This paper summarizes key emerging issues in fragile X-associated tremor/ataxia syndrome (FXTAS) as presented at the First International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2013.

Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.

Summary. The mammalian fetus receives energy fuels from its mother through the placenta. The (Freinkel et al., 1971(Freinkel et al., , 1972(Freinkel et al., , 1974 Knopp, 1978) and the principal results will be summarized briefly.Adaptation of maternal fuel metabolism to fetal growth.During gestation, the increased food intake by the pregnant mother contributes to a steady weight gain. This weight gain has 2 main components which accumulate at different times in gestation. During the first and second part of gestation the mother accumulates fat stores (Beaton et al., 1954 ;Hytten and Leicht, 1971) In all the species studied, the fetal blood glucose levels are lower than the maternal levels, but they are directly correlated with the maternal levels over a wide range of concentrations Shelley, 1973 ;Silver, 1976 (Haour and Bertrand, 1974 ;Marshall et al., 1974 ;Posner, 1975).In most of the species studied, fetal lactate concentration is 2 or 3 fold higher than maternal lactate concentration (table 1) Char and Creasy, 1976a ;Silver, 1976). High rates of lactate production by the placenta, under aerobic conditions in vitro, have also been found in rat and man. The rate of placental lactate production is closely related to the rate of glucose utilization by the placenta.In several species (sheep, goat, cow, pig and horse) a part of glucose (10 p. 100) taken up by the placenta is converted into fructose which is transferred to the fetus. Fructose is present in very high concentration in the blood of the fetus of those species but is absent from maternal blood, since it is not passed back to the mother. When the mother is in the fed state, there is no evidence for utilization of fructose by the fetus. However, during maternal starvation, a small but significant utilization by the sheep fetus has been shown (Schreiner et al., 1978). This suggests that fructose may be a carbohydrate store, as glycogen, which could be used in situation of emergency by the fetus.2) Amino acids.The level of amino acids is 2 to 3 fold higher in the fetal blood than in the maternal blood (table 1). The amino acids are concentrated by the placenta and released to the fetus against a concentration gradient, by an active transport mechanism (review in Young and Hill, 1973). In the sheep (Lemons et al., 1976) fetal uptake of glutamine, branched chain amino-acids, arginine, phenylalanine and tyrosine is in excess of estimated growth requirements, suggesting that they are used for other purposes than protein synthesis. In the rat, fetal uptake of glutamine has also been found to be much higher than for other amino-acids (Yamamoto et al.,1974). This will be discussed later.3) Free fatty acids.In (Char and Creasy, 19766). In the cow and guinea-pig a significant umbilical uptake of acetate has been shown, and it is dependant upon maternal acetate concentration (Silver, 1976 ;Jones, 1976a). 4) Ketone bodies.Ketone bodies are readily transferred from the mother to the fetus in human and rat (Sabata et al., 1968 ;Scow et al., 1958), and there is a c...

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.