Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somaticorgan systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.

Psychosis and catatonia in fragile X: Case report and literature review

“…We review the literature and report an exemplary case of a 25 year old male premutation carrier with elevated FMR1 mRNA, lowexpansion sequesters important proteins needed for normal cellular function (11). In those with FXTAS there is inclusion formation in both neurons and astroglial cells in the brain and in the peripheral nervous system and these inclusions have the excess FMR1 mRNA, fragile X mental retardation protein (FMRP) and many other proteins and neurofilaments (11)(12)(13). Decreased levels of FMRP are observed in some premutation carriers due to reduced translational efficiency of FMR1 mRNA containing the expanded CGG repeat (14)(15)(16).…”

Induced expression of expanded CGG RNA causes mitochondrial dysfunctionin vivo

“…Medical co-morbidities may include thyroid disease, fibromyalgia, gastro-intestinal symptoms, hypertension, migraine, auto-immune disease, impotence and neuropathy. 3,4 The prevalence of premutation carriers in the general population is approximately 1 in 200 females and 1 in 400 males. 5,6 Premutation carriers irrespective of showing signs of FXTAS, have been shown to have up to 8-fold elevated FMR1 mRNA levels in peripheral blood leukocytes, despite close to normal or slightly lowered FMRP protein levels.…”

Current research, diagnosis, and treatment of fragile X-associated tremor/ataxia syndrome

“…Impairments in executive function abilities including working memory, inhibitory control and visuospatial processing begin as early as middle adulthood, and progressively worsen with increasing age (22)(23)(24)(25)(26). Subsequently dementia develops in approximately 50% of male PMC and autonomic dysfunction which is thought to be a consequence of involvement of the peripheral nervous system in common (27,28). Premutation-associated psychiatric problems are common in adulthood but these problems can worsen before the appearance of tremor and ataxia (20,(29)(30)(31).…”

“…The neuronal toxicity is thought to be led by the formation of pathognomonic eosinophilic and ubiquitinpositive intranuclear inclusions in neurons and astrocytes throughout the brain, peripheral nervous system and other organs such as the adrenals, thyroid, heart, Leydig cells and pancreas (28,(76)(77)(78). Other findings include mild brain atrophy and involvement of the cerebellum (MPC sign), loss of Purkinje neuronal cells, spongiosis of the deep cerebellar white matter, Bergman gliosis, and swollen axons (51,77).…”