Fragile X Syndrome

📖 Overview

Fragile X Syndrome is the most common inherited cause of intellectual disability and the most common known single-gene cause of autism spectrum features. It is caused by a mutation in the FMR1 gene on the X chromosome — specifically an expansion of a CGG repeat sequence that silences the gene and prevents production of FMRP, a protein essential for normal brain development and function.

THE GENETICS OF FRAGILE X

Full Mutation
A CGG repeat count above 200 causes full Fragile X Syndrome. The FMR1 gene is silenced (methylated) and FMRP is not produced. This causes the characteristic intellectual disability and associated features.

Premutation
A CGG repeat count of 55-200 is called a premutation. Premutation carriers do not have Fragile X Syndrome but are at risk of two associated conditions: Fragile X-associated tremor/ataxia syndrome (FXTAS) in older males — a progressive neurological condition causing tremor, ataxia, cognitive decline, and autonomic dysfunction; and Fragile X-associated primary ovarian insufficiency (FXPOI) in females — premature ovarian failure causing early menopause and fertility difficulties.

Premutation carriers may also have milder cognitive, emotional, and social features — anxiety, social difficulties, and executive function differences are more common in premutation carriers than the general population.

X-LINKED INHERITANCE
Because the FMR1 gene is on the X chromosome, Fragile X affects males and females differently. Males have one X chromosome — if it carries the full mutation, they will have Fragile X Syndrome. Females have two X chromosomes — if one carries the mutation, the other X can partially compensate. This is why males with Fragile X are typically more significantly affected than females.

Female carriers of the full mutation have a highly variable presentation — some have significant intellectual disability and autistic features, others have very mild or no learning difficulties. The degree of activation of the normal X chromosome in each cell (X-inactivation) determines the impact.

INTELLECTUAL DISABILITY IN FRAGILE X
Males with Fragile X typically have moderate intellectual disability. Language, memory, and adaptive functioning are affected. Verbal abilities are often relative strengths compared to visual-spatial and abstract reasoning. Short-term memory and sequential processing are particularly affected.

Females with the full mutation may have intellectual disability, but many have functioning in the borderline or low average range with specific learning difficulties rather than global intellectual disability.

AUTISM FEATURES IN FRAGILE X
Approximately 30-50% of males with Fragile X meet diagnostic criteria for autism. Autistic features in Fragile X include: poor eye contact (gaze aversion is a distinct Fragile X feature as well as an autistic one), social anxiety, repetitive behaviours, sensory sensitivities, and communication differences.

ADHD features are very common — attention difficulties, hyperactivity, and impulsivity affect the majority of males with Fragile X.

THE ANXIETY PROFILE
Anxiety is a hallmark of Fragile X and is central to understanding the behaviour and support needs. Sensory hypersensitivity, social anxiety, anxiety about transitions and change, and generalised anxiety are significant for most people with Fragile X. Hand-flapping and hand-biting are often anxiety expressions as much as stimming.

Anxiety management — through environment, routine, low-demand approaches, and where appropriate medication — is central to effective support.

PHYSICAL FEATURES
In males after puberty, characteristic physical features include: long face, large prominent ears, high arched palate, macroorchidism (enlarged testes), and joint hypermobility. These features are not usually obvious in young children and should never be used as the basis for screening.

FAMILY IMPLICATIONS
Fragile X has significant implications for the extended family. The mutation is inherited through carrier females. Sisters of a carrier mother have a 50% chance of being carriers themselves. Genetic counselling for the whole family is important — aunts, grandmothers, and female cousins may be premutation carriers who are at risk of FXPOI and whose children are at risk of Fragile X.