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Fragile X tremor/ataxia syndrome(FXTAS)

MedGen UID:
333403
Concept ID:
C1839780
Disease or Syndrome
Synonyms: FMR1-Related Disorders; Fragile X-Associated Tremor/Ataxia Syndrome; FXTAS
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM, 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.
X-linked dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Fragile X associated tremor ataxia syndrome (448045004)
 
Gene (location): FMR1 (Xq27.3)
OMIM®: 300623

Disease characteristics

Excerpted from the GeneReview: FMR1-Related Disorders
FMR1-related disorders include fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS), and FMR1-related primary ovarian insufficiency (POI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function mutation and is nearly always characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Because FMR1 mutations are complex alterations involving non-classic gene-disrupting alterations (trinucleotide repeat expansion) and abnormal gene methylation, affected individuals occasionally have an atypical presentation with an IQ above 70, the traditional demarcation denoting intellectual disability (previously referred to as mental retardation). Males with an FMR1 full mutation accompanied by aberrant methylation may have a characteristic appearance (large head, long face, prominent forehead and chin, protruding ears), connective tissue findings (joint laxity), and large testes after puberty. Behavioral abnormalities, sometimes including autism spectrum disorder, are common. FXTAS occurs in males (and some females) who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor. FMR1-related POI (age at cessation of menses <40 years) occurs in approximately 20% of females who have an FMR1 premutation. [from GeneReviews]
Authors:
Robert A Saul  |  Jack C Tarleton   view full author information

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 GHR
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. 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://ghr.nlm.nih.gov/condition/fragile-x-associated-tremor-ataxia-syndrome

Clinical features

Hypotension
MedGen UID:
5715
Concept ID:
C0020649
Finding
You've probably heard that high blood pressure is a problem. Sometimes blood pressure that is too low can also cause problems. Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps out blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is the diastolic pressure. Your blood pressure reading uses these two numbers. Usually they're written one above or before the other, such as 120/80. If your blood pressure reading is 90/60 or lower, you have low blood pressure. . Some people have low blood pressure all the time. They have no symptoms and their low readings are normal for them. In other people, blood pressure drops below normal because of a medical condition or certain medicines. Some people may have symptoms of low blood pressure when standing up too quickly. Low blood pressure is a problem only if it causes dizziness, fainting or in extreme cases, shock. . NIH: National Heart, Lung, and Blood Institute.
Hypertension
MedGen UID:
635666
Concept ID:
C0497247
Finding
A finding of increased blood pressure; not necessarily hypertensive disorder
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.
Premature ovarian failure
MedGen UID:
9963
Concept ID:
C0025322
Disease or Syndrome
Premature ovarian failure is characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin levels in women younger than 40 years.
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Urinary incontinence (UI) is loss of bladder control. Symptoms can range from mild leaking to uncontrollable wetting. It can happen to anyone, but it becomes more common with age. Women experience UI twice as often as men. Most bladder control problems happen when muscles are too weak or too active. If the muscles that keep your bladder closed are weak, you may have accidents when you sneeze, laugh or lift a heavy object. This is stress incontinence. If bladder muscles become too active, you may feel a strong urge to go to the bathroom when you have little urine in your bladder. This is urge incontinence or overactive bladder. There are other causes of incontinence, such as prostate problems and nerve damage. Treatment depends on the type of problem you have and what best fits your lifestyle. It may include simple exercises, medicines, special devices or procedures prescribed by your doctor, or surgery. . NIH: National Institute of Diabetes and Digestive and Kidney Diseases.
Impotence
MedGen UID:
368760
Concept ID:
C1961100
Pathologic Function
Abnormal renal physiology
MedGen UID:
489768
Concept ID:
CN168062
Finding
An abnormal functionality of the kidney.
Hypotension
MedGen UID:
5715
Concept ID:
C0020649
Finding
You've probably heard that high blood pressure is a problem. Sometimes blood pressure that is too low can also cause problems. Blood pressure is the force of your blood pushing against the walls of your arteries. Each time your heart beats, it pumps out blood into the arteries. Your blood pressure is highest when your heart beats, pumping the blood. This is called systolic pressure. When your heart is at rest, between beats, your blood pressure falls. This is the diastolic pressure. Your blood pressure reading uses these two numbers. Usually they're written one above or before the other, such as 120/80. If your blood pressure reading is 90/60 or lower, you have low blood pressure. . Some people have low blood pressure all the time. They have no symptoms and their low readings are normal for them. In other people, blood pressure drops below normal because of a medical condition or certain medicines. Some people may have symptoms of low blood pressure when standing up too quickly. Low blood pressure is a problem only if it causes dizziness, fainting or in extreme cases, shock. . NIH: National Heart, Lung, and Blood Institute.
Hypertension
MedGen UID:
635666
Concept ID:
C0497247
Finding
A finding of increased blood pressure; not necessarily hypertensive disorder
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Bowel incontinence
MedGen UID:
851546
Concept ID:
C2712028
Finding
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Finding
A general term for the complete or partial loss of the ability to hear from one or both ears.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Fear and anxiety are part of life. You may feel anxious before you take a test or walk down a dark street. This kind of anxiety is useful - it can make you more alert or careful. It usually ends soon after you are out of the situation that caused it. But for millions of people in the United States, the anxiety does not go away, and gets worse over time. They may have chest pains or nightmares. They may even be afraid to leave home. These people have anxiety disorders. Types include. -Panic disorder . -Obsessive-compulsive disorder . -Post-traumatic stress disorder . -Phobias . -Generalized anxiety disorder . Treatment can involve medicines, therapy or both. NIH: National Institute of Mental Health .
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Depression is a serious medical illness that involves the brain. It's more than just a feeling of being &quot;down in the dumps&quot; or &quot;blue&quot; for a few days. If you are one of the more than 20 million people in the United States who have depression, the feelings do not go away. They persist and interfere with your everyday life. Symptoms can include : -Sadness. -Loss of interest or pleasure in activities you used to enjoy. -Change in weight. -Difficulty sleeping or oversleeping. -Energy loss. -Feelings of worthlessness. -Thoughts of death or suicide. Depression is a disorder of the brain. There are a variety of causes, including genetic, environmental, psychological, and biochemical factors. Depression usually starts between the ages of 15 and 30, and is much more common in women. Women can also get postpartum depression after the birth of a baby. Some people get seasonal affective disorder in the winter. Depression is one part of bipolar disorder. There are effective treatments for depression, including antidepressants and talk therapy. Most people do best by using both. . NIH: National Institute of Mental Health.
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.
Paresthesia
MedGen UID:
14619
Concept ID:
C0030554
Sign or Symptom
Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.
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.
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
Finding
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 rhythmically tapping the fingers on the knee.
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Incoordination
MedGen UID:
141714
Concept ID:
C0520966
Sign or Symptom
Diffuse cerebral atrophy
MedGen UID:
108958
Concept ID:
C0598275
Finding
Diffuse unlocalised atrophy affecting the cerebrum.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Sign or Symptom
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Atrophy (wasting) of the cerebellum.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
Impairment of the ability to coordinate the movements required for normal ambulation (WALKING) which may result from impairments of motor function or sensory feedback. This condition may be associated with BRAIN DISEASES (including CEREBELLAR DISEASES and BASAL GANGLIA DISEASES); SPINAL CORD DISEASES; or PERIPHERAL NERVOUS SYSTEM DISEASES.
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.
Loss of developmental milestones
MedGen UID:
373115
Concept ID:
C1836550
Finding
Loss of developmental skills, as manifested by loss of developmental milestones.
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
Aplasia/Hypoplasia of the cerebellum
MedGen UID:
480852
Concept ID:
C3279222
Finding
Disinhibition
MedGen UID:
504576
Concept ID:
CN000690
Finding
A lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment.
Parkinsonism
MedGen UID:
504793
Concept ID:
CN001191
Finding
Characteristic neurologic anomaly resulting form 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.
Bradykinesia
MedGen UID:
505077
Concept ID:
CN001869
Finding
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).
Intention tremor
MedGen UID:
505089
Concept ID:
CN001882
Finding
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).
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Bowel incontinence
MedGen UID:
851546
Concept ID:
C2712028
Finding
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in a muscle or group of muscles.
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
Your thyroid is a butterfly-shaped gland in your neck, just above your collarbone. It is one of your endocrine glands, which make hormones. Thyroid hormones control the rate of many activities in your body. These include how fast you burn calories and how fast your heart beats. All of these activities are your body's metabolism. If your thyroid gland is not active enough, it does not make enough thyroid hormone to meet your body's needs. This condition is hypothyroidism. Hypothyroidism is more common in women, people with other thyroid problems, and those over 60 years old. Hashimoto's disease, an autoimmune disorder, is the most common cause. Other causes include thyroid nodules, thyroiditis, congenital hypothyroidism, surgical removal of part or all of the thyroid, radiation treatment of the thyroid, and some medicines. The symptoms can vary from person to person. They may include. -Fatigue. -Weight gain. -A puffy face. -Cold intolerance. -Joint and muscle pain. -Constipation. -Dry skin. -Dry, thinning hair. -Decreased sweating. -Heavy or irregular menstrual periods and fertility problems. -Depression. -Slowed heart rate. To diagnose hypothyroidism, your doctor will look at your symptoms and blood tests. Treatment is with synthetic thyroid hormone, taken every day. NIH: National Institute of Diabetes and Digestive and Kidney Diseases.

Professional guidelines

PubMed

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. [Epub ahead of print] PMID: 25227148Free PMC Article
van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, Klockgether T, Mariotti C, Pandolfo M, Riess O
Eur J Neurol 2014 Apr;21(4):552-62. Epub 2014 Jan 13 doi: 10.1111/ene.12341. [Epub ahead of print] PMID: 24418350
Monaghan KG, Lyon E, Spector EB; erican College of Medical Genetics and Genomics
Genet Med 2013 Jul;15(7):575-86. Epub 2013 Jun 13 doi: 10.1038/gim.2013.61. [Epub ahead of print] PMID: 23765048
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. [Epub ahead of print] PMID: 21540884Free PMC Article
Gasser T, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Harbo HF; EFNS
Eur J Neurol 2010 Feb;17(2):179-88. Epub 2009 Dec 28 doi: 10.1111/j.1468-1331.2009.02873.x. [Epub ahead of print] PMID: 20050888
Kronquist KE, Sherman SL, Spector EB
Genet Med 2008 Nov;10(11):845-7. doi: 10.1097/GIM.0b013e31818b0c8a. PMID: 18941415Free PMC Article
Sherman S, Pletcher BA, Driscoll DA
Genet Med 2005 Oct;7(8):584-7. doi: 10.109701.GIM.0000182468.22666.dd. PMID: 16247297Free PMC Article
Maddalena A, Richards CS, McGinniss MJ, Brothman A, Desnick RJ, Grier RE, Hirsch B, Jacky P, McDowell GA, Popovich B, Watson M, Wolff DJ
Genet Med 2001 May-Jun;3(3):200-5. doi: 10.109700125817-200105000-00010. PMID: 11388762Free PMC Article

Recent clinical studies

Etiology

Mateu-Huertas E, Rodriguez-Revenga L, Alvarez-Mora MI, Madrigal I, Willemsen R, Milà M, Martí E, Estivill X
Neurobiol Dis 2014 May;65:43-54. Epub 2014 Jan 10 doi: 10.1016/j.nbd.2013.12.020. [Epub ahead of print] PMID: 24418349
Kogan CS, Cornish KM
Brain Cogn 2010 Aug;73(3):236-43. Epub 2010 Jun 22 doi: 10.1016/j.bandc.2010.05.008. [Epub ahead of print] PMID: 20573435
Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada(SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists(CCMG), Chitayat D, Wyatt PR, Wilson RD, Johnson JA, Audibert F, Allen V, Gagnon A, Langlois S, Blight C, Brock JA, Désilets V, Farell SA, Geraghty M, Nelson T, Nikkel SM, Skidmore D, Shugar A
J Obstet Gynaecol Can 2008 Sep;30(9):837-46. PMID: 18845054
Jin P, Duan R, Qurashi A, Qin Y, Tian D, Rosser TC, Liu H, Feng Y, Warren ST
Neuron 2007 Aug 16;55(4):556-64. doi: 10.1016/j.neuron.2007.07.020. PMID: 17698009Free PMC Article
Tan EK, Zhao Y, Puong KY, Law HY, Chan LL, Yew K, Tan C, Shen H, Chandran VR, Teoh ML, Yih Y, Pavanni R, Wong MC, Ng IS
Neurology 2004 Jul 27;63(2):362-3. PMID: 15277639

Diagnosis

Eye PG, Hawley JS
Neurology 2015 Feb 17;84(7):e43-5. doi: 10.1212/WNL.0000000000001267. PMID: 25688154
Mateu-Huertas E, Rodriguez-Revenga L, Alvarez-Mora MI, Madrigal I, Willemsen R, Milà M, Martí E, Estivill X
Neurobiol Dis 2014 May;65:43-54. Epub 2014 Jan 10 doi: 10.1016/j.nbd.2013.12.020. [Epub ahead of print] PMID: 24418349
Mascalchi M, Vella A, Ceravolo R
J Magn Reson Imaging 2012 Feb;35(2):239-56. doi: 10.1002/jmri.22825. PMID: 22271273
Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada(SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists(CCMG), Chitayat D, Wyatt PR, Wilson RD, Johnson JA, Audibert F, Allen V, Gagnon A, Langlois S, Blight C, Brock JA, Désilets V, Farell SA, Geraghty M, Nelson T, Nikkel SM, Skidmore D, Shugar A
J Obstet Gynaecol Can 2008 Sep;30(9):837-46. PMID: 18845054

Therapy

Zesiewicz TA, Sullivan KL, Freeman A, Juncos JL
Acta Neurol Scand 2009 Feb;119(2):135-8. Epub 2008 Sep 3 doi: 10.1111/j.1600-0404.2008.01070.x. [Epub ahead of print] PMID: 18771524
Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada(SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists(CCMG), Chitayat D, Wyatt PR, Wilson RD, Johnson JA, Audibert F, Allen V, Gagnon A, Langlois S, Blight C, Brock JA, Désilets V, Farell SA, Geraghty M, Nelson T, Nikkel SM, Skidmore D, Shugar A
J Obstet Gynaecol Can 2008 Sep;30(9):837-46. PMID: 18845054

Clinical prediction guides

Filley CM, Brown MS, Onderko K, Ray M, Bennett RE, Berry-Kravis E, Grigsby J
Neurology 2015 May 26;84(21):2146-52. Epub 2015 Apr 29 doi: 10.1212/WNL.0000000000001612. [Epub ahead of print] PMID: 25925982Free PMC Article
Mascalchi M, Vella A, Ceravolo R
J Magn Reson Imaging 2012 Feb;35(2):239-56. doi: 10.1002/jmri.22825. PMID: 22271273

Recent systematic reviews

Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada(SOGC); Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists(CCMG), Chitayat D, Wyatt PR, Wilson RD, Johnson JA, Audibert F, Allen V, Gagnon A, Langlois S, Blight C, Brock JA, Désilets V, Farell SA, Geraghty M, Nelson T, Nikkel SM, Skidmore D, Shugar A
J Obstet Gynaecol Can 2008 Sep;30(9):837-46. PMID: 18845054

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