Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder clinically characterized by intention tremor and gait ataxia, in addition to other conditions including hypothyroidism, autonomic dysfunction, hypertension, peripheral neuropathy, and cognitive decline. FXTAS affects some males (approximately 40%) and in less degree female premutation carriers (8-16%) older than 50 years with an age-dependent symptomatology and penetrance. The CGG repeat number appears to influence the severity and the age of onset of the disorder. The neuropathological hallmark of FXTAS is the presence of eosinophillic, ubiquitin-positive intranuclear inclusions in both neurons and astroglia throughout brain. FXTAS is due to RNA toxicity caused by elevated levels of CGG-expanded mRNA containing 55-200 CGG repeats, which is found in the intranuclear inclusions that sequester various proteins including ubiquitin, αB-crystallin, lamin A/C, hnRNP A2, myelin basic protein, and Sam68. The expression of the expanded CGG repeat FMR1 mRNA also induces a cellular stress response and leads to a disruption of the nuclear lamin A/C architecture. These alterations are observable even in early development, suggesting that the expanded-repeat mRNA triggers pathogenic mechanisms that can provide a molecular basis for the neurodevelopmental abnormalities observed in some children who are carriers of an FMR1 premutation allele. Finally, the presence of cellular dysregulation in older adults who do not present clinical features of FXTAS may suggest that additional genetic or environmental protective factors may play a role in the pathogenesis of FXTAS.
| Original language | English (US) |
|---|---|
| Title of host publication | Results and Problems in Cell Differentiation |
| Pages | 337-357 |
| Number of pages | 21 |
| Volume | 54 |
| DOIs | |
| State | Published - 2012 |
Publication series
| Name | Results and Problems in Cell Differentiation |
|---|---|
| Volume | 54 |
| ISSN (Print) | 00801844 |
| ISSN (Electronic) | 18610412 |
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ASJC Scopus subject areas
- Developmental Biology
- Cell Biology
Cite this
The fragile X-associated tremor ataxia syndrome. / Tassone, Flora; Hagerman, Randi J.
Results and Problems in Cell Differentiation. Vol. 54 2012. p. 337-357 (Results and Problems in Cell Differentiation; Vol. 54).Research output: Chapter in Book/Report/Conference proceeding › Chapter
}
TY - CHAP
T1 - The fragile X-associated tremor ataxia syndrome
AU - Tassone, Flora
AU - Hagerman, Randi J
PY - 2012
Y1 - 2012
N2 - Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder clinically characterized by intention tremor and gait ataxia, in addition to other conditions including hypothyroidism, autonomic dysfunction, hypertension, peripheral neuropathy, and cognitive decline. FXTAS affects some males (approximately 40%) and in less degree female premutation carriers (8-16%) older than 50 years with an age-dependent symptomatology and penetrance. The CGG repeat number appears to influence the severity and the age of onset of the disorder. The neuropathological hallmark of FXTAS is the presence of eosinophillic, ubiquitin-positive intranuclear inclusions in both neurons and astroglia throughout brain. FXTAS is due to RNA toxicity caused by elevated levels of CGG-expanded mRNA containing 55-200 CGG repeats, which is found in the intranuclear inclusions that sequester various proteins including ubiquitin, αB-crystallin, lamin A/C, hnRNP A2, myelin basic protein, and Sam68. The expression of the expanded CGG repeat FMR1 mRNA also induces a cellular stress response and leads to a disruption of the nuclear lamin A/C architecture. These alterations are observable even in early development, suggesting that the expanded-repeat mRNA triggers pathogenic mechanisms that can provide a molecular basis for the neurodevelopmental abnormalities observed in some children who are carriers of an FMR1 premutation allele. Finally, the presence of cellular dysregulation in older adults who do not present clinical features of FXTAS may suggest that additional genetic or environmental protective factors may play a role in the pathogenesis of FXTAS.
AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder clinically characterized by intention tremor and gait ataxia, in addition to other conditions including hypothyroidism, autonomic dysfunction, hypertension, peripheral neuropathy, and cognitive decline. FXTAS affects some males (approximately 40%) and in less degree female premutation carriers (8-16%) older than 50 years with an age-dependent symptomatology and penetrance. The CGG repeat number appears to influence the severity and the age of onset of the disorder. The neuropathological hallmark of FXTAS is the presence of eosinophillic, ubiquitin-positive intranuclear inclusions in both neurons and astroglia throughout brain. FXTAS is due to RNA toxicity caused by elevated levels of CGG-expanded mRNA containing 55-200 CGG repeats, which is found in the intranuclear inclusions that sequester various proteins including ubiquitin, αB-crystallin, lamin A/C, hnRNP A2, myelin basic protein, and Sam68. The expression of the expanded CGG repeat FMR1 mRNA also induces a cellular stress response and leads to a disruption of the nuclear lamin A/C architecture. These alterations are observable even in early development, suggesting that the expanded-repeat mRNA triggers pathogenic mechanisms that can provide a molecular basis for the neurodevelopmental abnormalities observed in some children who are carriers of an FMR1 premutation allele. Finally, the presence of cellular dysregulation in older adults who do not present clinical features of FXTAS may suggest that additional genetic or environmental protective factors may play a role in the pathogenesis of FXTAS.
UR - http://www.scopus.com/inward/record.url?scp=80455158035&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80455158035&partnerID=8YFLogxK
U2 - 10.1007/978-3-642-21649-7_18
DO - 10.1007/978-3-642-21649-7_18
M3 - Chapter
C2 - 22009361
AN - SCOPUS:80455158035
SN - 9783642216480
VL - 54
T3 - Results and Problems in Cell Differentiation
SP - 337
EP - 357
BT - Results and Problems in Cell Differentiation
ER -