BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS.
METHODS: A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week.
CONCLUSIONS: This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

Despite significant advances in understanding and treating social anxiety in the general population, progress in this area lags behind for individuals with intellectual disability. Fragile X syndrome is the most common cause of inherited intellectual disability and is associated with an elevated prevalence rate of social anxiety. The phenotype of fragile X syndrome encompasses multiple clinically significant characteristics that are posed as risk markers for social anxiety in other populations. Here, evidence is reviewed that points to physiological hyperarousal, sensory sensitivity, emotion dysregulation, cognitive inflexibility, and intolerance of uncertainty as primary candidates for underlying mechanisms of heightened social anxiety in fragile X syndrome. A multilevel model is presented that provides a framework for future research to test associations.

A novel class of superficial CD34+ and S100+ cutaneous spindle cell neoplasm harboring ALK rearrangements has recently been described. Morphologically, these neoplasms have been characterized by bland spindled cells organized in whorls and cords against myxoid stroma, eventuating in the designation \"superficial ALK-rearranged myxoid spindle cell neoplasm.\" Here, we report a 78-year-old male with a 3-mm pink papule on the chest, clinically concerning for cutaneous carcinoma. Biopsy of the specimen showed a biphasic tumor with hypercellular and hypocellular zones consisting of epithelioid cells and monomorphic, bland spindled cells. The spindled cells were arranged in perineurial-like concentric whorls and cords embedded in a myxo-collagenous stroma. Neoplastic cells were diffusely positive for CD34, S100, and D5F3-ALK, without SOX10 expression. Negative markers included GLUT1, EMA, factor XIIIa, desmin, actin, and SMA. ALK-rearrangement was identified on fluorescence in situ hybridization break-apart assay. A corresponding novel FMR1-ALK fusion was found by next-generation sequencing (NGS) based RNA sequencing. Identification of this new FMR1-ALK fusion signature adds to the spectrum of diagnostic genomic alterations in this newly described class of tumors.

Fragile X syndrome (FXS) is caused by an abnormal expansion of the number of trinucleotide CGG repeats located in the 5\' UTR in the first exon of the FMR1 gene. Size and methylation mosaicisms are commonly observed in FXS patients. Both types of mosaicisms might be associated with less severe phenotypes depending on the number of cells expressing FMRP. Although this dynamic mutation is the main underlying cause of FXS, other mechanisms, including point mutations or deletions, can lead to FXS. Several reports have demonstrated that de novo deletions including the entire or a portion of the FMR1 gene end up with the absence of FMRP and, thus, can lead to the typical clinical features of FXS. However, very little is known about the clinical manifestations associated with FMR1 gene deletions in mosaicism. Here, we report an FXS case caused by an entire hemizygous deletion of the FMR1 gene caused by maternal mosaicism. This manuscript reports this case and a literature review of the clinical manifestations presented by carriers of FMR1 gene deletions in mosaicism.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and the second most common cause after Down syndrome. FXS is an X-linked disorder due to a full mutation of the CGG triplet repeat of the FMR1 gene which codes for a protein that is crucial in synaptogenesis and maintaining functions of extracellular matrix-related proteins, key for the development of normal neuronal and connective tissue including collagen. In addition to neuropsychiatric and behavioral problems, individuals with FXS show physical features suggestive of a connective tissue disorder including loose skin and joint laxity, flat feet, hernias and mitral valve prolapse. Disturbed collagen leads to hypermobility, hyperextensible skin and tissue fragility with musculoskeletal, cardiovascular, immune and other organ involvement as seen in hereditary disorders of connective tissue including Ehlers−Danlos syndrome. Recently, FMR1 premutation repeat expansion or carrier status has been reported in individuals with connective tissue disorder-related symptoms. We examined a cohort of females with features of a connective tissue disorder presenting for genetic services using next-generation sequencing (NGS) of a connective tissue disorder gene panel consisting of approximately 75 genes. In those females with normal NGS testing for connective tissue disorders, the FMR1 gene was then analyzed using CGG repeat expansion studies. Three of thirty-nine females were found to have gray zone or intermediate alleles at a 1:13 ratio which was significantly higher (p < 0.05) when compared with newborn females representing the general population at a 1:66 ratio. This association of connective tissue involvement in females with intermediate or gray zone alleles reported for the first time will require more studies on how the size variation may impact FMR1 gene function and protein directly or in relationship with other susceptibility genes involved in connective tissue disorders.

Clinical management of patients with fragile X-associated tremor/ataxia syndrome (FXTAS) is a challenge, and there has been not an established treatment for FXTAS, which is now treated symptomatically. Diagnosis of coexistent idiopathic normal pressure hydrocephalus (iNPH) with FXTAS is also hard because clinical and imaging features can overlap between the FXTAS patients coexistent with and without iNPH. We present a 79-year-old male genetically diagnosed with FXTAS who was successfully treated by a shunt surgery and consequently diagnosed with iNPH, and suggest the management of coexistent iNPH with FXTAS when it is clinically suspicious.

BACKGROUND: Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID.
METHODS: The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID.
CONCLUSIONS: For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.

OBJECTIVE: To explore the genetic basis for a child with febrile seizures.
METHODS: Peripheral venous blood samples were taken from the child and his parents for the analysis of chromosomal karyotype and dynamic variant of the FMR1 gene. The family trio was also subjected to target capture and next generation sequencing (NGS) with a gene panel related to developmental retardation, mental retardation, language retardation, epilepsy and special facial features.
RESULTS: The child was found to have a normal karyotype by conventional cytogenetic analysis (400 bands). No abnormal expansion was found with the CGG repeats of the FMR1 gene. NGS revealed that the child has carried a heterozygous c.864+1 delG variant of the MEF2C gene, which may lead to abnormal splicing and affect its protein function. The same variant was found in neither parent, suggesting that it has a de novo origin. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.864+1delG variant of MEF2C gene was predicted to be pathogenic (PVS1+PS2+PM2).
CONCLUSIONS: MEF2C, as the key gene for chromosome 5q14.3 deletion syndrome which was speculated as a cause for febrile seizures, has an autosomal dominant effect. The c.864+1delG variant of the MEF2C gene may account for the febrile seizures in this patient.

While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked.
To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.
We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.
Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity.
Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

OBJECTIVE: To screen for mutations of fragile X mental retardation 1 (FMR1) gene during early and middle pregnancy and provide prenatal diagnosis for those carrying high-risk CGG trinucleotide expansions.
METHODS: Peripheral blood samples of 2316 pregnant women at 12 to 21(+6) gestational weeks were collected for the extraction of genomic DNA. CGG repeats of the FMR1 gene were detected by fluorescence PCR and capillary electrophoresis. Genetic counseling and prenatal diagnosis were provided for 3 women carrying the premutations.
RESULTS: The carrier rate of CGG repeats of the FMR1 gene was 1 in 178 for the intermediate type and 1 in 772 for the premutation types. The highest frequency allele of CGG was 29 repeats, which accounted for 49.29%, followed by 30 repeats (28.56%) and 36 repeats (8.83%). In case 1, the fetus had a karyotype of 45,X, in addition with premutation type of CGG expansion of the FMR1 gene. Following genetic counseling, the couple chose to terminate the pregnancy through induced labor. The numbers of CGG repeats were respectively 70/- and 29/30 for the husband and wife. In case 2, amniocentesis was performed at 20 weeks of gestation. The number of CGG repeats of the FMR1 gene was 29/-. No abnormality was found in the fetal karyotype and chromosomal copy number variations. The couple chose to continue with the pregnancy. Case 3 refused prenatal diagnosis after genetic counseling and gave birth to a girl at full term, who had a birth weight of 2440 g and no obvious abnormality found during follow-up.
CONCLUSIONS: Pregnant women should be screened for FMR1 gene mutations during early and middle pregnancy, and those with high-risk CGG expansions should undergo prenatal diagnosis, genetic counseling and family study.