Genomic and transcriptomic analyses distinguish classic Rett and Rett-like syndrome and reveals shared altered pathways

AbstractRett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by derangements in nervous system especially in cognition and behavior. The present study aims to understand the molecular underpinnings of two subtypes of RTT, classic RTT and Rett-like, and to elucidate common pathways giving rise to common RTT phenotype using genomic and transcriptomic approaches. Mutation screening on selected nuclear genes revealed only MECP2 mutations in a subset of classic RTT patients. MLPA assays and mtDNA screenings were all negative. Genome-wide copy number analysis indicated a novel duplication on X chromosome. Transcriptional profiling revealed blood gene signatures that clearly distinguish classic RTT and RTT-like patients, as well as shared altered pathways in interleukin-4 and NF-κB signaling pathways in both subtypes of the syndrome. To our knowledge, this is the first report on investigating common regulatory mechanisms/signaling pathways that may be relevant to the pathobiology of the “common RTT” phenotype

Epilepsy Surgery Series: A Study of 502 Consecutive Patients from a Developing Country

Purpose. To review the postoperative seizure outcomes of patients that underwent surgery for epilepsy at King Faisal Specialist Hospital & Research Centre (KFSHRC). Methods. A descriptive retrospective study for 502 patients operated on for medically intractable epilepsy between 1998 and 2012. The surgical outcome was measured using the ILAE criteria. Results. The epilepsy surgery outcome for temporal lobe epilepsy surgery (ILAE classes 1, 2, and 3) at 12, 36, and 60 months is 79.6%, 74.2%, and 67%, respectively. The favorable 12- and 36-month outcomes for frontal lobe epilepsy surgery are 62% and 52%, respectively. For both parietal and occipital epilepsy lobe surgeries the 12- and 36-month outcomes are 67%. For multilobar epilepsy surgery, the 12- and 36-month outcomes are 65% and 50%, respectively. The 12- and 36-month outcomes for functional hemispherectomy epilepsy surgery are 64.2% and 63%, respectively. According to histopathology diagnosis, mesiotemporal sclerosis (MTS) and benign CNS tumors had the best favorable outcome after surgery at 1 year (77.27% and 84.3%, resp.,) and 3 years (76% and 75%, resp.,). The least favorable seizure-free outcome after 3 years occurred in cases with dual pathology (66.6%). Thirty-four epilepsy patients with normal magnetic resonance imaging (MRI) brain scans were surgically treated. The first- and third-year epilepsy surgery outcome of 17 temporal lobe surgeries were (53%) and (47%) seizure-free, respectively. The first- and third-year epilepsy surgery outcomes of 15 extratemporal epilepsy surgeries were (47%) and (33%) seizure-free. Conclusion. The best outcomes are achieved with temporal epilepsy surgery, mesial temporal sclerosis, and benign CNS tumor. The worst outcomes are from multilobar surgery, dual pathology, and normal MRI.Peer Reviewe

A novel X-linked disorder with developmental delay and autistic features

Objective: Genomic duplications that lead to autism and other human diseases are interesting pathological lesions since the underlying mechanism almost certainly involves dosage sensitive genes. We aim to understand a novel genomic disorder with profound phenotypic consequences, most notably global developmental delay, autism, psychosis, and anorexia nervosa

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a shift of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis