Fragile X Syndrome: Comprehensive Guide

Overview

Fragile X Syndrome is the most common cause of inherited cognitive retardation and occurs in approximately 1/4000 males. Fragile X syndrome occurs with hypermethylation in the FMR1 (Fragile X Mental Retardation 1) gene and an increase in CGG repeat number.

Genetic Foundations

Fragile X mental retardation protein (FMRP) is a major regulatory protein in many mRNA translations, including synaptic plasticity. FMRP loss causes many changes including altered synaptic function and altered dendritic morphology.

Clinical Symptoms

Morphological Features

• Macrocephaly (large head)
• Long face and prominent forehead
• Prominent ears
• Joint laxity
• Macroorchidism (large testes)

Behavioral Features

• Hyperactivity
• Anxiety
• Tactile defensiveness
• Avoidance of eye contact
• Socialization difficulties
• Repetitive speech

Fragile X syndrome can present with a wide variety of symptoms ranging from normal function to moderate and severe cognitive retardation.

Autism Spectrum Disorder Relationship

While it has been reported that 60% of males with Fragile X syndrome have a comorbid diagnosis of autism spectrum disorder (ASD), some studies suggest that 86.4% of males and 61.7% of females meet the DSM-5 criteria for “restricted-repetitive interests and behaviors”, but only 29.4% of males and 13% of females meet the criteria for social communication and interaction disorder.

In Fragile X syndrome, restricted-repetitive behaviors and interests may be related to intellectual development problems. Detection and differential diagnosis of ASD symptoms in children with cognitive retardation may be difficult.

Epilepsy and Neurological Findings

Epilepsy Frequency

Epilepsy has been reported in 10-20% of those with Fragile X syndrome, most commonly complex partial seizures. Seizures are usually easily controlled in childhood.

EEG Findings

Slowed background activity and multifocal EEG abnormalities are observed on EEG. The frequent seizure/EEG pattern in Fragile X syndrome is similar to benign centrotemporal spike epilepsy.

Status Epilepticus

In a study published by Gauthey et al., they reported detecting status epilepticus in their patients with Fragile X syndrome (five patients). Patients presented with status epilepticus at their first seizure and prolonged seizures were detected in some during follow-up.

While prolonged seizures have been reported in Fragile X syndrome, status epilepticus is rare. During follow-up, refractory epilepsy did not develop in these patients and only rare additional seizures were observed.

Pathophysiological Mechanisms

Epilepsy is one of the frequent reasons for presentation in Fragile X syndrome. Various mechanisms are responsible for this. In Fragile X mouse models, low GABAa production and high glutamic acid decarboxylase production have been observed in the hippocampus, diencephalon, and brainstem.

Inhibition-Excitation Imbalance

This imbalance in the inhibition-excitation system may cause seizure development. This imbalance may begin in the first 6 months of life but usually does not lead to seizures before 2 years of age. Epileptic seizures are rare in patients with Fragile X syndrome, but EEG abnormalities may become severe several years later.

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