Explore the vast range of titles available.

نقدم بين أيديكم ترجمة لهذا الكتاب العلمي، والذي تضمن كما زاخرا من مادة علمية مهمة، ساق بها المؤلفون العديد من البحوث والتجارب العلمية الإكلينيكية والمراجع الغنية لمن أراد الاستفاضة بالمعرفة للعديد من المجالات المرضية والتناذرات، وشمل تفصيل دقيقا على مستوى الكيمياء الحيوية الخلوية، ووصفا وشرحا لآليات متعددة تستند إلى علوم الوراثة الجزيئية والطفرات المختلفة ببحوث موثقة وتفصيلية، ونتائجها الظاهرية وآثارها الصحية العصبية أو النفسية أو الأجهزة الحيوية الأخرى. وتطرق للمحكات التشخيصية (ليست بإصداراتها الأحدث) ذلك أن الكتاب كان قد نشر قبل هذه التحديثات التشخيصية، وتعامل أيضا مع التشخيص الإفريقي والأحوال الطبية المشابهة وطرائق المعالجات الدوائية وغيرها في حاضرها أو آفاق مستقبلية لها، ومدار البحث الدولي في المستقبل. وقد آلينا على أنفسنا-ما استطعنا-أن نورد المصطلحات الطبية بالإنجليزية قبالة تعريبها درءا للالتباس. وكان جليا بأن هذا المؤلف سيكون منهلا مهما لمحبي المعرفة الطبية بشكل عام، لكنه ذو ثروة لاختصاصيي الطب النفسي والعاملين في حقل العلوم النفسية كعلم النفس الإكلينيكي واختصاصيي التربية الخاصة والإرشاد النفسي، ويبدو أنه مرجع لاختصاصيي طب الأعصاب وطب الأطفال وبخاصة طب الأطفال التطوري والنمائي، عدا أن ينبض بالمعرفة للباحثين والأكاديميين والعاملين في العلوم البيولوجية وعلم الوراثة وعلوم الكيمياء الحيوية والخلية والصيدلة.

Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55–200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

Key Points Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset condition in carriers of premutations in the FMR1 gene; only 40–75% of males and 16–20% of females with premutations develop FXTAS Premutation carriers can experience neurodevelopmental and reproductive problems earlier in life, as well as other symptoms that may require treatment, including hypertension, hypothyroidism, primary ovarian insufficiency, migraines, insomnia, sleep apnoea, depression and anxiety Presentation of FXTAS is variable and can include tremor, cerebellar ataxia, neuropathy and/or cognitive decline; radiological features include brain atrophy and white matter disease in specific brain regions The clinical manifestations of FXTAS require expression of the abnormal FMR1 mRNA, but the mechanistic link between the mRNA and disease manifestations is unclear Proposed molecular mechanisms of FXTAS pathogenesis, including sequestration of proteins by the excess FMR1 mRNA, production of toxic FMRPolyG protein, and chronic activation of the DNA damage repair process Advances in understanding the pathogenesis of FXTAS could enable development of targeted therapies that are more effective than current management Premutation CGG expansions in the FMR1 gene can lead to various premutation disorders throughout life and ultimately lead to fragile X-associated tremor/ataxia syndrome (FXTAS) in late life. In this Review, the authors summarize our current understanding of the clinical features and management of FXTAS, and consider how our advancing understanding of the pathogenic mechanisms could lead to new therapies. Many physicians are unaware of the many phenotypes associated with the fragile X premutation, an expansion in the 5′ untranslated region of the fragile X mental retardation 1 ( FMR1 ) gene that consists of 55–200 CGG repeats. The most severe of these phenotypes is fragile X-associated tremor/ataxia syndrome (FXTAS), which occurs in the majority of ageing male premutation carriers but in fewer than 20% of ageing women with the premutation. The prevalence of the premutation is 1 in 150–300 females, and 1 in 400–850 males, so physicians are likely to see people affected by FXTAS. Fragile X DNA testing is broadly available in the Western world. The clinical phenotype of FXTAS at presentation can vary and includes intention tremor, cerebellar ataxia, neuropathic pain, memory and/or executive function deficits, parkinsonian features, and psychological disorders, such as depression, anxiety and/or apathy. FXTAS causes brain atrophy and white matter disease, usually in the middle cerebellar peduncles, the periventricular area, and the splenium and/or genu of the corpus callosum. Here, we review the complexities involved in the clinical management of FXTAS and consider how targeted treatment for these clinical features of FXTAS will result from advances in our understanding of the molecular mechanisms that underlie this neurodegenerative disorder. Such targeted approaches should also be more broadly applicable to earlier forms of clinical involvement among premutation carriers.

Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice. Fragile X syndrome (FXS) is characterized by severe behavioural alterations, such as hyperactivity, anxiety and symptoms of autism spectrum disorder. These behavioural manifestations, in addition to the molecular pathophysiology, diagnosis and management of FXS, are reviewed in this Primer.

While behavioral interventions remain the mainstay of treatment of autism spectrum disorder (ASD), several potential targeted treatments addressing the underlying neurophysiology of ASD have emerged in the last few years. These are promising for the potential to, in future, become part of the mainstay treatment in addressing the core symptoms of ASD. Although it is likely that the development of future targeted treatments will be influenced by the underlying heterogeneity in etiology, associated genetic mechanisms influencing ASD are likely to be the first targets of treatments and even gene therapy in the future for ASD. In this article, we provide a review of current psychopharmacological treatment in ASD including those used to address common comorbidities of the condition and upcoming new targeted approaches in autism management. Medications including metformin, arbaclofen, cannabidiol, oxytocin, bumetanide, lovastatin, trofinetide, and dietary supplements including sulforophane and N-acetylcysteine are discussed. Commonly used medications to address the comorbidities associated with ASD including atypical antipsychotics, serotoninergic agents, alpha-2 agonists, and stimulant medications are also reviewed. Targeted treatments in Fragile X syndrome (FXS), the most common genetic disorder leading to ASD, provide a model for new treatments that may be helpful for other forms of ASD.

Gastrointestinal (GI) symptoms are a common comorbidity in patients with autism spectrum disorder (ASD), but the underlying mechanisms are unknown. Many studies have shown alterations in the composition of the fecal flora and metabolic products of the gut microbiome in patients with ASD. The gut microbiota influences brain development and behaviors through the neuroendocrine, neuroimmune and autonomic nervous systems. In addition, an abnormal gut microbiota is associated with several diseases, such as inflammatory bowel disease (IBD), ASD and mood disorders. Here, we review the bidirectional interactions between the central nervous system and the gastrointestinal tract (brain-gut axis) and the role of the gut microbiota in the central nervous system (CNS) and ASD. Microbiome-mediated therapies might be a safe and effective treatment for ASD.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55–200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

No proven prognosis is available for the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Artificial neural network analyses (ANN) were used to predict FXTAS progression using data from 127 adults (noncarriers and FMR1 premutation carriers with and without FXTAS) with five outcomes from brain MRI imaging and 22 peripheral bioenergetic outcomes from two cell types. Diagnosis accuracy by ANN predictions ranged from 41.7 to 86.3% (depending on the algorithm used), and those misclassified usually presented a higher FXTAS stage. ANN prediction of FXTAS stages was based on a combination of two imaging findings (white matter hyperintensity and whole-brain volumes adjusted for intracranial volume) and four bioenergetic outcomes. Those at Stage 3 vs. 0–2 showed lower mitochondrial mass, higher oxidative stress, and an altered electron transfer consistent with mitochondrial unfolded protein response activation. Those at Stages 4–5 vs. 3 had higher oxidative stress and glycerol-3-phosphate-linked ATP production, suggesting that targeting mGPDH activity may prevent a worse prognosis. This was confirmed by the bioenergetic improvement of inhibiting mGPDH with metformin in affected fibroblasts. ANN supports the prospect of an unbiased molecular definition in diagnosing FXTAS stages while identifying potential targets for personalized medicine.