Clinical Guidance

The phenotype of males with an FMR1 pathogenic variant depends almost entirely on the nature of the variant; the phenotype of females with an FMR1 pathogenic variant depends on both the nature of the FMR1 variant and random X-chromosome inactivation .

Table 3.

Types of FMR1 Repeat Expansion Pathogenic Variants

Variant Type | # of CGG Trinucleotide Repeats | Methylation Status of FMR1 | Clinical Status

Male | Female

Premutation

| ~55-200 | Unmethylated | At risk for FXTAS1 | • At risk for FXPOI FXTAS

• Potential risk of other fragile X-assoc disorders1

Full mutation

| 200 | Completely methylated | 100% have ID. | ~50% w/ID, ~50% normal intellect

Repeat size mosaicism

| Varies between premutation full mutation in different cell lines | Partial: unmethylated in premutation cell line; methylated in full-mu...

Source: GeneReviews — "FMR1 Disorders"

Diagnostic Criteria

Suggestive Findings

FMR1 disorders should be considered in individuals with the following clinical and associated findings.

Fragile X syndrome (FXS)

• Males and females with intellectual disability or developmental delay of unknown cause

• Males with unexplained autism spectrum disorder and females with unexplained autism spectrum disorder and the presence of an additional indicator: phenotype compatible with FXS; family history of X-linked neurodevelopmental disorders; or premature ovarian failure, ataxia, or tremors in close relatives

Fragile X-associated tremor/ataxia syndrome (FXTAS)

Source: GeneReviews — "FMR1 Disorders"

Differential Diagnosis

Developmental delay/ intellectual disability (DD/ID). The signs of fragile X syndrome (FXS) in early childhood are nonspecific, with DD being an almost universal manifestation among affected individuals. Any child (male or female) with delay of speech, language, or motor development of unknown etiology should be considered for fragile X testing, especially in the presence of a family history of ID and a consistent physical and behavioral phenotype, and the absence of structural abnormalities of the brain or other birth defects . When fragile X molecular genetic testing is used regularly in this large and loosely defined group of unselected males with ID, the yield of positive test results is relatively low (~3%-6%) . In a more recent study, found the yield to be 1.2%. Because chromosome abnormalities and copy number variants have been identified as frequently or more frequently than FMR1 pathogenic variants in individuals with DD or ID who are referred for fragile X testing, microarray testing should be performed as a part of the laboratory evaluation . Conditions to be considered in the differential diagnosis of FXS include those summarized in . Table 5. Disorders to Consider in the Differential Diagnosis of Fragile X Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an FMR1 disorder, the evaluations summarized in phenotype-specific , , and (if not performed as part of the evaluation that led to diagnosis) are recommended. For all phenotypes, consultation with a clinical geneticist and/or genetic counselor is recommended. Table 6. Fragile X Syndrome: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "FMR1 Disorders"

Clinical Guidance

FXTAS. Affected individuals should avoid the following:

• Typical and atypical antipsychotics with significant anti-dopaminergic effects, which can exacerbate parkinsonism

• Metoclopramide, which can exacerbate parkinsonism

• Anticholinergic agents, which can exacerbate cognitive complaints

• Excessive alcohol, which can increase cerebellar dysfunction and postural instability

• Agents with known cerebellar toxicity or side effects (use with caution)

FXPOI. Affected individuals should avoid tobacco products. Tobacco use decreases ovarian reserve and the age of onset of FXPOI. Women who are smokers have, on average, POI onset five years earlier than nonsmokers .

Source: GeneReviews — "FMR1 Disorders"

Therapies Under Investigation

There are multiple ongoing trials of medication for behavior or drugs targeting the underlying neurobiological mechanism of fragile X syndrome (FXS) based on animal model studies. For example:

Source: GeneReviews — "FMR1 Disorders"

Surveillance Guidelines

Table 11. Recommended Surveillance for Individuals with Fragile X Syndrome

Source: GeneReviews — "FMR1 Disorders"