Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS)

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome

“…Six cases (cases 1,7,9,11,12,14) were diagnosed with mood disorders, while 4 cases (cases 4, 7, 9, 11) were diagnosed with anxiety disorders. Table 2 details demographic data, number of CGG repeats, years of FXTAS, age of FXTAS onset, FXTAS stage, psychiatric diagnoses, degree of MCP sign, and other MRI findings, as well as a description of FXTAS stages.…”

Reduced Hippocampal Activation During Recall is Associated with Elevated FMR1 mRNA and Psychiatric Symptoms in Men with the Fragile X Premutation

“…In a study of the knock-in mouse model of the premutation (Entezam et al 2007), FMRP expression was significantly reduced in several brain regions, including the hippocampus. In those brain areas sampled in post mortem studies of brain tissue from older premutation males with FXTAS, the hippocampus shows the largest percentage of cells with intranuclear inclusions, again suggesting that this brain region may be particularly affected in FXTAS (Greco et al 2002(Greco et al , 2006. Our current working hypothesis for psychiatric and cognitive involvement among carriers of premutation alleles posits that clinical features arise through a combination of RNA toxicity and mild reductions of FMRP.…”

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

“…Kenneson et al (2001) [10] found that these patients have an increase in FMR1 RNA transcription proportionally related to the number of CGG repeats and a decrease in FMRP translation inversely related to the number of CGG repeats. The excess of FMR1 mRNA seen in carriers leads to dysregulation of several proteins and its deposition, along with FMR1 mRNA, in the form of cellular inclusions in several parts of the body including the central nervous system, peripheral nervous system (especially autonomic ganglia), Leydig cells, and pituitary among others [11][12][13]. Therefore, any pathology associated with FMR1 premutations would not be caused by a complete absence of FMRP like FXS is, but probably due to partial FMRP deficiency and/or RNA toxicity.…”