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Fragile X-associated tremor/ataxia syndrome(FXTAS)

MedGen UID:
333403
Concept ID:
C1839780
Disease or Syndrome
Synonym: Fragile X tremor/ataxia syndrome
SNOMED CT: Fragile X associated tremor ataxia syndrome (448045004)
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Gene (location): FMR1 (Xq27.3)
 
Monarch Initiative: MONDO:0010382
OMIM®: 300623
Orphanet: ORPHA93256

Definition

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). 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. [from GeneReviews]

Additional descriptions

From OMIM
Jacquemont et al. (2007) provided a review of fragile X syndrome, which they characterized as a neurodevelopmental disorder, and FXTAS, which they characterized as a neurodegenerative disorder. Amiri et al. (2008) provided a review of FXTAS and noted that the pathogenesis of the disorder is distinct from that in fragile X syndrome. FXTAS results form a toxic gain of function of FMR1 RNA, whereas fragile X syndrome results from a loss of FMR1 function. The penetrance of FXTAS in male carriers aged 50 years and over, ascertained through families with a fragile X syndrome proband, is at least 33% (Hagerman and Hagerman, 2004); its penetrance in female carriers is approximately 5-10% (Greco et al., 2008).  http://www.omim.org/entry/300623
From MedlinePlus Genetics
Fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by problems with movement and thinking ability (cognition). FXTAS is a late-onset disorder, usually occurring after age 50, and its signs and symptoms worsen with age. This condition affects males more frequently and severely than females. Affected individuals have areas of damage in the part of the brain that controls movement (the cerebellum) and in a type of brain tissue known as white matter, which can be seen with magnetic resonance imaging (MRI). This damage leads to the movement problems and other impairments associated with FXTAS.

The characteristic features of FXTAS are intention tremor, which is trembling or shaking of a limb when trying to perform a voluntary movement such as reaching for an object, and problems with coordination and balance (ataxia). Typically, intention tremors will develop first, followed a few years later by ataxia, although not everyone with FXTAS has both features. Many affected individuals develop other movement problems, such as a pattern of movement abnormalities known as parkinsonism, which includes tremors when not moving (resting tremor), rigidity, and unusually slow movement (bradykinesia). In addition, affected individuals may have reduced sensation, numbness or tingling, pain, or muscle weakness in the lower limbs (peripheral neuropathy). Some people with FXTAS experience problems with the autonomic nervous system, which controls involuntary body functions, leading to the inability to control the bladder or bowel.

People with FXTAS commonly have cognitive disabilities. They may develop short-term memory loss and loss of executive function, which is the ability to plan and implement actions and develop problem-solving strategies. Loss of this function impairs skills such as impulse control, self-monitoring, focusing attention appropriately, and cognitive flexibility. Many people with FXTAS experience anxiety, depression, moodiness, or irritability.

Some women develop immune system disorders, such as hypothyroidism or fibromyalgia, before the signs and symptoms of FXTAS appear.  https://medlineplus.gov/genetics/condition/fragile-x-associated-tremor-ataxia-syndrome

Clinical features

From HPO
Bowel incontinence
MedGen UID:
41977
Concept ID:
C0015732
Disease or Syndrome
Involuntary fecal soiling in adults and children who have usually already been toilet trained.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Premature ovarian insufficiency
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Amenorrhea due to loss of ovarian function before the age of 40. Primary ovarian inssuficiency (POI) is a state of female hypergonadotropic hypogonadism. It can manifest as primary amenorrhea with onset before menarche or secondary amenorrhea.
Impotence
MedGen UID:
1720680
Concept ID:
CN208474
Finding
Inability to develop or maintain an erection of the penis.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Memory impairment
MedGen UID:
68579
Concept ID:
C0233794
Mental or Behavioral Dysfunction
An impairment of memory as manifested by a reduced ability to remember things such as dates and names, and increased forgetfulness.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Action tremor
MedGen UID:
65875
Concept ID:
C0234376
Sign or Symptom
A tremor present when the limbs are active, either when outstretched in a certain position or throughout a voluntary movement.
Postural tremor
MedGen UID:
66696
Concept ID:
C0234378
Sign or Symptom
A type of tremors that is triggered by holding a limb in a fixed position.
Resting tremor
MedGen UID:
66697
Concept ID:
C0234379
Sign or Symptom
A resting tremor occurs when muscles are at rest and becomes less noticeable or disappears when the affected muscles are moved. Resting tremors are often slow and coarse.
Dysdiadochokinesis
MedGen UID:
115975
Concept ID:
C0234979
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to perform rapidly alternating movements, such as pronating and supinating his or her hand on the dorsum of the other hand as rapidly as possible.
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Disinhibition
MedGen UID:
633911
Concept ID:
C0474398
Finding
Reduced ability to control, or a failure to resist a temptation, urge, or impulse. Examples include disregard for social conventions, general impulsivity, and poor risk assessment.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Diffuse cerebral atrophy
MedGen UID:
108958
Concept ID:
C0598275
Finding
Diffuse unlocalised atrophy affecting the cerebrum.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Obsessive-compulsive trait
MedGen UID:
322417
Concept ID:
C1834433
Finding
The presence of one or more obsessive-compulsive personality traits. Obsessions refer to persistent intrusive thoughts, and compulsions to intrusive behaviors, which the affected person experiences as involuntary, senseless, or repugnant.
Impaired distal vibration sensation
MedGen UID:
381262
Concept ID:
C1853767
Finding
A decrease in the ability to perceive vibration in the distal portions of the limbs.
Poor fine motor coordination
MedGen UID:
356863
Concept ID:
C1867864
Finding
An abnormality of the ability (skills) to perform a precise movement of small muscles with the intent to perform a specific act. Fine motor skills are required to mediate movements of the wrists, hands, fingers, feet, and toes.
Impaired tandem gait
MedGen UID:
476998
Concept ID:
C3275367
Finding
Reduced ability to walk in a straight line while placing the feet heel to toe.
Intention tremor
MedGen UID:
1642960
Concept ID:
C4551520
Sign or Symptom
A type of kinetic tremor that occurs during target directed movement is called intention tremor. That is, an oscillatory cerebellar ataxia that tends to be absent when the limbs are inactive and during the first part of voluntary movement but worsening as the movement continues and greater precision is required (e.g., in touching a target such as the patient's nose or a physician's finger).
Mask-like facies
MedGen UID:
140860
Concept ID:
C0424448
Finding
A lack of facial expression often with staring eyes and a slightly open mouth.
Hypothyroidism
MedGen UID:
6991
Concept ID:
C0020676
Disease or Syndrome
Deficiency of thyroid hormone.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Saccadic smooth pursuit
MedGen UID:
373096
Concept ID:
C1836479
Finding
An abnormality of tracking eye movements in which smooth pursuit is interrupted by an abnormally high number of saccadic movements.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFragile X-associated tremor/ataxia syndrome

Professional guidelines

PubMed

Hagerman R, Hagerman P
Curr Opin Neurol 2021 Aug 1;34(4):541-546. doi: 10.1097/WCO.0000000000000954. PMID: 33990099Free PMC Article
Spector E, Behlmann A, Kronquist K, Rose NC, Lyon E, Reddi HV; ACMG Laboratory Quality Assurance Committee
Genet Med 2021 May;23(5):799-812. Epub 2021 Apr 1 doi: 10.1038/s41436-021-01115-y. PMID: 33795824
Biancalana V, Glaeser D, McQuaid S, Steinbach P
Eur J Hum Genet 2015 Apr;23(4):417-25. Epub 2014 Sep 17 doi: 10.1038/ejhg.2014.185. PMID: 25227148Free PMC Article

Curated

Jacquemont S, Birnbaum S, Redler S, Steinbach P, Biancalana V
Eur J Hum Genet 2011 Sep;19(9) Epub 2011 May 4 doi: 10.1038/ejhg.2011.55. PMID: 21540884Free PMC Article

American College of Medical Genetics and Genomics Genetic Testing ACT Sheet, Fragile X [FraX] Syndrome, 2012

Recent clinical studies

Etiology

Flavell J, Franklin C, Nestor PJ
J Neuropsychiatry Clin Neurosci 2023 Spring;35(2):110-120. Epub 2022 Sep 29 doi: 10.1176/appi.neuropsych.21110282. PMID: 36172690
Zafarullah M, Tassone F
Methods Mol Biol 2019;1942:173-189. doi: 10.1007/978-1-4939-9080-1_15. PMID: 30900185
Hessl D, Grigsby J
Clin Neuropsychol 2016 Aug;30(6):810-4. Epub 2016 Jun 29 doi: 10.1080/13854046.2016.1186661. PMID: 27355274Free PMC Article
Leehey MA, Hagerman PJ
Handb Clin Neurol 2012;103:373-86. doi: 10.1016/B978-0-444-51892-7.00023-1. PMID: 21827901
Leehey MA
J Investig Med 2009 Dec;57(8):830-6. doi: 10.2310/JIM.0b013e3181af59c4. PMID: 19574929Free PMC Article

Diagnosis

Tassone F, Protic D, Allen EG, Archibald AD, Baud A, Brown TW, Budimirovic DB, Cohen J, Dufour B, Eiges R, Elvassore N, Gabis LV, Grudzien SJ, Hall DA, Hessl D, Hogan A, Hunter JE, Jin P, Jiraanont P, Klusek J, Kooy RF, Kraan CM, Laterza C, Lee A, Lipworth K, Losh M, Loesch D, Lozano R, Mailick MR, Manolopoulos A, Martinez-Cerdeno V, McLennan Y, Miller RM, Montanaro FAM, Mosconi MW, Potter SN, Raspa M, Rivera SM, Shelly K, Todd PK, Tutak K, Wang JY, Wheeler A, Winarni TI, Zafarullah M, Hagerman RJ
Cells 2023 Sep 21;12(18) doi: 10.3390/cells12182330. PMID: 37759552Free PMC Article
Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ
Int J Mol Sci 2020 Jun 20;21(12) doi: 10.3390/ijms21124391. PMID: 32575683Free PMC Article
Reches A
Methods Mol Biol 2019;1942:3-10. doi: 10.1007/978-1-4939-9080-1_1. PMID: 30900171
Hoem G, Koht J
Tidsskr Nor Laegeforen 2017 Oct 31;137(20) Epub 2017 Oct 30 doi: 10.4045/tidsskr.17.0317. PMID: 29094559

Therapy

Pagano G, Lyakhovich A, Pallardó FV, Tiano L, Zatterale A, Trifuoggi M
Mol Biol Rep 2024 Apr 5;51(1):480. doi: 10.1007/s11033-024-09415-7. PMID: 38578387Free PMC Article
Santos E, Clark C, Biag HMB, Tang SJ, Kim K, Ponzini MD, Schneider A, Giulivi C, Montanaro FAM, Gipe JT, Dayton J, Randol JL, Yao PJ, Manolopoulos A, Kapogiannis D, Hwang YH, Hagerman P, Hagerman R, Tassone F
Cells 2023 Dec 5;12(24) doi: 10.3390/cells12242773. PMID: 38132093Free PMC Article
Hessl D, Rosselot H, Miller R, Espinal G, Famula J, Sherman SL, Todd PK, Cabal Herrera AM, Lipworth K, Cohen J, Hall DA, Leehey M, Grigsby J, Weber JD, Alusi S, Wheeler A, Raspa M, Hudson T, Sobrian SK
J Med Genet 2022 Dec;59(12):1165-1170. Epub 2022 Jun 14 doi: 10.1136/jmedgenet-2022-108568. PMID: 35701103Free PMC Article
Birch RC, Cohen J, Trollor JN
Aust Fam Physician 2017;46(7):487-491. PMID: 28697292
Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N, Lachiewicz A, Kronk R, Delahunty C, Hessl D, Visootsak J, Picker J, Gane L, Tranfaglia M
Pediatrics 2009 Jan;123(1):378-90. doi: 10.1542/peds.2008-0317. PMID: 19117905Free PMC Article

Prognosis

Salcedo-Arellano MJ, Johnson MD, McLennan YA, Hwang YH, Juarez P, McBride EL, Pantoja AP, Durbin-Johnson B, Tassone F, Hagerman RJ, Martínez-Cerdeño V
Cells 2023 Aug 23;12(17) doi: 10.3390/cells12172132. PMID: 37681866Free PMC Article
Aishworiya R, Hwang YH, Santos E, Hayward B, Usdin K, Durbin-Johnson B, Hagerman R, Tassone F
Sci Rep 2023 Apr 29;13(1):7050. doi: 10.1038/s41598-023-33528-x. PMID: 37120588Free PMC Article
Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Valor LM, Morales JC, Hervás-Corpión I, Marín R
Int J Mol Sci 2021 Aug 4;22(16) doi: 10.3390/ijms22168368. PMID: 34445074Free PMC Article
Foote M, Arque G, Berman RF, Santos M
Cerebellum 2016 Oct;15(5):611-22. doi: 10.1007/s12311-016-0797-6. PMID: 27255703Free PMC Article

Clinical prediction guides

Coarelli G, Wirth T, Tranchant C, Koenig M, Durr A, Anheim M
J Neurol 2023 Jan;270(1):208-222. Epub 2022 Sep 24 doi: 10.1007/s00415-022-11383-6. PMID: 36152050Free PMC Article
Aishworiya R, Protic D, Hagerman R
J Neurol 2022 Sep;269(9):4676-4683. Epub 2022 Jun 20 doi: 10.1007/s00415-022-11209-5. PMID: 35723724
Foote M, Arque G, Berman RF, Santos M
Cerebellum 2016 Oct;15(5):611-22. doi: 10.1007/s12311-016-0797-6. PMID: 27255703Free PMC Article
Hagerman P
Acta Neuropathol 2013 Jul;126(1):1-19. Epub 2013 Jun 21 doi: 10.1007/s00401-013-1138-1. PMID: 23793382Free PMC Article
Baba Y, Uitti RJ
Curr Opin Neurol 2005 Aug;18(4):393-8. doi: 10.1097/01.wco.0000168332.99305.50. PMID: 16003114

Recent systematic reviews

Flavell J, Franklin C, Nestor PJ
J Neuropsychiatry Clin Neurosci 2023 Spring;35(2):110-120. Epub 2022 Sep 29 doi: 10.1176/appi.neuropsych.21110282. PMID: 36172690
Gohel D, Berguerand NC, Tassone F, Singh R
Biochim Biophys Acta Mol Basis Dis 2020 Dec 1;1866(12):165918. Epub 2020 Aug 12 doi: 10.1016/j.bbadis.2020.165918. PMID: 32800941
Artusi CA, Farooqi A, Romagnolo A, Marsili L, Balestrino R, Sokol LL, Wang LL, Zibetti M, Duker AP, Mandybur GT, Lopiano L, Merola A
J Neurol 2018 Nov;265(11):2473-2493. Epub 2018 Mar 6 doi: 10.1007/s00415-018-8823-x. PMID: 29511865Free PMC Article
Brown SS, Stanfield AC
J Neurol Sci 2015 May 15;352(1-2):19-28. Epub 2015 Mar 27 doi: 10.1016/j.jns.2015.03.031. PMID: 25847019
Birch RC, Cornish KM, Hocking DR, Trollor JN
Neuropsychol Rev 2014 Dec;24(4):491-513. Epub 2014 May 15 doi: 10.1007/s11065-014-9262-9. PMID: 24828430

Supplemental Content

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    Practice guidelines

    • PubMed
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      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics Genetic Testing ACT Sheet, Fragile X [FraX] Syndrome, 2012
    • EuroGenetest, 2011
      Clinical utility gene card for: fragile X mental retardation syndrome, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency.

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