Peri-ictal EEG in infants with PRRT2-related self-limited infantile epilepsy

Objective

Pathogenic PRRT2 variants cause self-limited (familial) infantile epilepsy (SeLIE), which is responsive to sodium channel blocking antiseizure medications. The interictal EEG is typically normal. We describe a cohort of infants with PRRT2-related SeLIE with striking peri-ictal EEG abnormalities.

Methods

We included all infants diagnosed with PRRT2-related SeLIE during July 2020 to November 2021 at the Royal Children's Hospital, Melbourne. Clinical features and results of aetiologic investigations were collected from electronic medical records. All EEGs were reviewed independently by two epileptologists.

Results

Ten infants presented with focal seizures at a median age of 5 months (range: 3–6 months). Eight had a family history of epilepsy, paroxysmal kinesigenic dyskinesia (PKD) or hemiplegic migraine. Seven of the eight infants with an EEG performed within 24 h of the most recent seizure had epileptiform discharges. Their EEGs showed focal sharp waves, spikes, polyspikes or fast activity independently over the left and right temporo-occipital regions. Conversely, the two infants with last known seizure greater than 24 h prior to their EEG had no epileptiform discharges. Oxcarbazepine was commenced in two infants and was effective. Eight infants were initially treated with levetiracetam, and all were subsequently switched to oxcarbazepine due to ongoing seizures or side effects.

Significance

Posterior polymorphic focal epileptiform discharges on a peri-ictal EEG recording are a feature of PRRT2-related SeLIE. This finding, particularly in the presence of a family history of infantile epilepsy, PKD or hemiplegic migraine, suggests a diagnosis of PRRT2-related SeLIE and has important treatment implications.     

Age-dependent and tissue-related glutathione redox status in a mouse model of Alzheimer's disease

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PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.     

Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive motor neuron degeneration and leads to death within a few years of diagnosis. One of the pathogenic mechanisms of ALS is proposed to be a dysfunction in the protein quality‐control machinery. Dorfin has been identified as a ubiquitin ligase (E3) that recognizes and ubiquitinates mutant SOD1 proteins, thereby accelerating their degradation and reducing their cellular toxicity. We examined the effects of human Dorfin overexpression in G93A mutant SOD1 transgenic mice, a mouse model of familial ALS. In addition to causing a decrease in the amount of mutant SOD1 protein in the spinal cord, Dorfin overexpression ameliorated neurological phenotypes and motor neuron degeneration. Our results indicate that Dorfin overexpression or the activation or induction of E3 may be a therapeutic avenue for mutant SOD1‐associated ALS. © 2009 Wiley‐Liss, Inc.     

Age-dependent changes in MRI of motor brain stem nuclei in a mouse model of ALS

Mice over-expressing the mutant human G93A-SOD1 are widely used as an animal model of amyotrophic lateral sclerosis (ALS). ALS is characterized by progressive degeneration of motor neurons in the motor cortex, brain stem and spinal cord. The underlying mechanisms for the selective death of motor neurons are still uncertain. To study factors that cause selective neuron degeneration or therapeutic approaches to delay the progression of the disease, a method is required to monitor the state of motor neurons under in-vivo conditions. Here, we demonstrate that in G93A-SOD1 mice the MRI signal intensities of nucleus V, VII, XII, and nucleus ambiguus show a time-dependent increase starting around day 90, parallel to first behavioral signs of a motoneuron disorder.     

Contributions of triggering-receptor-expressed-on-myeloid-cells-2 to neurological diseases

Recent laboratory and gene sequencing data suggest that variations in receptors called the “triggering-receptors-expressed-on-myeloid-cells” (TREMs) are implicated in Alzheimer's disease, Parkinson's disease, multiple sclerosis, and frontotemporal lobar degeneration. TREM receptors are thought to play a critical role in regulating the immune system, inflammation, and certain cellular functions. One TREM, in particular, TREM2, is highly expressed on cells of the myeloid lineage. The binding of TREM2 to the adapter protein, DNAX activating protein of 12 kD (DAP12), in microglial cells has been shown to modulate phagocytosis within the nervous system. This review highlights the role of TREM2 in neurological diseases. Moreover, here we consider potential contributions of TREM2 and mechanisms underlying TREM2 activity as contributing to neurodegeneration. These findings may provide novel insights and opportunities to consider, especially for clinicians, as they diagnose and treat certain neurological diseases.     

Fused in sarcoma-amyotrophic lateral sclerosis as a novel member of DNA single strand break diseases with pure neurological phenotypes

正Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer's disease,Parkinson's disease,Huntington's disease,premature aging diseases as well as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Until recently these studies were largely correlative in nature,though raising the possibility that defects in the DNA damage response (DDR)underlie neurodegenerative diseases.However,more light needs to be shed     

动手能力与神经内科诊疗模式的转变

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Insomnia in neurological diseases

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Constipation in neurological diseases

Hippocrates noted that "it is a general rule, that intestines become sluggish with age", though the precise mechanisms for this association remains uncertain even today.     

Laryngospasm in neurological diseases

Laryngospasm is a clinical symptom characterized by involuntary spasms of the laryngeal muscles, which leads to paroxysms of coughing, inspiratory stridor, and sometimes to episodes of complete upper-airway occlusion. Although laryngospasm is a symptom mainly seen in otolaryngeal diseases and in the context of anesthesiological complications, it also occurs in neurological disorders. In this review of the occurrence of laryngospasms in neurological diseases, the clinical symptomatology, additional circumstances, possible underlying causes, and therapeutic options are presented.     

7, 8-dihydroxycoumarin improves neurological function in a mouse model of sciatic nerve injury

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