Fragile X syndrome and other causes of developmental delay

Fragile X syndrome and other causes of developmental delay

Genetics in Family Medicine: The Australian Handbook for General Practitioners

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Fragile X syndrome and other � causes of developmental delay

GP’s role 3

Developmental delay and intellectual disability 3

Genetic causes of DD/ID 3

Chromosomal conditions 3

Single gene conditions 3

Congenital infections/ teratogens 4

Fragile X syndrome 4

Features 4

Males with a full mutation 5

Females with a full mutation 5

Individuals with a premutation 6

At-risk individuals 6

Genetics 6

Prevalence 8

Investigations 8

Preconception testing 8

Prenatal testing 8

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:

Developmental delay and intellectual disability

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007

Fragile X syndrome and other causes of developmental delay �

Fragile X syndrome and other causes of developmental delay

GP’s 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 child’s 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

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007Fragile X syndrome and other causes of developmental delay �

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(see ‘Genetics’ below)

• 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(see ‘Genetics’ below)

• 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 father’s Y chromosome.

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

No.ofrepeats GeneStatus Effect Estimatesoffrequencyinthegeneralpopulation

6 - 54 (average 30)

Normal (including grey zone)

Unaffected

55 - 200 or 230 (laboratory reporting varies)

Premutation

Females usually unaffected carriers

1 in 100 - 1 in 500

Males usually unaffected carriers

1 in 800

>200 or 230 (laboratory reporting varies)

Full mutation

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

Premutationfemale

eg 32,126 refers to 32 repeats on one X chromosome and 126 repeats on the other

Fullmutationfemale

25

120

30

3228

406

25,30 85

30 17

272 29 17 30

27832

Fullmutationmale

eg 278 refers to 278 repeats on X chromosome

Premutationmale

30,70

23,32 17,30

28,132 32,126 32 17,85

30,252 37,100 32,257

28,30 29,32 30,32

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Fragile X syndrome and other 10 causes of developmental delay

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 InformationThe 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

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007Fragile X syndrome and other causes of developmental delay 11

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.

Genetics in Family Medicine: The Australian Handbook for General Practitioners ©2007 Fragile X syndrome and other 1� causes of developmental delay

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, 64:196–97.



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.

Patient and family fact sheet

Fragile X syndrome and other causes of developmental delay 1


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 freecallAustralia-wide1800631276 or email [email protected] or visit Biotechnology Australia's website at http://www.biotechnology.gov.au

Fragile X syndrome and other � causes of developmental delay

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Fragile X syndrome and other causes of developmental delay