Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and the leading form of the monogenic cause of autism. Fragile X mental retardation type 1 (FMR1) gene premutation is the first single-gene cause of primary ovarian failure (Fragile X-associated primary ovarian insufficiency [FXPOI]) and one of the most common causes of ataxia (fragile X-associated tremor/ataxia syndrome [FXTAS]), multiple additional phenotypes such as fibromyalgia, hypothyroidism, migraine headaches, sleep disturbances, sleep apnea, restless legs syndrome, central pain syndrome, neuropathy and neuropsychiatric alterations has been described. Clinical involvement in men and women carrying the FMR1 premutation currently constitutes a real health problem in the society that should be taken into account. It is important to highlight that while in FXS there is a loss-of-function of the FMR1 gene, in premutation associated disorders there is a gain of FMR1 mRNA function. To date, the tremendous progress achieved in the understanding of the pathophysiology of FXS, has led to the development of several targeted therapies aimed at preventing or improving the neurological manifestations of the disease. This review is an update of the diseases associated with the FMR1 gene. tions. In 1999, the study of fragile X pedigrees revealed a higher incidence of primary ovarian insufficiency related to the FMR1 gene, and this condition was named premature ovarian failure (POF) and then later fragile X premature ovarian insufficiency (FXPOI). 6 This term encompasses a continuum of severity in ovarian dysfunction ranging from normal menses and normal hormonal levels, although reduced fertility, to the most severe form of this condition in which folliclestimulating hormone is elevated, menses are abnormal or absent, and fertility is drastically reduced. 7 After further studies, Hagerman et al described a neurological disease related to the FMR1 premutation that was named fragile X-associated tremor/ataxia syndrome (FXTAS). 8 Finally, since 2007 the spectrum of the clinical phenotype associated with the FMR1 premutation has continuously widened. This review is an update of the diseases associated with the FMR1 gene.2 | FRAGILE X SYNDROME FXS (#MIM300624; ORPHA 908) is the most common cause of inherited ID (1%-2% of all ID) and the leading form of the monogenic cause of autism and autism spectrum disorders (ASD) (Figure 1). The

Mitochondrial involvement plays an important role in neurodegenerative diseases. At least one-third of adult carriers of a FMR1 premutation (55-200 CGG repeats) are at risk of presenting an adult-onset neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). In an attempt to provide new insights into the mechanisms involved in the pathogenesis of FXTAS, we characterized mitochondrial function and dynamics by the assessment of oxidative respiratory chain function, mitochondrial content, oxidative stress levels, and mitochondrial network complexity. Regarding mitochondrial function, we found that mitochondrial respiratory capacity is compromised in skin fibroblasts whereas in blood, no differences were observed between the FXTAS and control groups. Furthermore, fibroblasts from FXTAS patients presented altered mitochondrial architecture, with more circular and less interconnected mitochondria being observed. Mitochondrial function and dynamics deregulation and characteristic of neurological disorders are present in FXTAS patients. These features might be limiting temporal and spatial bioenergetics cells supply and thus contributing to disease pathogenesis.

We report a case of spontaneous abortion associated with Zika virus infection in a pregnant woman who traveled from Spain to the Dominican Republic and developed a rash. Maternal Zika viremia persisted at least 31 days after onset of symptoms and 21 days after uterine evacuation.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with FMR1 gene premutation alleles (55-200 CGG repeats).Fragile X-associated tremor/ataxia syndrome clinical core features include action tremor, gait ataxia, cognitive deficits progressing to dementia, and frequently parkinsonism. Although the pathogenic molecular mechanism of FXTAS is not completely understood, the restriction of the phenotype to the FMR1 premutation range has given rise to a model based on a RNA toxic gain-offunction. Since the identification of the first microRNAs (miRNAs) and their role in normal development, several studies have associated them with neurodegenerative diseases such as Parkinson, Alzheimer and Huntington diseases, suggesting that they play a key role in brain development, as well as in its morphogenesis. Herein, we present the characterization of miRNA expression profiles in FXTAS male patients using deep sequencingbased technologies and microarray technology. Deep sequencing analysis evidenced 83 miRNAs that were significantly deregulated whereas microarray analysis showed 31. When comparing these results, 14 miRNAs were found deregulated in FXTAS patients. MiR-424 and miR-574-3p showed significant fold change adjusted P-values in both platforms in FXTAS patients. MiR-424 has been founded substantially and specifically enriched in human cerebral cortical white matter of Alzheimer disease patients, which, together with cerebral atrophy, is a prominent imaging finding in individuals with FXTAS. The study provides the first systematic evidence of differential miRNA expression changes in FXTAS blood samples. Although further studies are necessary to better characterize the miRNA function in FXTAS disorder, our results suggest that they might contribute to its pathogenesis.

Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

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Original research articleFragile X-associated tremor/ataxia syndrome (FXTAS, OMIM no. 300623) is a late-onset neuropsychiatric degenerative disorder that occurs in FMR1 premutation carriers . Clinical symptoms, which appear in patients in their 50s or later, include action tremor, progressive cerebellar ataxia, peripheral neuropathy, autonomic dysfunction, cognitive decline, and dementia. [1][2][3][4] Magnetic resonance imaging in patients with FXTAS demonstrates mild to moderate cerebellar and brain atrophy, as well as white matter hyperintensities. In addition, hyperintensities in the middle cerebellar peduncles on T2 have been described as a characteristic finding in patients with FXTAS and therefore constitute a major diagnostic feature of the disorder.3,5 It has been estimated that at least one-third of all FMR1 premutation carriers will develop an FXTAS syndrome, although there is significant variability in the progression of neurological dysfunction. 2,6,7 Apolipoprotein E (ApoE) is a lipoprotein that transports cholesterol and other lipids and lipid-soluble molecules into the central nervous system. [8][9][10][11] ApoE also modulates the inflammatory response to cellular damage in the brain.12 The human ApoE gene shows polymorphic variation, and three alleles, designated as ApoE ε2, ε3, and ε4, are common in the general population. 13 Variant distribution of these alleles has been shown to be associated with a number of age-related diseases including atherosclerosis, cardiovascular disease, and neurodegenerative disorders.14-16 Although the pathogenic mechanism involving ApoE in these diseases is still unclear, it has been demonstrated that the ApoE ε4 allele is a well-established genetic risk factor for neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease, and other disorders in which dementia is present. [17][18][19] On the basis of this observation, we have evaluated the ApoE genotypes and allelic distribution among a FMR1 premutation carrier cohort presenting with FXTAS. These data might contribute to uncover a new genetic risk factor for FXTAS and might be useful to identify new genes involved in the disease onset and progression. METHODS SubjectsA total of 44 unrelated FMR1 premutation carriers (22 presenting with FXTAS symptoms and 22 without FXTAS clinical symptoms) were included. Samples from subjects belong to the Hospital Clinic of Barcelona and were molecularly diagnosed in the genetics laboratory of the same hospital. All participants were enrolled from families with members known to be affected with fragile X syndrome, and all of them are of Caucasian ethnicity. A classification on the basis of the gender and the age of the participants is summarized in Table 1. Although clinical data is scarce for some of the patients and we did not diagnose dementia in all of them, none of the cases included in the study had a diagnosis of AD. Overall, FXTAS encompasses patients who meet criteria in any of the three categories of involvement: definite, probable, and possible.3 ...

Advances in high-throughput technologies and its implementation worldwide have had a considerable impact on the elucidation of the molecular causes underlying neurodevelopmental psychiatric disorders, especially for autism spectrum disorder and intellectual disability (ID). Nevertheless, etiology remains elusive in close to 50% of cases, even in those families with multiple affected individuals, strongly hinting at a genetic cause. Here we present a case report of two siblings affected with severe ID and other comorbidities, who embarked on a genetic testing odyssey until diagnosis was reached by using whole genome sequencing (WGS). WGS identified a maternally inherited novel missense variant (NM_031466.7:c.1037G > A; p.Gly346Glu) and a paternally inherited 90 kb intragenic deletion in TRAPPC9 gene. This report demonstrates the clinical utility of WGS in patients who remain undiagnosed after whole exome sequencing.