Fragile-X premutation associated conditions

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Fragile-X premutation associated conditions (FXPAC) are a wide range of conditions that affect individuals who carry a fragile-X premutation (and occasionally, intermediate allele carriers). They are associated with carrying premutations on the FMR1 gene.

Traditionally, fragile-X premutation carriers were not thought to have any clinical involvement, but this has since been proven false.

Types

Types of FXPAC include:

• fragile-X associated premature ovarian insufficiency, FXPOI (formerly fragile-X associated primary ovarian failure)
• fragile-X associated ataxia/tremor syndrome, FXTAS
• fragile-X associated neuropsychiatric conditions, FXANC

FMR1 premutation carriers may also display subtle features of fragile-X syndrome such as joint hypermobility or long ears.

Fragile-X associated premature ovarian insufficiency

Fragile-X associated premature ovarian insufficiency (FXPOI) refers to a spectrum of ovarian dysfunction in FMR1 premutation carriers, ranging from delayed puberty to slightly early menopause. This results, frequently, in difficulties getting pregnant.

It is the most common known genetic cause of POI.

The effects of POI lead to estrogen deficiency which may lead to:

• osteoporosis or otherwise reduced bone density
• hot flashes
• earlier onset of coronary artery disease
• possibly increased vulnerability to mood disorders

Fragile-X associated tremor/ataxia syndrome

Fragile-X associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegeneration that shows a male predominance.

Females with FXTAS are likely to have a later onset and a relatively milder progression.

FXTAS has a penetrance that increases with age.

As the name suggests, FXTAS is characterised by gait ataxia and intention tremor.

The major symptoms are:

• intention tremor
• gait ataxia
• MCP signs on an MRI (although not unique to FXTAS)

And minor symptoms include:

• executive dysfunction
• other MRI findings
• dysautonomia
• psychiatric problems
• peripheral neuropathy
• dementia

The progression of FXTAS varies widely from person to person and the reasons for this are unclear.

Occasionally, those with FXTAS can present with parkinsonism although this is often minimally responsive to dopamine, and may even be exacerbated by it.

Fragile-X associated neuropsychiatric conditions

Often those with a fragile-X premutation will have mild differences in cognition. For example, infants with an FMR1 premutation have been found to have greater sensory sensitivity as well as weaknesses in visuospatial activities.

However, some individuals with FMR1 premutations meet the diagnosis for neuropsychiatric conditions and these include:

• increased rates of neurodevelopmental conditions:
  • diagnoseable autism or ADHD
  • broader autism phenotype
  • epilepsy
  • intellectual disability
• increased rates of psychiatric conditions:
  • most notably, anxiety (particularly social anxiety)
  • as well as depression
  • substance abuse (especially in those with chronic pain that may be a manifestation of another FXPAC)
  • psychotic disorders

Cause

Fragile-X premutation associated conditions are known to be related to carrying a premutation on the FMR1 gene, on chromosome

The presence of the gene on the X chromosome means that males tend to be more affected than females, who generally have another X chromosome to compensate for the one carrying the mutated FMR1 allele. However, the degree to which a female is affected depends on the proportion of expressed X chromosomes carrying the mutated allele are expressed (determined by lyonisation).

This gene contains trinucleotide (CGG) repeats in one of its non-coding regions. The numbers of repeats present varies from individual to individual.

When repeats are above a certain threshold, they can cause the fragile-X premutation or full mutation.

The number of repeats can be classified into one of four categories:

• common alleles (<40 CGG repeats)
• intermediate, or gray-zone alleles (45-54 CGG repeats)
• premutation alleles (55-200 CGG repeats)
• full mutation alleles, which give rise to fragile-X syndrome (>200 CGG repeats)

However, the boundaries for a given allele vary from definition to definition.

The exact way that the FMR1 premutation causes FXPACs is unclear but there are theories as to their mechanisms. For example, FXTAS may be the result of RNA toxicity (such as in type 1 myotonic dystrophy) aggregating in the brain and forming inclusions.

The causes of most of these conditions are thought to be distinct from fragile-X syndrome, which has its symptoms caused by decreased to absent FMRP.

And whilst the exact pathogenesis of any of these conditions is unclear, it is known that environmental toxicity is known to decrease the age of onset of FXTAS (and FXPOI to an extent). These include:

• general anesthesia
• illicit drugs
• chemotherapy
• alcohol
• smoking

Managements and Treatments

As the mechanisms of these conditions are unclear, treatments currently focus on managing symptoms and improving the quality of life of these individuals. These may include:

• talking therapies for psychiatric conditions
• pain management
• medications for psychiatric conditions (eg. stimulants for ADHD)
• mobility aids

They can also focus on slowing the progression of these conditions if they are progressive.

Naming

The title of the article is 'fragile-X premutation associated conditions' to acknowledge the views of many individuals who these affect.

Many of these people felt that describing these conditions as 'disorders' created stigma around things that are often part of the general human experience, such as depression.

Most articles will continue to refer to these conditions as 'fragile-X premutation associated disorders'.

Fragile-X premature ovarian insufficiency was previously named fragile-X primary ovarian failure but is no longer referred to as such as people with the condition can, and do, become pregnant, indicating dysfunction, or insufficiency, rather than failure.

References

This article "Fragile-X premutation associated conditions" is from Wikipedia. The list of its authors can be seen in its historical and/or the page Edithistory:Fragile-X premutation associated conditions. Articles copied from Draft Namespace on Wikipedia could be seen on the Draft Namespace of Wikipedia and not main one.

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