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Diagnosis

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Molecular genetic testing of the FMR1 gene is the primary method of diagnosis. Uses include:

  • Confirmation of diagnosis in children with unexplained speech, language or motor delay; intellectual disability; and/or autism
  • Prenatal diagnosis in pregnant women with a positive family history. See Risk Assessment for more information.

More information about the uses of molecular testing of FMR1

  • Evaluation of possible Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) in women with menopause prior to age 40.
  • Confirmation of diagnosis of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) in individuals over 50 years of age with movement disorders.
  • Screening of unaffected relatives to assess reproductive risks and risk of FXPOI and FXTAS. See Risk Assessment section for more information.

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Algorithm

See Diagnostic Algorithm for FMR1-Related Conditions

Diagnostic Testing and Evaluation

Diagnostic Criteria

Identification of a loss-of-function mutation in the FMR1 gene (see Genetics section) is sufficient to diagnose fragile X syndrome in an individual exhibiting developmental delay or intellectual disability.

Fragile X-Associated Premature Ovarian Insufficiency (FXPOI)

Diagnostic criteria for FXPOI

Menopause before age 40 years in a woman who has one FMR1 premutation allele (55-200 trinucleotide repeats)

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Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

Diagnostic criteria for FXTAS

  • A definite diagnosis of FXTAS requires the presence of a premutation in FMR1 (55-200 trinucleotide repeats) and white matter lesions on MRI in the middle cerebellar peduncles and/or brain stem with either intention tremor or gait ataxia.
  • A probable diagnosis of FXTAS requires either one major neuroradiologic sign and one minor clinical sign or two major clinical signs.
  • A possible diagnosis of FXTAS is based on one minor neuroradiologic sign and one major clinical sign
Major diagnostic criteria

Neuroradiologic

  • Premutation in FMR1 (55-200 trinucleotide repeats) and white matter lesions on MRI in the middle cerebellar peduncles and/or brain stem

Clinical

  • Intention tremor
  • Gait ataxia
Minor diagnostic criteria

Neuroradiologic

  • MRI white matter lesions in the cerebral white matter
  • Moderate to generalized atrophy

Clinical

  • Parkinsonism
  • Moderate to severe working memory deficits
  • Executive cognitive function deficits

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First Steps

  1. History and evaluation of development, behavior, and cognitive function.
  2. Targeted family history for features of the condition and related FMR1 disorders (see Risk Assessment section).
  3. Molecular genetic testing.

More information about importance of diagnosis

Diagnosis is often delayed due to absence of stereotypic features prior to adolescence. Earlier diagnosis can significantly impact management, family adaptation, and reproductive decision-making. Screening checklists have been used to identify individuals who may benefit from molecular testing.

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Testing Strategy

  • Targeted mutation analysis to the trinucleotide repeat region of FMR1. (See Genetics section for more information on trinucleotide repeats.)
  • If this testing is normal and family history or clinical findings are very suspicious for Fragile X, consider referral to genetics professional. (See Genetics section for more information on the genetic variants associated with fragile X syndrome.)

(See Risk Assessment/Screening section for information on testing strategy in at-risk relatives.)

Tests that are NOT Helpful

  • Chromosome analysis with specialized culture techniques to identify fragile sites is no longer used to rule out fragile X syndrome, due to expense and low sensitivity.
  • SNP microarrays used to detect genetic variations associated with developmental disability are NOT sensitive for Fragile X.
  • Neuroimaging is of limited utility in diagnosis or management of Fragile X syndrome, but may be indicated in evaluation for Fragile X-Associated Tremor/Ataxia Syndrome.

Subsequent Evaluation

None

Lifestyle/Environmental Contributors to Disease

No specific information available.

Differential Diagnosis

Fragile X Syndrome

Developmental delay/intellectual disability/behavioral issues differential

  • Other chromosome abnormalities
  • Sotos syndrome
  • Prader-Willi syndrome
  • Other causes of autism
  • Other causes of ADHD Attention problems and hyperactivity are frequent in individuals with fragile X syndrome.
  • Fragile XE syndrome (FRAXE)

Fragile X-Associated Premature Ovarian Insufficiency (FXPOI)

Premature ovarian insufficiency differential.>>

  • Other chromosomal abnormalities
  • Turner syndrome
  • Congenital disorders of glycosylation (CDG, formerly named carbohydrate-deficient glycoprotein syndromes) (recessive)
  • Galactosemia (recessive)
  • Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) (female-limited, dominant)
  • Pseudohypoparathyroidism (PHP) type Ia (parental imprinting : maternal inheritance)
  • Follicle stimulating hormone (FSH) receptor mutations (FSHR), (recessive)
  • Luteinizing hormone (LH) receptor mutations (LHR), (recessive)
  • Bone morphogenetic protein 15 (BMP15) mutations (female-limited defect, heterozygous mutation)
  • Iatrogenic origin (surgery, chemotherapy, radiations);
  • Autoimmune
  • Infections (e.g. herpes zoster, cytomegalovirus)
  • Idiopathic

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Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS)

Tremor/ataxia differential>>

  • Other genetic ataxia syndromes (e.g., Friedreich ataxia, ataxia-telangiectasia, spinocerebellar ataxia)
  • Stroke or transient ischemic attack TIA (posterior circulation), brain trauma
  • Tumor or abscess of posterior fossa
  • Toxins (e.g., lead, anticonvulsants, salicylates, aminoglycosides, sedatives, alcohol)
  • Infection (e.g., viral encephalitis, HIV, Creutzfeldt-Jacob Disease)
  • Multiple Sclerosis
  • Paraneoplastic Disorder: Breast, Lung, Ovarian, Uteriane, or cervical cancers
  • Vit. E deficiency
  • Miller-Fischer Syndrome (variant of Guillain-Barre Syndrome)

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Consensus Statements and Guidelines

American College of Medical Genetics Professional Practice and Guidelines Committee . A brief overview of the condition and recommendations for use of DNA testing in screening and diagnosis of fragile X:

  • Sherman S, Pletcher BA, Driscoll DA. 2005. Fragile X syndrome: diagnostic and carrier testing. Genet Med, 7: 584-587. [ PubMed]
  • Kronquist KE, Sherman SL, Spector EB. Clinical significance of tri-nucleotide repeats in Fragile X testing: a clarification of American College of Medical Genetics guidelines. Genet Med. 2008;10:845–7. [PubMed]

National Society of Genetic Counselors. A brief overview of the condition and educational, psychosocial, testing and decision-making considerations:

  • Finucane B, Abrams L, Cronister A, Archibald AD, Bennett RL, McConkie-Rosell A. Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors. J Genet Couns. 2012 Dec;21(6):752 [PubMed]

American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol. 2010 Oct;116(4):1008-10. [ PubMed]

Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG) . Discussion of testing practices in the prenatal setting:

  • Chitayat D et al. Fragile X testing in obstetrics and gynaecology in Canada. J Obstet Gynaecol Can. 2008;30:837–46. [ PubMed]