Dr Sherel Levy ( left ) GP ; researcher in vitamin D , bone metabolism and child development , Sydney Children ’ s Hospitals Network ( SCHN ), Westmead , NSW .

Associate Professor Natalie Silove ( right ) Developmental paediatrician ; senior lecturer , University of Sydney ; head of the child development services , Sydney Children ’ s Hospitals Network ( SCHN ), Westmead , NSW .

First published online on 26 January 2024

BACKGROUND

FRAGILE X syndrome ( FXS ), an

X-linked neurodevelopmental disorder

, is the leading inherited cause of intellectual developmental disorder ( IDD , previously known as intellectual disability ). The condition is the second most common cause of intellectual developmental disorder after Down syndrome . FXS is also the leading single gene cause of autism spectrum disorder ( ASD ). 1-3

FXS is a multisystem disorder caused by mutations in the FMR1 gene . The resulting clinical presentations include physical , developmental , neuropsychiatric and behavioural abnormalities . 4 Males with FXS typically present in the first two years of life with speech , language and developmental delay , together with behavioural presentations , which may include sensory disorders , learning disabilities , anxiety , ASD and attention deficit hyperactivity disorder ( ADHD ). 3 The presentation in females may be milder , with many attaining a higher level of independence and quality of life compared with males with FXS . Females with FXS frequently present with learning disabilities , socio-emotional difficulties and mental health

issues . 5 Females are frequently treated for the specific developmental issues ( anxiety or language impairments ) but not tested for FXS . This results in a lost opportunity for best care and support for the individual and may have major consequences for family planning . 5 This How to Treat discusses fragile X syndrome , its clinical presentation and management , and aims to ensure GPs can recognise it early and provide well informed , evidenced-based interventions , support and guidance to affected individuals and their families .

GENETICS

FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein , or FMRP , which is critical for neuronal maturation and functioning . Under normal circumstances , the cytosine-guanine-guanine ( CGG ) trinucleotide triplet repeat is 5-45 , resulting in normal production and functioning of the protein .

In FXS , the mutation presents as an expansion of a CGG sequence , to more than 200 repeats (‘ full mutation expansion ’, and therefore methylation ), in the 5 ’ non-coding region of the FMR1 gene on the X chromosome

( see figure 1 ). DNA methylation is an epigenetic process by which methyl groups are added to the DNA molecule , changing the activity of a DNA segment without changing the sequence . In FXS , the methylation results in FMR1 gene silencing and the absence of the FMRP protein encoded by this gene . 4

In the absence of FMRP , synaptic dysfunction affecting multiple signalling pathways occurs , resulting in enhanced neuronal excitability and decreased inhibitory signalling mechanisms . These deficits result in the cognitive and behavioural deficits seen in FXS . 1 , 4

Those who have greater than 200 CGG repeats have a full mutation with the repeat region being hypermethylated . Those who have 55-200 CGG repeats are classified as having a fragile X premutation and are usually unmethylated . 5 For unknown reasons , the premutation leads to the overproduction of abnormal FMR1 mRNA that contains the expanded repeat region . As a result , premutation carriers may present with specific learning difficulties , anxiety , shyness , attention deficit issues , prominent ears , fragile X-associated primary ovarian insufficiency

and fragile X-associated tremor / ataxia syndrome . 6

Because the FMR1 gene is located on the X chromosome , fathers with a premutation will pass on their premutation to all their daughters and not their sons ( to whom they pass on their Y chromosome ). The premutation remains stable in the transmission from father to daughter . In contrast , there is a 50 % chance of a mother passing on her affected X chromosome equally to her sons and daughters ( see figure 2 ). 6 Furthermore , for presently unknown reasons , there is a risk of this premutation expanding to a full mutation in the transition from mother to child ( although it can also remain stable for generations without expanding ). 3

The FMRP levels are a key factor in the severity of the presentation . 7 Males with a full mutation will always present with the symptoms of FXS , with intellectual impairment ranging from mild to severe and associated developmental and behavioural issues . In contrast , because girls have two X chromosomes , the affected chromosome may be the one to be randomly inactivated , and therefore they may have variable amounts of FMRP