Mutations in the ATRX gene are a primary cause of alpha-thalassemia intellectual disability X-linked (ATRX) syndrome, which is characterized by intellectual disability, autism, and a range of brain structural abnormalities, including microcephaly. We previously showed that mice with conditional ATRX ablation in forebrain excitatory neurons display deficits in fear memory and autism-related behaviors, with some effects exhibiting sexual dimorphism. In this study, we used high-resolution magnetic resonance imaging (MRI) to systematically characterize brain structural changes associated with these behavioral abnormalities. Whole-brain analysis revealed male-specific microcephaly, while subregional analysis identified significant reductions in hippocampal structures and increased volume of the caudal cortex in mutant animals of both sexes. We also identified structural alterations in regions retaining ATRX expression, such as the thalamus, midbrain, cerebellum, and several fiber tracts. These findings suggest that ATRX loss disrupts the coordinated development of interconnected brain regions. Overall, our results implicate impaired cortico-thalamic-cerebellar connectivity as a potential neural substrate underlying the autistic-like behaviors observed in this mouse model, providing new insights into the neurobiological basis of ATR-X syndrome. Changes in a gene called ATRX are known to affect brain development and are linked to intellectual disability and autism. In our previous work, we found that removing this gene early in brain development caused mice to show behaviors like those seen in people with autism. In this study, we used detailed brain scans to see if these behavioral changes were linked to differences in brain structure. We found that male mice without ATRX had smaller brains and bodies, while female mice did not show the same brain size reduction. However, both male and female mice had smaller areas of the brain important for memory and movement, and larger areas involved in thinking and sensing. We also saw changes in parts of the brain where ATRX was still present, suggesting that early changes in one area can affect how the whole brain develops. These findings help us understand how early disruptions in brain development might lead to autism‐related behaviors.

The Alpha Thalassemia mental Retardation syndrome, X-linked (ATR-X syndrome, MIM: 301040) is a rare genetic disorder characterized by alpha thalassemia, intellectual disability, peculier facial characteristics and genital abnormalities. Detailed information regarding the clinical phenotype is lacking. Detailed descriptions of the clinical phenotype are rare. The aim of this study was to describe the clinical phenotype of ATR-X syndrome. Data was collected through questionnaires, interviews, physical examination and the study of medical records. Twenty-two individuals, aged 2-68 years old, were included. Three individuals were deceased at the time of the study. The individuals had a variable degree of intellectual disability. Alpha thalassemia was found in 30 % and genital anomalies in 70 % of the individuals. First clinical signs of the syndrome were most frequently feeding problems, started in the neonatal period in the majority. Other main reported health problems were reflux (59 %), constipation (72 %), periods of anorexia and adipsia (45 %), heart defects (28 %), epilepsy (33 %), scoliosis/kyphosis (48 %), visual impairment (61 %) and hearing loss (38 %). Behavioral problems (86 %) and sleeping problems (64 %) also occurred frequently. We report on the largest cohort of clinically studied individuals with ATR-X syndrome, including the eldest individuals, reported to date. Clinical knowledge is essential to improve care and to evaluate future therapies for this group.

Prostate cancer (PC) is the most common cancer and a leading cause of cancer-related mortality in men worldwide. It has become clear that signaling pathways that are implicated in prostatic carcinoma (PCa) initiation and propagation evolved through interactions of several factors. Alpha Thalassemia/Intellectual Disability syndrome X-linked (ATRX) is a chromatin remodeling protein that has an essential role in telomere stability. The androgen receptor (AR) and growth factors especially the epidermal growth factor receptor (EGFR) seem not to function independently in PCa proliferation. This work aimed to study the expression of ATRX in primary prostatic adenocarcinoma in relation to AR and EGFR expression and the significance of biomarkers expression to the known clinicopathological factors. Eighty-two primary prostatic adenocarcinoma paraffin blocks were stained immunohistochemically with AR, ATRX, and EGFR polyclonal antibodies. PCa was divided into AR+/hi and AR-/lo depending on the percentage and intensity of stained cells regardless of AR heterogeneity. ATRX immunostaining was categorized into ATRX preserved expression or ATRX loss. EGFR expression was grouped into low and high expression according to the staining percentage and intensity. AR+/hi and preserved ATRX expression significantly were linked to low pT stage, low-grade group, and absence of lymph node invasion. While significant EGFR high expression was related to the high-grade group and the presence of lymph node invasion. ATRX preserved expression varies significantly between AR+/hi and AR-/lo PCa which is related to favorable clinicopathological factors. However, the loss of ATRX expression correlated significantly with AR-/low, high EGFR expression, and adverse clinicopathological factors.

Alpha-thalassemia/intellectual disability syndrome (ATR-X) (OMIM # 301040) was first described by Wilkie et al. (1). Several studies found that children who presented with significantly consistent clinical phenotypes of hemoglobin H (Hb H) disease and profound mental handicap carried ATRX chromatin remodeler (ATRX, OMIM*300032) gene variants. With the recent development of exome sequencing (ES), ATRX gene variants of severe to profound intellectual disability without alpha-thalassemia have been implicated in intellectual disability-hypotonic facies syndrome, X-linked, 1(MRXHF1, OMIM #309580). These two diseases present similar clinical manifestations and the same pattern of inheritance. We reported a 3-year-old boy with intellectual disability, language impairment, hypotonia, and mild craniofacial abnormalities (flat nasal bridge, small and triangular nose, anteverted nostrils, and widely spaced incisors) and reviewed MRXHF1 cases. At an early stage, the patient developed global developmental delay (GDD). After 6 months of rehabilitation therapy, the patient's motor ability did not make big progress, as well as his speech or nonverbal communication. We performed whole-genome sequencing (WGS), Sanger sequencing, reverse transcription-polymerase chain reaction (RT-PCR), and X-inactivation studies. A novel hemizygous intronic variant in ATRX (c.5786+4A>G; NM_000489.6) was identified, which led to exon 24 skipping. The carrier mother showed extremely skewed X-chromosome inactivation (XCI). These results may contribute to the patient's phenotypes. The novel hemizygous intronic variant in ATRX is the genetic etiology of the boy. Identification of this variant is helpful for parents to take prenatal diagnostic tests. Also, this new case expands the phenotypes of MRXHF1 and the mutational spectrum of the ATRX gene.

Prothymosin-α (PTMA), a nuclear protein, is strikingly associated with unfavorable clinical outcomes in many cancers. However, no information about its clinical relevance in glioma was available. Therefore in the present study, we evaluated the prognostic utility of this protein in a cohort of 81 glioma patients. The PTMA expression was assessed by immunohistochemical analysis, quantitative PCR, and Western blotting. Furthermore, the association of PTMA with clinicopathological features and molecular alterations were assessed in the patient cohort and validated in multiomics datasets, The Cancer Genome Atlas (TCGA; n=667) and Chinese Glioma Genome Atlas (CGGA; n=1013). We observed an increase in PTMA expression with increasing histological grades of this malignancy. PTMA immunostaining also displayed a strong positive association with the MIB-1 index. Univariate analysis revealed a superior prognostic value of PTMA to predict overall survival (OS) as compared with the routinely used markers (p53, isocitrate dehydrogenase (IDH) 1 (IDH1), α-thalassemia/intellectual disability syndrome X-linked (ATRX), and Ki-67). Interestingly, in Cox regression analysis it emerged as an independent predictor of OS (hazard ratio (HR) = 13.71, 95% CI = 5.96-31.52, P<0.0001). Thus, our results demonstrate the potential prognostic utility of PTMA in glioma which may prove useful in the management of this deadly malignancy.