Clinical Aspects of Fragile X Syndrome

Question 1

When was Fragile X first reported?

Answer 1

Fragile X was first reported by Martin-Bell in 1943. It was reported in a family with non-syndromic XLMR, 11 affected males.

Lubs 1969 observed constriction in the q arm of the X chromosome in another family with XLMR, both in affected males and carrier females.

Sutherland in 1977 performed the first diagnostic test and reinvestigated the original Martin-Bell family.

Question 2

How many fragile sites are there in the human genome?

Answer 2

Over 100

Question 3

What are the typical fragile sites seen in Fragile X?

Answer 3

Folate sensitive fragile sites:

• FRAXA (Xq27.3)
• FRAXE (Xq28)
• FRAXF (Xq28)

FRAXD and FRAXF are not related to mental retardations.

Question 4

Describe Fragile X syndrome.

Answer 4

Fragile X syndrome is the commonest inherited cause of mental retardation and the second most common cause of mental impairment after trisomy 21.

The prevalence of affected males is 1 in 5,500.

It is found in 4-8% of boys with and IQ of 35-70.

The classic phenotype evolves after puberty. There are a triad of:

• typical facies
• mental retardation
• macro-orchidism (only exhibited by 60% of post-pubertal males)

Question 5

What is the prevalence of Fragile X?

Answer 5

The prevalence of affected males is 1 in 5,500.

It is found in 4-8% of boys with and IQ of 35-70.

Question 6

What is the classic phenotype of Fragile X?

Answer 6

The classic phenotype evolves after puberty. There are a triad of:

• typical facies
• mental retardation
• macro-orchidism (only exhibited by 60% of post-pubertal males)

Phenotype is often more subtle in younger children.

Question 7

Describe the typical facial features of a Fragile X male.

Answer 7

• Long face (dolichocephaly)
• High forehead
• Prominent chin
• Prominent supraorbital ridges
• Puffiness around eyes
• Nose usually broad based
• Prominent ears

Question 8

Describe some of the less common clinical findings seen in Fragile X syndrome.

Answer 8

• Macro-orchidism (uni- or bilateral) seen after puberty in 75% of adult hemizygotes.
• Joint laxity (especially of thumbs - 75%).
• Mitral valve prolapse: 50% of adults.
• Increased birth weight and head circumference.
• Recurrent otitis media in 60-80% of affected individuals.
• Seizures in up to 20% of affected individuals.

Question 9

What developmental problems are associated with Fragile X syndrome?

Answer 9

• Motor problems such as hypotonia and mild motor delay are quite common.
• Speech - variable delay. Often not fluent. Repetition, echolalia, incomplete sentences.
• IQ - mean IQ or 41 (full mutation).
• Autistic spectrum disorder
• Some individuals have some strengths in skill of daily living but adults often need supported living.

Question 10

What are the behavioural phenotypes of Fragile X syndrome?

Answer 10

• Hyperactivity, impulsiveness, poor concentration (but not increased to similar children with other learning disorders).
• Overwhelmed by sensory stimuli.
• Gaze avoidance/shyness (rather than poor eye contact seen in autism).
• Repetitive behaviours - hand flapping, hand biting.
• Affectionate and interested in social interactions but shy and anxious in groups.
• Sometimes aggressive/antisocial behaviour in adult life but probably no more so than other adults with their degree of learning difficulty.

Question 11

What is the inheritance pattern of Fragile X syndrome?

Answer 11

Fragile-X syndrome is inherited in an X-linked recessive manner. Females usually carry the condition and can pass on the relevant gene fault to their male offspring. If a male gets the mutated gene then they will be affected.

Generally, a carrier will have a 1 in 4 chance of having an affected son.

Question 12

What is the Sherman paradox that is displayed by fragile X syndrome?

Answer 12

The Sherman paradox was noted when the daughter of an unaffected male was more likely to have affected offspring than the mother of the unaffected male carrier. The risk of expressing mental retardation was dependant on the individual’s position in the pedigree, with risk increasing in later generations.

There is a hypothesis about this which involves the individual having a premutation with no clinical symptoms and a second event is required to convert this to a full mutation. The mutation is thought to change upon translation by a carrier female.

Question 13

Describe the gene involved in Fragile X. What mutation is involved in Fragile X syndrome?

Answer 13

• The FMR1 gene characterized in 1991. This is the Fragile X Mental Retardation gene 1.

This is a dynamic mutation disorder and there is expansion of a CGG trinucleotide repeat in the 5’ untranslated region of the FMR1 gene within exon 1 (non-coding).

A minority of patients have other types of mutations in FMR1 that will not be detected by usual testing.

Question 14

What are trinucleotide repeats (TNRs)?

Answer 14

Trinucleotides were first described in the early 1990’s. Triplet repeats are blocks of three bases (nucleotides) repeated over and over again. Tandem TNRs are not infrequent in the genome and most are not disease associated. Repeats below a certain length are stable in meiosis. Above a certain threshold level the repeats are unstable in meiosis (expansions and contractions can occur). The bias is toward expansion. These unstable repeats are virtually never transmitted unchanged from parent to child. Likelihood of expansion depends on the length of the repeat. Degree of expansion can depend on the sex of the transmitting parent.

Question 15

What can happen to trinucleotide repeats during meiosis?

Answer 15

Repeats below a certain length are stable in meiosis. Above a certain threshold level the repeats are unstable in meiosis (expansions and contractions can occur). The bias is toward expansion. These unstable repeats are virtually never transmitted unchanged from parent to child. Likelihood of expansion depends on the length of the repeat. Degree of expansion can depend on the sex of the transmitting parent.

Question 16

What is usually considered a full mutation allele size in fragile X syndrome?

Answer 16

> 200 repeats. All males will exhibit the fragile X phenotype and around 50% of girls will have some degree of learning difficulties.

Question 17

What is usually considered a premutation allele size in fragile X syndrome?

Answer 17

Premutation: 59-approx. 200 repeats, high chance of expansion in offspring of females.

59-200 repeats = Premutation carrier females/normal transmitting males are not affected but have a high chance of the repeat expanding to a full mutation, particularly for the children of female carrier. Women are at risk of POF and men (and also possibly women) of FXTAS phenotype.

Question 18

What is usually considered an intermediate allele size in fragile X syndrome?

Answer 18

Intermediate: 46-55 repeats- possible expansion in future generations.

Intermediate/Premutation: 56-58, one report of a patient with 56 CGGs expanding to a full mutation in offspring.

Question 19

What is usually considered a normal allele size in fragile X syndrome?

Answer 19

Normal:

Question 20

Describe the classifications of different allele sizes in fragile X syndrome.

Answer 20

Normal:

Question 21

How does the larger repeat size in the fragile X gene lead to disease?

Answer 21

In a full mutation there is increased methylation of the FMR1 gene. This results in no FMR protein being produced due to the impairment of translation of mRNA. It is the loss of FMRP that produces the fragile X syndrome. While FMRP is normally expressed in many tissues, it is most abundant in neurons and appears to play a role in the functional and structural maturation of the synapses.

Question 22

What is the usually function of FMR protein?

Answer 22

While FMRP is normally expressed in many tissues, it is most abundant in neurons and appears to play a role in the functional and structural maturation of the synapses.

Question 23

What is the pathological mechanism behind fragile X syndrome?

Answer 23

In a full mutation there is increased methylation of the FMR1 gene. This results in no FMR protein being produced due to the impairment of translation of mRNA. It is the loss of FMRP that produces the fragile X syndrome. While FMRP is normally expressed in many tissues, it is most abundant in neurons and appears to play a role in the functional and structural maturation of the synapses.

Question 24

Describe how a full fragile X mutation might affect females.

Answer 24

There is a variable phenotype seen in female heterozygotes of a full mutation. The normal X produces variable amounts of FMR protein as a result of variable X-inactivation. The level of FMR protein correlates with the degree of cognitive impairment seen. Up to 50% of female full mutation heterozygote females demonstrate learning and behavioural difficulties, similar but less severe than seen in males. Subtle problems are common even if IQ is normal.

It is important to note that in prenatal diagnosis the prediction of a phenotype in a female with a full mutation is not possible.

Question 25

In prenatal diagnosis is it possible to predict the phenotype of a female with a full mutation?

Answer 25

It is important to note that in prenatal diagnosis the prediction of a phenotype in a female with a full mutation is not possible.

Question 26

Describe the features of a fragile X premutation female carrier and normal transmitting male.

Answer 26

• A premutation is 59-200 repeats in length.
• This repeat size is unstable during meiosis.
• The expansion of the CGG repeat to a full mutation occurs exclusively during transmission from female carriers.
• Rarely, femal premutation carriers may have learning difficulties but we cannot assume that the premutation is the cause of this.
• They are not affected with fragile X syndrome.
• In males, on transmission expansion of the premutation does not usually occur. Only premutation alleles have been identified in sperm even in men with full mutations.
• For male premutation carriers all daughters and none of their sons will have the premutation
• It was initially thought that male premutation carriers were asymptomatic but there are potential long term complications, in particular FXTAS

Question 27

How will male fragile X premutation carriers present?

Answer 27

• In males, on transmission expansion of the premutation does not usually occur. Only premutation alleles have been identified in sperm even in men with full mutations.
• For male premutation carriers all daughters and none of their sons will have the premutation
• It was initially thought that male premutation carriers were asymptomatic but there are potential long term complications, in particular FXTAS

Question 28

How will female fragile X premutation carriers present?

Answer 28

• The expansion of the CGG repeat to a full mutation occurs exclusively during transmission from female carriers.
• Rarely, femal premutation carriers may have learning difficulties but we cannot assume that the premutation is the cause of this.
• They are not affected with fragile X syndrome.
• They have an increased risk of POF.

Question 29

What is FXTAS?

Answer 29

• FXTAS is Fragile X Associated Tremor and Ataxia Syndrome.
• It is a late-onset progressive cerebellar ataxia and intention tremor in males with premutations.
• Other neurological findings include peripheral neuropathy, short-term memory loss, muscle weakness and autonomic dysfunction.
• Neuropathology consists of general cerebral and cerebellar atrophy.
• 40-50% of males over 50 with a Fragile X premutation will develop this phenotype. Penetrance increases with age (50-59 risk is 17%, 60-69 risk is 38%, 70-79% risk is 47% and 80+ risk is 75%).

Question 30

What percentage of males with a fragile X premutation over 50 will develop FXTAS?

Answer 30

40-50% of males over 50 with a Fragile X premutation will develop this FXTAS. Penetrance increases with age.

Question 31

How is FXTAS diagnosed?

Answer 31

A diagnosis require the presence of a premutation plus:

• white matter lesions on MRI in the middle cerebellar peduncles and/or brain stem with either intention tremor gait ataxia.
• Minor criteria include parkinsonism, memory or cognitive function deficits.
• Approximately 2-4% of men presenting with apparent sporadic adult-onset ataxia may have FXTAS.
• The differential diagnosis for FXTAS is broad.

Question 32

Approximately what percentage of men presenting with apparent sporadic adult-onset ataxia may have FXTAS?

Answer 32

Approximately 2-4% of men presenting with apparent sporadic adult-onset ataxia may have FXTAS. The differential diagnosis for FXTAS is broad.

Question 33

Can FXTAS present in females?

Answer 33

• Women with premutations may also develop FXTAS but the condition is usually milder.
• FXTAS occurs in 8-16.5% of premutation carriers.
• Female carriers may have children affected by fragile X syndrome.

Question 34

About what % of female premutation carriers does FXTAS affect?

Answer 34

FXTAS occurs in 8-16.5% of premutation carriers.

Question 35

What are the possible outcomes of a pregnancy for a female fragile X premutation carrier?

Answer 35

Each pregnancy may result in one of the following outcomes:

• normal male
• normal female
• male premutation/full mutation
• female premutation/full mutation

Prenatal diagnosis is possible via CVS but it is not able to predict the phenotype for females.

The risk of expansion to the full mutation depends primarily on the size of the premutation.

Question 36

What factor mainly determines the risk of expansion of a premutation to a full mutation?

Answer 36

Expansion to a full mutation may occur depending on the size of the premutation:

• 50-70 repeats = transmitted with little or no change.
• 70-79 repeats = 39% risk of expanding to FM.
• 80-89 repeats = 76% risk of expanding to FM.
• 90-99 repeats = 89% risk of expanding to FM.
• 100+ repeats = nearly 100% risk of expanding to FM.

Question 37

What is premature ovarian failure and what women are at increased risk?

Answer 37

Premature ovarian failure (POF) is a potential long term complication seen in females who carry a fragile X premutation. POF is cessation of menses before 40yr. The risk of POF is 25% or 1 in 5 in premutation carriers (with more than 35 repeats) compared to a 1% background risk. 6.5% of women with POF have a premutation in FMR1. 13% of women with a family history of POF will have a premutation compared to 3% of women without a family history of POF.

Question 38

True or false? An intermediate allele can expand to a full mutation in 1 generation.

Answer 38

False. By definition, only premutations can expand to full mutation range in one generation. Intermediate alleles will only cause effects in subsequent generations.

Question 39

What reproductive options are available to individuals with a family history of Fragile X?

Answer 39

• Do nothing
• Prenatal test
• Preimplantation genetic diagnosis
• Other IVF donor eggs or sperm
• Not possible to predict phenotype of female with full mutation

Question 40

Describe the testing strategy for Fragile X syndrome.

Answer 40

• Individuals of either sex with intellectual disability, developmental delay, or autism may be tested, especially if they have any physical or behavioural characteristics of fragile X syndrome, a family history of fragile X syndrome, or relatives with undiagnosed intellectual disability. (that may fit in with an X-inked pedigree).
• Males and females older than 50yrs who have progressive cerebellar ataxia and intention tremor with a positive family history of FMR1-related disorders whom other common causes of ataxia have been excluded should be tested.
• Women with unexplained POF should also be tested for fragile X syndrome.

Question 41

What is FRAXE?

Answer 41

• FRAXE is a second fragile site on the X chromosome caused by a GCC repeat in FMR2 on Xq28.
• FRAXE is less common (1 in 23,000 males carrying a full mutation).
• The FRAXE phenotype tends to be milder.
• FRAXE is usually only tested if the family history is suggestive of X-linked mental retardation and FRAXA testing has been negative.

Question 42

What is the incidence of the FRAXE mutation?

Answer 42

FRAXE is less common (1 in 23,000 males carrying a full mutation).

Question 43

Where is the FRAXE fragile site located?

Answer 43

FRAXE is a second fragile site on the X chromosome caused by a GCC repeat in FMR2 on Xq28.

Question 44

When may FRAXE be tested?

Answer 44

FRAXE is usually only tested if the family history is suggestive of X-linked mental retardation and FRAXA testing has been negative.

Question 45

Give the Fragile X allele sizes as updated in August 2015.

Answer 45

Normal: