Fmr1 Disorders

Allele Size

FMR1 alleles are categorized according to the number of 5' UTR CGG trinucleotide repeats and the methylation status of the repeat region. However, the distinction between allele categories is not absolute and must be made by considering both family history and repeat instability. The size boundary between intermediate and premutation categories listed below is not precise and caution is advised. See Table 3 for a summary of the types of FMR1 alleles and clinical status of individuals with expanded alleles.

Stability of alleles of fewer than 90 repeats is heavily influenced by the number of AGG interspersions within the CGG repeat sequence, both with respect to risk for size change in intermediate alleles and small premutations and expansion to a full mutation in premutation alleles larger than about 60 repeats [Nolin et al 2013, Nolin et al 2019]. This information should be utilized when appropriate for counseling families about expansion risk.

See Anticipation for detailed information on factors such as AGGs that influence FMR1 CGG repeat stability.

Normal alleles. Approximately 5-44 repeats

• Alleles of this size have little meiotic or mitotic instability and are typically transmitted without any increase or decrease in repeat number. However, some instability in normal repeats has been reported, with alleles that contain no AGG interspersions having a greater likelihood to be unstable [Nolin et al 2019].
• The population distribution of FMR1 repeat alleles shows the highest percentage of individuals with approximately 29-31 repeats; smaller but significant percentages cluster around 20 and 40 repeats.

Intermediate alleles (also termed "gray zone" or "borderline"). Approximately 45-54 repeats

• Intermediate alleles do not cause FXS. However, about 14% of intermediate alleles are unstable and may expand into the premutation range when transmitted by the mother [Nolin et al 2011]. They are not known to expand to full mutations; therefore, offspring are not at increased risk for FXS.
• Historically, the largest repeat included in the intermediate range has been 54; the use of 54 as the upper limit for normal alleles is a conservative estimate reflecting observations that transmission of alleles with 54 or fewer repeats from mothers to their offspring has not resulted in an affected individual to date. The conservative nature of the estimate also reflects potential imprecision (usually stated as ±2-3 repeats) in laboratory measurement of repeat number during diagnostic testing; however, to date no transmission of alleles with 55 or fewer repeats is known to have resulted in an affected individual [Nolin et al 2015, Nolin et al 2019].
  Note: Clinical laboratories performing FMR1 analysis typically state their estimated precision range when measuring intermediate alleles and usually report their estimates as ±2-3 repeats. Thus, it may be prudent to consider reported test results with 55 repeats as potential premutations. If the repeat precision estimate is not on the laboratory report, the laboratory should be contacted in order to determine if a result should be considered as a potential premutation.

Premutation alleles. Approximately 55-200 repeats

• Alleles of this size are not associated with FXS but do convey increased risk for FXTAS and FXPOI (Table 3). Because of potential repeat instability upon transmission of premutation alleles, women with alleles in this range are considered to be at risk of having children with FXS, although this risk is heavily dependent on the number of AGG interspersions for small premutation alleles [Nolin et al 2013, Nolin et al 2019].
  Note: The upper limit of the premutation range is sometimes noted as approximately 230. Both numbers (200 and 230) are estimates derived from Southern blot analysis, in which repeat size can only be roughly estimated.

Full-mutation alleles. More than 200 CGG repeats, with several hundred to several thousand repeats being typical and, in most cases, associated with aberrant hypermethylation of the FMR1 promoter. Almost always, extensive somatic variation of repeat number is observed in a peripheral blood specimen of an individual with a full mutation. As a result, clinical laboratories may report this somatic variation as a range of several hundred repeats.

FXTAS

Three levels are used to indicate the confidence of a diagnosis of FXTAS in individuals with an FMR1 premutation based on symptom manifestation at the time of the evaluation [Jacquemont et al 2003, Berry-Kravis et al 2007, Hagerman & Hagerman 2016, National Fragile X Foundation FXTAS Guideline]. The three diagnostic categories:

• Definite. Presence of one major radiologic sign plus one major clinical sign, or presence of FXTAS inclusions (characteristic ubiquitin-positive intranuclear inclusions within the nuclei of neurons and astrocytes)
• Probable. Presence of either one major radiologic sign plus one minor clinical sign, or two major clinical signs
• Possible. Presence of one minor radiologic sign plus one major clinical sign

Radiologic signs

• Major. MRI white matter lesions in middle cerebellar peduncles (MCP sign)
• Minor
  • MRI white matter lesions in cerebral white matter
  • Moderate-to-severe generalized brain atrophy
  • MRI white matter lesions in the splenium of the corpus callosum

Clinical signs

• Major
  • Intention tremor
  • Cerebellar gait ataxia
• Minor
  • Parkinsonism
  • Moderate-to-severe short-term memory deficiency
  • Executive function deficit
  • Neuropathy in lower extremities

Neuropathologic signs. A major criterion is FXTAS intranuclear eosinophilic inclusions that are ubiquitin positive.

FXPOI

Diagnostic criteria are based on hypergonadotropic hypogonadism in women younger than age 40 who carry a premutation allele. POI is diagnosed when a woman has (1) experienced four to six months of amenorrhea (absent menses) and (2) has two serum menopausal level FSH values obtained at least one month apart [Nelson 2009, Fink et al 2018].

See Published Guidelines / Consensus Statements.

Males with Fragile X Syndrome (Full-Mutation Alleles)

The phenotypic features of males with fragile X syndrome (FXS) vary in relation to puberty [Kidd et al 2014].

Prepubertal features

• Medical problems in infancy and childhood include hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Excessive softness and smoothness of the skin also have been noted.
• Normal growth is typical but large occipitofrontal head circumference (>50th percentile) is often seen.
• Delayed attainment of motor milestones and speech is apparent in the first several years of life. Developmental milestones (usual age of attainment in boys):
  • Sit alone (10 months)
  • Walk (20.6 months)
  • First clear words (20 months)
• Intellectual disability. The mean IQ has been reported as 40-45 with a range from less than 10 to within the normal range [Sansone et al 2014].
• Behavior is a prominent issue in males and some females with FXS of all ages. Behavior issues can include attention-deficit/hyperactivity disorder (ADHD) symptoms: hyperactivity, problems with impulse control, distractibility stereotypies such as hand flapping, tactile defensiveness, anxiety, shyness, poor eye contact (gaze aversion), perseverative speech, temper tantrums, irritability, aggression, and self-injurious behavior such as hand biting. The behaviors tend to evolve over time, becoming more obvious, with reduced responsiveness and activity sometimes seen in children before age two years, and then progressively increasing hyperactivity and ADHD symptoms with anxiety and irritable behaviors emerging (to varying degrees) during childhood [Berry-Kravis et al 2012].
• Autism spectrum disorder (ASD) is present in 50%-70% of individuals with FXS and when present, tends to be associated with more severe behavioral issues and an increased rate of seizures [Kidd et al 2019].
• Physical features involving the craniofacies (long face, prominent forehead, large ears, and prominent jaw) not readily recognizable in the preschool-age child become more obvious with age. Only a subset of affected individuals have typical physical features of FXS and presence of these is not reliable for diagnosis.

Postpubertal features

• Medical problems including mitral valve prolapse and aortic root dilatation have been noted, most commonly in adults with FXS.
• Anxiety and irritable/aggressive behavior may increase during or after puberty. Anxiety, including social phobia and specific phobias, anticipatory anxiety, performance anxiety, and separation anxiety, as well as generalized anxiety, is very common in FXS and often disabling, having been reported by caregivers as the most disabling problem for individuals with FXS [Weber et al 2019].
• Macroorchidism may be obvious earlier in childhood but is identified in essentially all males after completion of puberty.

Females with FXS (Heterozygous for Full-Mutation Alleles)

The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the full mutation, but with lower frequency and milder involvement [Bartholomay et al 2019].

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

FXTAS is characterized by late-onset progressive cerebellar ataxia and intention tremor in persons who have an FMR1 premutation [Hagerman & Hagerman 2016].

Onset is typically between ages 60 and 65 years. The age of onset and progression of symptoms of FXTAS vary significantly among individuals. Both age of onset and disease severity are related to repeat length, sex, and other features.

The first sign of FXTAS is typically tremor followed by ataxia and cognitive impairment [Bourgeois 2016, Hall & Berry-Kravis 2018].

• Ataxia can lead to gait and postural instability with most individuals needing a walking aid within ten years of diagnosis.
• Cognitive impairment typically starts with executive function impairment and expands to other domains such as working memory and information processing speed. Almost half of individuals with FXTAS meet criteria for dementia.

Other findings include short-term memory loss, parkinsonism, peripheral neuropathy and neuropathic pain, lower-limb proximal muscle weakness, and autonomic dysfunction [Hagerman & Hagerman 2016, Hall et al 2016].

Psychiatric disorders are common and include anxiety, irritability, agitation, hostility, obsessive-compulsive disorder, apathy, and depression [Seritan et al 2013].

Both males and females with a premutation are at risk for FXTAS. Increasing premutation repeat lengths correlate with increasing likelihood of developing FXTAS [Tassone et al 2007, Leehey et al 2008]. The penetrance in individuals older than age 50 years is lower in females (16.5%) than in males (45.5%) [Rodriguez-Revenga et al 2009].

Males. The prevalence of FXTAS is estimated at approximately 40% overall for males with a premutation who are older than age 50 years [Hagerman & Hagerman 2016]. Penetrance in males is related to age (see Table 2) and repeat length.

Females. While FXTAS is more difficult to ascertain in females because of milder clinical presentation, prevalence estimates range from approximately 16% to 20% of female premutation heterozygotes [Hagerman & Hagerman 2016].

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population [Sherman 2000].

• Ovarian insufficiency has occurred as early as age 11 years and can present with primary amenorrhea and delayed puberty.
• Women with FXPOI have high rates of infertility and menopausal-type symptoms, including vasomotor symptoms, mood changes, and vaginal dryness.
  • In contrast to menopause, ovarian function in women with POI is more erratic and unpredictable, so that some women continue to have irregular ovulation and menses for years after diagnosis. Some women are completely amenorrheic.
  • The diagnosis of POI does not eliminate the possibility of subsequent conception. It is estimated that up to 12.6% of women conceive after a diagnosis of FXPOI [Hipp et al 2016]. See Fink et al [2018] for a review.
• Women with FXPOI are at risk of long-term health sequelae from a hypoestrogenic environment. These include osteoporosis and cardiovascular disease.
• Women with POI (including those with FXPOI) are at increased risk of developing thyroid disease.

The earlier findings that alleles in the high normal and intermediate range conferred an increased risk for FXPOI [Bretherick et al 2005, Bodega et al 2006] have not been supported by more recent robust studies [Voorhuis et al 2014, Schufreider et al 2015].

Women with full-mutation alleles are not at increased risk for FXPOI, nor do they have signs of diminished ovarian reserve [Avraham et al 2017].

Other Fragile X-Associated Phenotypes

In addition to FXTAS and FXPOI, the following have been reported in the literature (see Wheeler et al [2017] for a review):

• Cognitive and behavioral challenges. Preliminary studies of the correlation of FMR1 allele size variations in the normal and premutation range suggested a possible relationship to mild intellectual disability in females [Allen et al 2005] and males [Loat et al 2006, Hagerman et al 2009]. Evidence also suggested an increased risk for autism spectrum disorder [Farzin et al 2006, Hagerman et al 2009] and neurodevelopmental diagnoses in individuals with a premutation [Bailey et al 2008, Renda et al 2014]. However, findings across studies have been contradictory, with some studies biased by assessment of individuals who had been clinically referred. Thus, additional studies are needed.
• Neuropsychiatric issues. Increased rates of anxiety, depression, and ADHD have been reported. Social phobia and social anxiety have also been reported. However, many studies on mental health outcomes are limited to women with a premutation who are mothers of children with FXS; thus, findings are likely confounded by the impact of elevated maternal stress on mental health [Wheeler et al 2017], though some studies have indicated that the premutation confers a heightened susceptibility to stress and dysregulation of the hypothalamic-pituitary axis [Hartley et al 2012, Seltzer et al 2012].
  The term "fragile X-associated neuropsychiatric disorders" (FXAND) has been proposed to promote research into fully characterizing neuropsychiatric outcomes associated with the premutation allele [Hagerman et al 2018].
• Medical findings. Some studies have reported elevated rates of hypertension, hypothyroidism, fibromyalgia, migraines, insomnia, sleep apnea, restless leg syndrome, central pain sensitivity syndrome, and autoimmune disorders in individuals with a premutation compared to those without a premutation [Hagerman & Hagerman 2016]. However, these findings differ by investigator (reviewed in Wheeler et al [2014]). Unfortunately, most studies have been focused on women with a premutation and are based on questionnaires and chart reviews rather than objective medical examinations, which has created inconsistencies between research groups. Thus, the generalizability of these findings is unclear.
  Elevated rates of neurologic findings, such as tremor and ataxia, have been reported in individuals with premutations who do not meet diagnostic criteria of FXTAS. A study of 110 daughters of men with FXTAS demonstrated an increased incidence of neurologic and psychiatric symptoms compared to controls, providing more evidence for such an association [Chonchaiya et al 2010].