Fragile X Syndrome

Genetics in Family Medicine:
The Australian Handbook for General Practitioners
Fragile X syndrome and other

causes of developmental delay
GPs role
Developmental delay and intellectual disability
Genetic causes of DD/ID
Chromosomal conditions
Single gene conditions
Congenital infections/ teratogens
Fragile X syndrome
Features
Males with a full mutation
Females with a full mutation
Individuals with a premutation
At-risk individuals
Genetics
Prevalence
Investigations
Preconception testing
Prenatal testing
Management
10
Implications for other family members
10
Referral Information
10
Further Information
10
Autism
11
Underlying genetic conditions in children presenting with autistic features 11

At-risk individuals
11
Bibliography
12
Patient and family fact sheet:


Genetics in Family Medicine: The Australian Handbook for General Practitioners 2007
Fragile X syndrome and other causes

of developmental delay
GPs role
Identify people who may have developmental delay, intellectual disability and/or dysmorphic
features and consider referral to a relevant specialist and/or Genetics Services for assessment.
Consider testing children or adults with developmental delay, intellectual disability,

dysmorphic features or autistic-like features by karyotype and fragile X DNA testing.
Assess family history for X linked developmental delay, including fragile X syndrome and
undiagnosed developmental delay.
Refer to Genetics Services for cascade testing of relatives.

Manage co-existent conditions.
Facilitate access to allied health services.
Refer family to relevant support group (see Contacts, support and testing).
Developmental delay/intellectual disability (DD/ID) is categorised as mild, moderate or severe and
diagnosis is dependent on adaptive behaviour as well as IQ.
There are many conditions such as Down syndrome and fetal alcohol syndrome that are diagnosed
at birth and are associated with DD/ID.
The majority of individuals are diagnosed with DD/ID due to a delay in reaching age-related milestones.
When DD/ID is caused by an underlying condition, knowledge of this condition may inform the ongoing
management of the childs condition. It will also inform parents regarding the risks to future children and
other family members, and enable family members to have better access to services and support.
Although there is no cure for developmental delay or intellectual disability, early diagnosis allows for early
intervention, which can improve learning outcomes.
Genetic causes of DD/ID

Chromosomal conditions (see Chromosomal conditions)
Aneuploidy, eg trisomy 21 (Down syndrome)

Chromosome deletion syndromes, eg Wolf-Hirschhorn syndrome, 5p- syndrome (Cri-du-chat syndrome)
Chromosome microdeletion syndromes, eg Williams syndrome, Prader-Willi syndrome, Angelman syndrome
Single gene conditions
Autosomal dominant inheritance, eg tuberous sclerosis

Autosomal recessive inheritance, eg metabolic conditions, including phenylketonuria (PKU)
(see Newborn screening)
X-linked inheritance, eg fragile X syndrome, Rett syndrome, X-linked lissencephaly, ARX gene mutations

Congenital infections/ teratogens
Congenital cytomegalovirus, congenital HIV

Fetal alcohol syndrome
Fetal anticonvulsant syndrome
Individuals with conditions that can cause developmental delay

may present at different ages:
Prenatally
Detected by ultrasound, eg fetal brain abnormality

Detected by chorionic villus sampling or amniocentesis, eg Down syndrome
(see Testing and pregnancy)
At birth or during the neonatal period
Dysmorphic features/birth defects, eg many chromosomal conditions or genetic syndromes

Neurological abnormality, eg hypotonia in Prader-Willi syndrome
Identified by newborn screening, eg PKU (see Newborn screening)
In infancy
Marked delays, eg congenital brain malformations, Rett syndrome

Regression in psychomotor skills
During early childhood
Mild/moderate ID/DD with speech or language delay and/or behavioural difficulties,

eg fragile X syndrome, Williams syndrome
During school age years
Learning/socialisation problems
Mild ID or borderline ability or specific learning disability, eg velocardiofacial syndrome
with 22q11 deletion

Fragile X syndrome
Features
Fragile X syndrome is the most common known inherited cause of intellectual disability and it has
a wide variety of presentations. It is the second most common genetic cause of intellectual disability
(Down syndrome is the most frequent).
Intellectual problems can vary from mild learning difficulties through to severe intellectual disability.
Emotional and behavioural problems may be present.
Females show varying degrees of the condition.
Early diagnosis can facilitate strategies that will enable individuals to achieve their maximum potential
Males with a full mutation
(see Genetics below)
Typical features may not always be present, and may vary in severity.
Developmental delay:

>
Intellectual disability (100% of males)
>
>
>
>
Speech delay
Fine and gross motor delay
Co-ordination difficulties
Hypotonia
Behavioural or emotional problems:

Attention-deficit disorders with or without hyperactivity
>
> Speech disturbances including variable pitch, perseverative speech (repetition of word or phrase)
and cluttering (rapid speech with repetitions and tangential remarks)
> Autistic-like features, eg hand flapping and biting, gaze aversion, repetitive speech mimicry
(echolalia) and preoccupation with objects

>
Sensory defensiveness (aversion to touch, loud noises, bright lights and strong smells)
>
>
Hyperarousal or anxiety
Mood instability with aggression and depression, especially in post-pubertal male
Medical conditions:

>
Up to 20% have epilepsy
>
>
>
Mitral valve prolapse

Recurrent ear infections
Eye problems, eg strabismus
Physical characteristics (may be subtle in childhood)

>
Large prominent ears
>
>
>
>
>
Long face
Large testicles
High, broad forehead
High arched palate
Connective tissue problems, eg:
Flat feet
Loose joints
Scoliosis

Females with a full mutation

Around 60% of females with a full mutation have cognitive deficiencies with IQ in borderline (70-84)
or mild disability range.
Females may also present with hyperactivity or a shy personality and some will present with selective
mutism.
Females may also have the emotional and behavioural characteristics seen in affected males.
Generally speaking, affected females have a milder phenotype than affected males.
Individuals with a premutation
Premature ovarian failure

> Female premutation carriers have approximately 20% risk of developing premature ovarian failure
(menopause before the age of 40 years).

Fragile X tremor/ataxia syndrome (FXTAS)

> FXTAS is a progressive neurological disorder that usually starts after 50 years of age. It is characterised
by intention tremor, cerebellar ataxia, Parkinsonism, peripheral neuropathy and dementia.

Both male and female premutation carriers may develop FXTAS.
>

> The risk increases with age and in males is approximately 50% by age 79 years. Female premutation
carriers are less likely to develop FXTAS; the risk is not quantifiable at this time.

At-risk individuals
Individuals of either sex with:

Intellectual disability
>
>
>
>
Developmental delay
Autistic-like characteristics
Learning disabilities of unknown cause, including borderline cases
> A family history of fragile X syndrome or relatives of a person with developmental

delay of unknown cause.

A previous fragile X cytogenetic test result that was inconclusive
>
Consider offering fragile X DNA testing to:

All individuals at risk.
>
> Adults (>50 years of age) who present with unexplained ataxia and/or intention tremor,
Parkinsonism and dementia.
> Preconceptionally or during pregnancy to any woman with a family history of fragile X syndrome
or intellectual disability of unknown cause or a family history of premature ovarian failure.
>

Offer prenatal testing to females who are known to have a fragile X premutation or full mutation
(see Genetics below for details). Where the cause of intellectual disability has not been determined
in the affected member(s) in the family, prenatal testing should be discussed and may be offered
concurrently with testing of family members if time allows.

Genetics
Fragile X syndrome follows an X-linked pattern of inheritance.

However, due to the type of genetic alteration involved, the pattern of X-linked inheritance is atypical.
It is caused by a mutation in a gene on the X chromosome (the FMR1 gene: fragile X mental retardation 1).
The FMR1 gene codes for a protein, FMRP, which is thought to be necessary for normal
neurological functioning.
Fragile X syndrome results from an increase in the number of copies of a tri-nucleotide sequence within

the gene (see Table 1). Most people have between 6 and 54 repeats, with an average of 30. Copy
numbers between 55 and 200 or 230 (depending on how it is reported by the laboratory) are said to
be premutations and copy numbers of 200 or 230 and above are said to be full mutations. Genes with
premutations and full mutations contain an expansion. Full mutations cause FMRP to be switched off,
resulting in an individual having fragile X syndrome.
Inheritance pattern
The size of the expansion in the FMR1 gene is unstable and can change through generations. Both men
and women with an expansion may pass it on to their children:

>
Mother to child transmission is unstable, and the expansion may increase in size
>
Mothers of affected males carry either a premutation or a full mutation
> Father to daughter transmission is stable within a small variation for premutations; that is,
the expansion will not increase to a full mutation
> There is limited data on men with full mutations; however, it appears that daughters usually inherit
a premutation from their affected fathers
Women who are carriers of a premutation or a full mutation have a 50% chance of passing it on to each
of their children.
The risk of a female premutation carrier having a child with the full mutation is related to the size of
her premutation.
Men pass a premutation or a full mutation on to all their daughters but to none of their sons, as the
sons receive only their fathers Y chromosome.
Table 1. Repeat numbers and variable presentation of fragile X syndrome

No. of repeats
Gene Status
Effect
6 - 54
(average 30)
Normal
(including grey zone)
Unaffected
55 - 200 or 230
(laboratory
reporting varies)
>200 or 230
(laboratory
reporting varies)
Premutation
Full mutation
Estimates of frequency in the

general population
Females usually
unaffected carriers
1 in 100 - 1 in 500
Males usually unaffected

carriers
1 in 800
Females: at least half

are affected
Approximately 1 in 8,000 females
Males: generally affected
Approximately 1 in 4,000 males

A male diagnosed with fragile X syndrome could have inherited this from:

A mother with a full mutation
>
OR

A mother with a premutation
>
Family studies are likely to identify individuals with premutations and may identify individuals with
full mutations. Genetic counselling is important and allows families to make informed decisions about
family planning (see Contacts, support and testing).
It is difficult to distinguish between a normal version of the gene and a small premutation.
The number of repeats of an intermediate size (so called grey zone in the upper end of normal range)
can change into a premutation when passed on to children.
Prevalence
Approximately 1 in 4,000 males has fragile X syndrome.

Between 1 in 100 and 1 in 500 females are estimated to carry the premutation for fragile X syndrome and
be variably affected.
Between 1 in 5,000 and 1 in 8,000 females have fragile X syndrome.

Investigations
Fragile X DNA testing should be considered for all people with an unknown cause of developmental delay.
DNA studies offer a definitive result for affected individuals and carriers.
The DNA test is available on the MBS, and requests must specify fragile X syndrome. The MBS criteria for
testing are:
A patient with one or more of the clinical features of fragile X syndrome
>
>
A patient who has a relative with a fragile X mutation
Testing should always be performed with appropriate pre- and post-genetic test counselling.
Preconception testing
DNA studies to determine carrier status for those with a family history of fragile X syndrome.
Prenatal testing
DNA studies can be offered using specimens obtained via chorionic villus sampling or amniocentesis.
A positive result for fragile X syndrome does not indicate the degree of intellectual disability, which varies
greatly between individuals.
Depending on test results, termination of pregnancy may be considered by the parents.

Referral for specialist genetic counselling is recommended (see Contacts, support and testing)

Figure 1: Family pedigree of fragile X syndrome showing genotype
25
120
23,32
28,132
30
32,126
28
30,252
32
28,30
406
30,70
25,30
85
30
272
29
29,32
Premutation female
17,30
17
32
17,85
37,100 17
32
30
32,257
30,32
278
Premutation male
eg 32,126 refers to 32 repeats on

one X chromosome and 126
repeats on the other
Full mutation female
Full mutation male

eg 278 refers to 278
repeats on X chromosome

Management
While there is no cure for fragile X syndrome, a wide range of specific treatment and management
strategies are available, which involve multiple health professionals as well as the parents and carers,
and are of great benefit to affected individuals and their families. These include:

>
Genetic counselling
>
>
>
>
Grief and anger counselling

Support for families, including the assistance of a community worker or social worker
Early intervention, ongoing speech and occupational therapies
Management of behavioural issues (sensory defensiveness, hyperarousal and attention problems)
Some clinicians find that behavioural symptoms may respond well to SSRIs (selective serotonin
re-uptake inhibitors) and psychostimulants

>
Educational strategies
>
Maximising strengths
> Pharmacological management of medical issues including epilepsy, attention disorders,

aggression and mood disorders
Implications for other family members
If an individual tests positive for a fragile X full mutation or premutation, their family should be referred
to Genetics Services for counselling.
The individual and their family should be supported in discussing fragile X syndrome with their
extended family, as counselling and genetic testing should be offered to those relatives at risk of having
the fragile X mutation.
Detection of fragile X carriers allows families to make informed decisions regarding family planning
Referral Information
Refer to paediatric and Genetics Services for assessment. Genetics Services will provide information
regarding availability of multidisciplinary clinics for fragile X syndrome (see Contacts, support and testing).
Refer to your local AGA Peak Body (see Contacts, support and testing) to find a relevant support group.
Further Information
The Fragile X Association of Australia. http://www.fragilex.org.au
FRAXA. http://www.fraxa.org (includes the very helpful listserver)
The National Fragile X Foundation. http://www.nfxf.org
Carolina Fragile X Project. http://www.fpg.unc.edu/~fx

10 causes of developmental delay
Autism
Autism is characterised by impairment in verbal and nonverbal communication, imaginative play activity
and social interaction.
Between 3 in 1,000 and 4 in 10,000 individuals have autism.

Onset is prior to 30 months of age.
Around 80% have learning disability.
Categorised within pervasive developmental conditions which also includes Asperger syndrome,
childhood disintegrative disorder and Rett syndrome.
May co-exist with other conditions including: intellectual disability, speech and language conditions,
anxiety and depression, epilepsy, attention disorders, Tourette syndrome and Down syndrome.
It is important to exclude specific genetic developmental conditions, specifically minor chromosomal

changes and fragile X syndrome, and autistic-like features of ID.
Autistic features can be the presenting symptoms in ID and other genetic conditions.
Early diagnosis and intervention for a child with autism has been shown to improve outcomes and
maximise learning opportunities. While there is no cure, a wide range of specific treatments and
management strategies are available. Early diagnosis also ensures families and carers have better access
to services and professional support.
There is no clear inheritance pattern, however family and twin studies have shown there is a familial
component to autism and pervasive developmental delay conditions.
As yet there is no known single gene that causes autism and therefore genetic testing is not available.
Underlying genetic conditions in children presenting with autistic features
Tuberous sclerosis, characterised by epilepsy, DD, depigmented macules

Fragile X syndrome
Chromosomal abnormalities, eg inversions, duplications, 15q deletions
Metabolic conditions
Rett syndrome, characterised by language and motor regression, loss of purposeful movement
At-risk individuals
Individuals, especially males with:

>
A close family history of autism or related pervasive developmental delay disorder
>
Autistic-like features
Tests that may be relevant for individuals with autistic features include:

>
Karyotype
>
>
Fragile X DNA testing

Repeat tests for newborn screening
Refer to:

>
Paediatrician for assessment of autistic features
>
>
>
Genetics Services if the individual is dysmorphic

Neurologist if regression of psychomotor skills occurs
AGA Peak Body for an appropriate support group (see Contacts, support and testing)
It is estimated that there is a 5% recurrence risk for siblings of children affected with autism.

causes of developmental delay 11
Bibliography
Barlow-Stewart K 2004. Fragile X syndrome. In The Australasian Genetics Resource Book (Ed Barlow-Stewart K),
Centre for Genetics Education, Royal North Shore Hospital, Sydney NSW ISBN 0-9580797-2-2.
http://www.genetics.com.au
Cohen J and Lennox N, 1999. Fragile X syndrome. In Management Guidelines: People with Developmental
& Intellectual Disabilities. (Eds Lennox N and Diggens J). Therapeutic Guidelines Ltd.
Gaff C, Newstead J and Metcalfe S, 2003. Fragile X syndrome. In The Genetics File. Victorian Department
of Human Services, Melbourne ISBN 0 7311 61777.
http://www.mcri.edu.au/GF/pages/GeneticsFile.asp
The Royal Australian College of General Practitioners, 2005. Guidelines for preventive activities
in general practice, 6th edition.
http://www.racgp.org.au
Turner, G, Webb, T, Wake, S and Robinson, H. 1996, The prevalence of fragile X syndrome, American
Journal of Medical Genetics, 64:19697.

12 causes of developmental delay
Patient and family fact sheet
Developmental delay and

intellectual disability
Developmental delay and intellectual disability are similar phrases. They describe aspects of a
person who is either slow to develop, or has not fully developed, in some of the following areas:
speech, language, mental capacity or physical capacity.
Developmental delay and intellectual disability can be extremely mild or they can be quite severe.
Some people with developmental delay or intellectual disability lead normal lives, while others have
very restricted lives and need care outside the family.
Sometimes children with developmental delay and intellectual disability are picked up soon after
birth. Sometimes the problems are noticed when children are slow to learn to talk. Sometimes
problems are not detected until the child starts school. Quite often, the parents have suspected
there is a problem well before it is diagnosed by doctors.
There are many different causes of developmental delay and intellectual disability. Some of the
causes include infections, injuries, difficult births and autism.
Genetic conditions can also cause developmental delay or intellectual disability. The most common
ones are:

Chromosomal conditions, such as Down syndrome

Single gene conditions, such as fragile X syndrome (which causes intellectual disability and a

range of behavioural problems) or phenylketonuria (where the body lacks a specific enzyme,
which causes abnormal metabolism that may result in brain damage).
In some cases, when someone in the family has developmental delay or intellectual disability, it is
wise to discuss whether or not other family members need to be assessed. It is also wise to see
whether or not any genetic testing is available.
While there is no cure for any form of developmental delay or intellectual disability, finding out the
cause early and getting help from a wide range of professionals, can help. Some young children
with developmental delay can catch up.

Contacts and further information

Your local genetic service, which you can contact through your nearest community health
centre, public hospital or health department.
Australasian Genetic Alliance at http://www.australasiangeneticalliance.org.au

National Organization for Rare Disorders at http://www.rarediseases.org
Better Health Channel at http://www.betterhealth.vic.gov.au
MyDr at http://www.mydr.com.au
The Centre for Genetics Education at http://www.genetics.edu.au
HealthInsite at http://www.healthinsite.com
MedicineNet at http://www.medicinenet.com
For other related fact sheets, you can contact the Gene Technology Information Service
on free call Australia-wide 1800 631 276 or email gtis-australia@unimelb.edu.au

or visit Biotechnology Australia's website at http://www.biotechnology.gov.au


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Genetics in Family Medicine:

The Australian Handbook for General Practitioners

Fragile X syndrome and other

Developmental delay and intellectual disability

Genetic causes of DD/ID

Single gene conditions

Congenital infections/ teratogens

Males with a full mutation

Females with a full mutation

Individuals with a premutation

Implications for other family members

Underlying genetic conditions in children presenting with autistic features 11

Patient and family fact sheet:

Fragile X syndrome and other

Fragile X syndrome and other causes

Consider testing children or adults with developmental delay, intellectual disability,

Refer to Genetics Services for cascade testing of relatives.

Genetic causes of DD/ID

Aneuploidy, eg trisomy 21 (Down syndrome)

Autosomal dominant inheritance, eg tuberous sclerosis

Fragile X syndrome and other

Congenital infections/ teratogens

Congenital cytomegalovirus, congenital HIV

Individuals with conditions that can cause developmental delay

Detected by ultrasound, eg fetal brain abnormality

At birth or during the neonatal period

Dysmorphic features/birth defects, eg many chromosomal conditions or genetic syndromes

Marked delays, eg congenital brain malformations, Rett syndrome

Mild/moderate ID/DD with speech or language delay and/or behavioural difficulties,

During school age years

Fragile X syndrome and other

Intellectual disability (100% of males)

Behavioural or emotional problems:

Attention-deficit disorders with or without hyperactivity

Up to 20% have epilepsy

Mitral valve prolapse

Physical characteristics (may be subtle in childhood)

Large prominent ears

Fragile X syndrome and other

Females with a full mutation

Premature ovarian failure

Fragile X tremor/ataxia syndrome (FXTAS)

Both male and female premutation carriers may develop FXTAS.

Individuals of either sex with:

> A family history of fragile X syndrome or relatives of a person with developmental

A previous fragile X cytogenetic test result that was inconclusive

Consider offering fragile X DNA testing to:

All individuals at risk.

Fragile X syndrome and other

Fragile X syndrome follows an X-linked pattern of inheritance.

Mothers of affected males carry either a premutation or a full mutation

Table 1. Repeat numbers and variable presentation of fragile X syndrome

Estimates of frequency in the

Males usually unaffected

Females: at least half

Approximately 1 in 8,000 females

Males: generally affected

Approximately 1 in 4,000 males

Fragile X syndrome and other

A mother with a full mutation

A mother with a premutation

Approximately 1 in 4,000 males has fragile X syndrome.

Between 1 in 5,000 and 1 in 8,000 females have fragile X syndrome.