy
• Psychologist/psychiatrist
• GP
• Specialist: developmental paediatrician, neurologist
• Genetic counsellor/clinical geneticist
• Special education teacher

Population screening
FXS satisfies the WHO criteria for population screening and there are currently a number of trials underway exploring how best to offer this. Newborn screening is being investigated and enables access to early intervention.

Other screening options are to offer carrier testing to women either before conception or in early pregnancy. While research confirms that this type of screening is feasible and acceptable, reproductive options are greater if carrier screening occurs before pregnancy.

Once a child is identified with FXS, in many cases there is no known family history of FXS. Therefore, many women may be carriers yet unaware of their carrier status.

This and other research is the subject of the current NHMRC funded fragile X carrier screening study run by the Murdoch Childrens Research Institute and other associated groups.         

KEY POINTS

• Management strategies are more effective if started early, so early diagnosis is paramount.
• Genetic testing and counselling are important for at-risk family members, particularly females of child-bearing age.
• Educational assessment includes hearing, vision and speech, as well as developmental assessment.
• Effective pharmacological treatments are available for anxiety, ADHD, seizures, mood instability and aggression, enuresis and encopresis, and sleep disorders.
• Associated medical conditions include reflux oesophagitis, constipation, vesicoureteric reflux, mitral valve prolapse, aortic root dissection, scoliosis, pes planus and strabismus.

REFERENCES & FURTHER INFORMATION
Guidelines
Hersh JH, Saul RA and Committee on Genetics from the American Academy of Pediatrics.
Health Supervision for Children with Fragile X Syndrome
Pediatrics Vol. 127 No. 5 May 1, 2011 pp. 994 -1006
http://pediatrics.aappublications.org/content/127/5/994?cited-by=yes&legid=pediatrics;127/5/994

Lennox N, Cohen J
Fragile X Syndrome - chapter in Management Guidelines  (Developmental Disability Version 2 (2005) (3rd ed in press 2012)

Therapeutic Guidelines (Australia)
Guidelines for testing (2003) - Human Genetic Society of Australasia (currently under review)
https://www.hgsa.org.au/website/wp-content/uploASD/2009/12/2003-GL01.pdf 

Medicare Benefits Schedule Nov 2011
http://www9.health.gov.au/mbs/fullDisplay.cfm?type=item&q=73300&qt=ItemID  

Books
Hagerman RJ and Hagerman PJ eds
Fragile X Syndrome - DIagnosis, Treatment and Research 3rd ed 2002
The Johns Hopkins University Press

Braden ML
Handle with Care - Understanding Fragile X Syndrome 2nd ed 2004
National Fragile X Foundation (USA) Reprinted under licence Fragile X Alliance Inc

Tranfaglia MR (and Cohen J Australian ed 2007)
A Medication Guide for Fragile X Syndrome
FRAXA Research Foundation. Reprinted under licence Fragile X Alliance Inc
CD Module 2009

Metcalfe SA and Cohen J
Fragile X Syndrome- Clinical and Molecular Aspects (2009) Version 2 – CD
University of Melbourne

Articles
Hagerman RJ et al
Review Article - Advances in the Treatment of Fragile X Syndrome
Pediatrics 2009;123;378-390
www.pediatrics.org/cgi/doi/10.1542/peds.2008-0317

Wang LW, Berry-Kravis E, Hagerman RJ l
Fragile X: Leading the Way for Targeted Treatments in Autism
Neurotherapeutics Vol. 7, 264–274, July 2010 © The American Society for Experimental NeuroTherapeutics, Inc.

Chonchaiya w, Schneider A, Hagerman RJ
Fragile X: A family of disorders
Advances in Pediatrics 56 (2009) 165–186

Hill MK, Archibald AD, Cohen J, Metcalfe SA.
A systematic review of population screening for fragile X syndrome.