Fragile X-associated tremor/ataxia syndrome

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Fragile X-associated tremor/ataxia syndrome
Abbreviation:FXTAS
Pronunciation:"FAX-tass" [1]
Location of the FMR1 gene Fmr1.jpeg
Location of the FMR1 gene
Location of the FMR1 gene
Specialty: Neurology, Movement Disorders
Symptoms: intention tremor, ataxia, and parkinsonism
Prevalence:In patients over 50 with FMR1 premutation:
Onset:Late-onset, diagnosed in patients >50 years [1]
Diagnosis:Presentation, family history, genetic testing, and MRI

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder most frequently seen in male premutation carriers of Fragile X syndrome (FXS) over the age of 50. [4] [5] The main clinical features of FXTAS include problems of movement with cerebellar gait ataxia and action tremor. [4] [6] Associated features include parkinsonism, cognitive decline, and dysfunction of the autonomic nervous system. [4] [6] FXTAS is found in Fragile X "premutation" carriers, which is defined as a trinucleotide repeat expansion of 55-200 CGG repeats in the Fragile X mental retardation-1 ( FMR1 ) gene. [7] 4-40 CGG repeats in this gene is considered normal, while individual with >200 repeats have full Fragile X Syndrome. [7]

Contents

In contrast to FXS full mutation, which is diagnosed early in childhood, symptoms of FXTAS manifest in individuals over the age of 50. [1] Like FXS, FXTAS is most common and most severe in males due to the mutation's X-linked inheritance pattern. [2] FXTAS has an incidence of 30-40% (male) and 8-15% (female) among FXS premutation carriers over the age of 50. [2] [3]

FMR1 mRNA is found to be elevated in patients with FXTAS [7] in contrast to FXS, where the FMR1 gene is transcriptionally silenced via DNA methylation. [8] In both diseases the FMR1 gene product, Fragile X mental retardation protein (FMRP) is diminished, but in FXTAS this is believed to be mediated by RNA toxicity, while in FXS, FMRP is absent due to transcriptional silencing. [7]

There is no cure for FXTAS, but several of the symptoms can be managed with medication. [7]

Symptoms and signs

The physical symptoms of FXTAS include an intention tremor, cerebellar ataxia, and parkinsonism. This includes small, shuffling steps, muscle rigidity and slowed speech, as well as neuropathic symptoms. As the disease progresses to the more advanced stages, an individual with FXTAS is also at risk of autonomic dysfunction: hypertension, bowel and bladder dysfunction, and impotence.[ citation needed ]

An individual with FXTAS may also exhibit the following symptoms: a decrease in cognition, which includes diminishing short-term memory and executive function skills, declining math and spelling abilities and decision-making abilities. FXTAS may also result in changes in personality, due to alterations of the limbic area in the brain. This includes increased irritability, angry outbursts, and impulsive behaviour[ citation needed ]

Diagnosis

FXTAS can be diagnosed using a combination of molecular, clinical, and radiological findings. In order for individuals to develop FXTAS, they must first be premutation carriers, having between 55 and 200 CGG trinucleotide repeat expansion of the FMR1 gene. A definite, probable, or possible diagnosis of FXTAS can be assigned based on combined clinical or radiological findings in conjunction with the molecular premutation. [9]

Clinical findings are divided into major and minor symptoms. Major symptoms include intention tremor and gait ataxia. Minor symptoms such as parkinsonism, short-term memory deficit, and executive function decline can further contribute to a diagnosis of FXTAS. Radiological findings are similarly divided into major and minor categories. As patients with FXTAS can have distinct brain scans from other movement disorders, a scan showing white matter lesions of the middle cerebellar peduncle is a major finding that can be attributed to FXTAS. Overall or generalized brain tissue atrophy and cerebral white matter lesions can also be minor indicators for a diagnosis. [9]

For a definite diagnosis to be made, a major radiological finding and one major clinical finding must be present. Probable diagnosis is based on the presence of either a major radiological finding and a minor clinical finding, or two major clinical findings alone. The possible category for diagnosis can be made with a minor radiological finding and a major clinical finding. [9]

Management

The medical management of FXTAS aims to reduce the level of disability and minimize symptoms. Currently, there are many gaps in the research on the management of FXTAS. The disorder was first described in the literature in 2001. There is no treatment modality aimed at reversing the pathology of FXTAS. However, there are a variety of drug therapies that are being utilized in the management of FXTAS symptoms. There is a lack of randomized control trials assessing the efficacy these therapies, and support is limited to anecdotal evidence. Therefore, many of the treatments are based on what has been helpful in disorders with similar clinical presentations. [9]

There is no cure for FXTAS. Current treatment includes medications for alleviating symptoms of tremor, ataxia, mood changes, anxiety, cognitive decline, dementia, neuropathic pain, or fibromyalgia. Neurological rehabilitation has not been studied for patients with FXTAS but should also be considered as a possible form of therapy. Additionally, occupational and physical therapy may help to improve function. . [9]

Prognosis

The progression of symptoms varies widely between each case of FXTAS; the onset of symptoms may be gradual, with progression of the disease spanning multiple years or decades. Alternatively, symptoms may progress rapidly.[ citation needed ]

FXTAS has shown strong age-dependent penetrance, affecting older premutation carriers with greater prevalence. Male carriers, age 50 and above have a 30% chance of developing FXTAS, while male carriers, age 75 and above, have a 75% chance of developing the disorder. While initially described as affecting male carriers, female carriers of the FMR1 gene mutation have also been found to develop FXTAS. However, due to X-inactivation, female carriers are much less likely to develop dementia or classic ataxia and tremor, instead demonstrating symptoms such as fibromyalgia, thyroid disease, hypertension, and seizures. [9]

See also

Related Research Articles

Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum. Ataxia can be limited to one side of the body, which is referred to as hemiataxia. Several possible causes exist for these patterns of neurological dysfunction. Dystaxia is a mild degree of ataxia. Friedreich's ataxia has gait abnormality as the most commonly presented symptom. The word is from Greek α- [a negative prefix] + -τάξις [order] = "lack of order".

<span class="mw-page-title-main">Fragile X syndrome</span> X-linked dominant genetic disorder

Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may include a long and narrow face, large ears, flexible fingers, and large testicles. About a third of those affected have features of autism such as problems with social interactions and delayed speech. Hyperactivity is common, and seizures occur in about 10%. Males are usually more affected than females.

<span class="mw-page-title-main">Multiple system atrophy</span> Neurodegenerative disorder

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by autonomic dysfunction, tremors, slow movement, muscle rigidity, and postural instability and ataxia. This is caused by progressive degeneration of neurons in several parts of the brain including the basal ganglia, inferior olivary nucleus, and cerebellum.

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

<span class="mw-page-title-main">Spinocerebellar ataxia</span> Medical condition

Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative, and often fatal. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder.

Trinucleotide repeat disorders, also known as microsatellite expansion diseases, are a set of over 50 genetic disorders caused by trinucleotide repeat expansion, a kind of mutation in which repeats of three nucleotides increase in copy numbers until they cross a threshold above which they become unstable. Depending on its location, the unstable trinucleotide repeat may cause defects in a protein encoded by a gene; change the regulation of gene expression; produce a toxic RNA, or lead to chromosome instability. In general, the larger the expansion the faster the onset of disease, and the more severe the disease becomes.

The Sherman paradox was a term used to describe the anomalous pattern of inheritance found in fragile X syndrome. The phenomenon is also referred to as anticipation or dynamic mutation.

<span class="mw-page-title-main">FMR1</span> Protein-coding gene in the species Homo sapiens

FMR1 is a human gene that codes for a protein called fragile X messenger ribonucleoprotein, or FMRP. This protein, most commonly found in the brain, is essential for normal cognitive development and female reproductive function. Mutations of this gene can lead to fragile X syndrome, intellectual disability, premature ovarian failure, autism, Parkinson's disease, developmental delays and other cognitive deficits. The FMR1 premutation is associated with a wide spectrum of clinical phenotypes that affect more than two million people worldwide.

Intention tremor is a dyskinetic disorder characterized by a broad, coarse, and low frequency tremor evident during deliberate and visually-guided movement. An intention tremor is usually perpendicular to the direction of movement. When experiencing an intention tremor, one often overshoots or undershoots one's target, a condition known as dysmetria. Intention tremor is the result of dysfunction of the cerebellum, particularly on the same side as the tremor in the lateral zone, which controls visually guided movements. Depending on the location of cerebellar damage, these tremors can be either unilateral or bilateral.

A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.

<span class="mw-page-title-main">Spinocerebellar ataxia type 6</span> Medical condition

Spinocerebellar ataxia type 6 (SCA6) is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, peripheral neuropathy, and ataxia of the gait, stance, and limbs due to cerebellar dysfunction. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel α subunit. These mutations tend to be trinucleotide repeats of CAG, leading to the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.

In genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product (progeny) of a dynamic mutation has a different likelihood of mutation than its predecessor. These mutations, typically short sequences repeated many times, give rise to numerous known diseases, including the trinucleotide repeat disorders.

<span class="mw-page-title-main">CGGBP1</span>

CGG triplet repeat-binding protein 1 is a protein that in humans is encoded by the CGGBP1 gene.

<span class="mw-page-title-main">FMR1-AS1 gene</span> Non-coding RNA in the species Homo sapiens

In molecular biology, FMR1 antisense RNA 1 (FMR1-AS1), also known as ASFMR1 or FMR4, is a long non-coding RNA. The FMR1-AS1 gene overlaps, and is antisense to, the CGG repeat region of the FMR1 gene. Its expression is upregulated in fragile X syndrome premutation carriers, and silenced in patients with fragile X syndrome. FMR1-AS1 has an anti-apoptotic function.

<span class="mw-page-title-main">Autosomal dominant cerebellar ataxia</span> Medical condition

Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.

Fragile X-associated Primary Ovarian Insufficiency (FXPOI) is the most common genetic cause of premature ovarian failure in women with a normal karyotype 46, XX. The expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene from the normal range of 5-45 repeats to the premutation range of 55-199 CGGs leads to risk of FXPOI for ovary-bearing individuals. It is present in 1:150-1:200 women in the US population. Women who carry an FMR1 premutation have a roughly 20% risk of being diagnosed with FXPOI, compared to 1% for the general population, and an 8-15% risk of developing the neurogenerative tremor/ataxia disorder (FXTAS). FMR1 premutation women are also at increased risk of having a child with a CGG repeat that is expanded to >200 repeats. Individuals with a full mutation, unlike the premutation, produce little to no mRNA or protein from the FMR1 gene and are affected with Fragile X syndrome.

<span class="mw-page-title-main">Metadoxine</span> Medication used for alcohol intoxication

Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol intoxication. Metadoxine accelerates alcohol clearance from the blood.

Nagwa Abdel Meguid is an Egyptian geneticist and 2002 winner of the L’Oreal UNESCO Award for Women in Science for Africa and the Middle East. Her research has "identified several genetic mutations that cause common syndromes such as the fragile X syndrome and Autism".

David L. Nelson is an American human geneticist, currently an associate director at the Intellectual and Developmental Disabilities Research Center (1995), and professor at the Department of Molecular and Human Genetics at Baylor College of Medicine BCM since 1999. Since 2018, he is the director at the Cancer and Cell Biology Ph.D program, and the director of Integrative Molecular and Biomedical Sciences Ph.D since 2015 at BCM.

Autosomal dominant cerebellar ataxia, deafness, and narcolepsy is a rare progressive genetic disorder that primarily affects the nervous system and is characterized by sensorineural hearing loss, narcolepsy with cataplexy, and dementia later in life. People with this disorder usually start showing symptoms when they are in their early-mid adulthoods. It is a type of autosomal dominant cerebellar ataxia.

References

  1. Jump up^ Amiri et al. Fragile X–Associated Tremor/Ataxia Syndrome. Archives of Neurology. VOL 65 (NO. 1), Jan 2008
  2. ^ Jump up to:a b
  3. ^ Jump up to:a b c
  4. Jump up^
  1. 1 2 3 "Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS): Overview". www.nichd.nih.gov. Retrieved 2017-07-07.
  2. 1 2 3 4 Saul, Robert A.; Tarleton, Jack C. (1993). "FMR1-Related Disorders". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301558.
  3. 1 2 3 Jacquemont, Sébastien (2004-01-28). "Penetrance of the Fragile X–Associated Tremor/Ataxia Syndrome in a Premutation Carrier Population". JAMA. 291 (4): 460–469. doi:10.1001/jama.291.4.460. ISSN   0098-7484. PMID   14747503.
  4. 1 2 3 Wheeler, Anne; Raspa, Melissa; Hagerman, Randi; Mailick, Marsha; Riley, Catharine (2017-06-01). "Implications of the FMR1 Premutation for Children, Adolescents, Adults, and Their Families". Pediatrics. 139 (Supplement 3): S172–S182. doi:10.1542/peds.2016-1159D. ISSN   0031-4005. PMC   5621635 . PMID   28814538.
  5. ↑ Tassone, Flora; Berry-Kravis, Elizabeth M, eds. (2010). The fragile X-associated tremor ataxia syndrome (FXTAS). Springer New York. doi:10.1007/978-1-4419-5805-1. ISBN   9781441958051.
  6. 1 2 Leehey, M. A.; Berry-Kravis, E.; Goetz, C. G.; Zhang, L.; Hall, D. A.; Li, L.; Rice, C. D.; Lara, R.; Cogswell, J. (2008-04-15). "FMR1 CGG repeat length predicts motor dysfunction in premutation carriers". Neurology. 70 (16 Pt 2): 1397–1402. doi:10.1212/01.wnl.0000281692.98200.f5. ISSN   1526-632X. PMC   2685188 . PMID   18057320.
  7. 1 2 3 4 5 Kong, Ha Eun; Zhao, Juan; Xu, Shunliang; Jin, Peng; Jin, Yan (2017-05-05). "Fragile X-Associated Tremor/Ataxia Syndrome: From Molecular Pathogenesis to Development of Therapeutics". Frontiers in Cellular Neuroscience. 11: 128. doi: 10.3389/fncel.2017.00128 . ISSN   1662-5102. PMC   5418347 . PMID   28529475.
  8. ↑ Colak, Dilek; Zaninovic, Nikica; Cohen, Michael S.; Rosenwaks, Zev; Yang, Wang-Yong; Gerhardt, Jeannine; Disney, Matthew D.; Jaffrey, Samie R. (2014-02-28). "Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome". Science. 343 (6174): 1002–1005. Bibcode:2014Sci...343.1002C. doi:10.1126/science.1245831. ISSN   1095-9203. PMC   4357282 . PMID   24578575.
  9. 1 2 3 4 5 6 Hall, Deborah A.; O'keefe, Joan A. (2012-05-11). "Fragile X-Associated Tremor Ataxia Syndrome: The Expanding Clinical Picture, Pathophysiology, Epidemiology, and Update on Treatment". Tremor and Other Hyperkinetic Movements. 2. doi:10.7916/D8HD7TDS. ISSN   2160-8288. PMC   3570061 . PMID   23439567.
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