Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy.

DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% of DMD mutations are deep intronic and analysis of muscle-derived RNA is an important diagnostic step for patients who have negative genomic testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 patients with clinical features of a dystrophinopathy, but negative clinical DMD mutation analysis. Reverse transcription-polymerase chain reaction or high-throughput RNA sequencing methods identified 19 mutations with one of three pathogenic pseudoexon types: deep intronic point mutations, deletions or insertions, and translocations. In association with point mutations creating intronic splice acceptor sites, we observed the first examples of DMD pseudo 3'-terminal exon mutations causing high efficiency transcription termination within introns. This connection between splicing and premature transcription termination is reminiscent of U1 snRNP-mediating telescripting in sustaining RNA polymerase II elongation across large genes, such as DMD. We propose a novel classification of three distinct types of mutations identifiable by muscle RNA analysis, each of which differ in potential treatment approaches. Recognition and appropriate characterization may lead to therapies directed toward full-length dystrophin expression for some patients.

Apparent False Lateralization of Seizure Onset by Scalp EEG in Temporal Lobe Epilepsy Associated with Cerebral Cavernous Malformation: A Case Report and Overview.

False lateralization of ictal onset by scalp electroencephalogram (EEG) is an infrequent entity that has been reported in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (HS). In these cases, a tendency for rapid seizures that spread through the frontal-limbic system and hippocampal commissural pathways to the contralateral hemisphere has been proposed. Cerebral cavernous malformations (CCMs), which constitute a collection of abnormally configured small blood vessels with irregular structures, is a well-defined epilepsy-associated pathology. Their primary association with seizures might be explained either as a result of physiological changes affecting the cerebral cortex immediately surrounding the CCM (an epileptogenic mechanism that is relevant for both, temporal and extratemporal lesions) or as a result of promoting epileptogenicity in remote but anatomo-functionally connected brain regions, a mechanism that is particularly relevant for temporal lobe lesions. To date, there have been only two publications on falsely lateralizing ictal onsets by EEG in temporal cavernoma, but not in other regions. Here, we report a rare case of apparent false lateralization of ictal onset by scalp EEG in a patient with a left medial frontal gyrus cavernoma (supplementary motor area), and discuss some relevant pathophysiological mechanisms of false lateralization.

Pathophysiological Mechanisms of Cognitive Impairment and Neurodegeneration by Toxoplasma gondii Infection.

Toxoplasma gondii is an obligate intracellular parasite considered one of the most successful pathogens in the world, owing to its ability to produce long-lasting infections and to persist in the central nervous system (CNS) in most warm-blooded animals, including humans. This parasite has a preference to invade neurons and affect the functioning of glial cells. This could lead to neurological and behavioral changes associated with cognitive impairment. Although several studies in humans and animal models have reported controversial results about the relationship between toxoplasmosis and the onset of dementia as a causal factor, two recent meta-analyses have shown a relative association with Alzheimer's disease (AD). AD is characterized by amyloid-ß (Aß) peptide accumulation, neurofibrillary tangles, and neuroinflammation. Different authors have found that toxoplasmosis may affect Aß production in brain areas linked with memory functioning, and can induce a central immune response and neurotransmitter imbalance, which in turn, affect the nervous system microenvironment. In contrast, other studies have revealed a reduction of Aß plaques and hyperphosphorylated tau protein formation in animal models, which might cause some protective effects. The aim of this article is to summarize and review the newest data in regard to different pathophysiological mechanisms of cerebral toxoplasmosis and their relationship with the development of AD and cognitive impairment. All these associations should be investigated further through clinical and experimental studies.

Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences.

Alzheimer's disease (AD) is the most common type of dementia, mainly encompassing cognitive decline in subjects aged ≥65 years. Further, AD is characterized by selective synaptic and neuronal degeneration, vascular dysfunction, and two histopathological features: extracellular amyloid plaques composed of amyloid beta peptide (Aß) and neurofibrillary tangles formed by hyperphosphorylated tau protein. Dementia and AD are chronic neurodegenerative conditions with a complex physiopathology involving both genetic and environmental factors. Recent clinical studies have shown that proton pump inhibitors (PPIs) are associated with risk of dementia, including AD. However, a recent case-control study reported decreased risk of dementia. PPIs are a widely indicated class of drugs for gastric acid-related disorders, although most older adult users are not treated for the correct indication. Although neurological side effects secondary to PPIs are rare, several preclinical reports indicate that PPIs might increase Aß levels, interact with tau protein, and affect the neuronal microenvironment through several mechanisms. Considering the controversy between PPI use and dementia risk, as well as both cognitive and neuroprotective effects, the aim of this review is to examine the relationship between PPI use and brain effects from a neurobiological and clinical perspective.