[Diversity of CACNA1A-related disorders]. / Raznoobrazie boleznei, svyazannykh s genom CACNA1A.

Four cases of autosomal dominant CNS disorders related to CACNA1A mutations and detected by massive parallel sequencing are reported: a non-familial case of episodic ataxia type 2 (EA2) with the previously reported mutation c.269_270insA (p.Tyr90Ter) in a 35-year-old man; familial hemiplegic migraine type 1 (FHM1) in a girl aged 3 years 10 months and her mother aged 38 yrs with a novel mutation 1829C>T (p.Ser610Phe), members of a family with 4 patients and incomplete penetrance; developmental and epileptic encephalopathy 42 (DEE42) in a 9-year-old girl and a 5-year-old boy from different families with the identical de novo mutation c.2137G>A (p.Ala713Thr) reported earlier. Clinical and genetic characteristics are analyzed compared to literature.

De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy.

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.

Reliability of electromyographic activity vs. bite-force from human masticatory muscles.

The reproducibility of electromyographic (EMG) activity in relation to static bite-force from masticatory muscles for a given biting situation is largely unknown. Our aim was to evaluate the reliability of EMG activity in relation to static bite-force in humans. Eighty-four subjects produced five unilateral static bites of different forces at different biting positions on molars and incisors, at two separate sessions, and the surface EMG activities were recorded from temporalis, masseter, and suprahyoid muscles bilaterally. Intraclass correlation coefficients (ICCs) were determined, and an ICC of ≥ 0.60 indicated good reliability of these slopes. The ICCs for jaw-closing muscles during molar biting were: temporalis muscles, ipsilateral 0.58-0.93 and contralateral 0.88-0.91; and masseter muscles, ipsilateral 0.75-0.86 and contralateral 0.69-0.88. The ICCs for jaw-closing muscles during incisor biting were: temporalis muscles, ipsilateral 0.56-0.81 and contralateral 0.34-0.86; and masseter muscles, ipsilateral 0.65-0.78 and contralateral 0.59-0.80. For the suprahyoid muscles the 95% CIs were mostly wide and most included zero. The slopes of the EMG activity vs. bite-force for a given biting situation were reliable for temporalis and masseter muscles. These results support the use of these outcome measurements for the estimation and validation of mechanical models of the masticatory system.

Role of glutamine in neuronal survival and death during brain ischemia and hypoglycemia.

In this review, we discuss the role of glutamine in the nervous system as a precursor of the excitatory neuromediator glutamate, on one hand, and as an energy substrate for mitochondria in nerve and glial cells during normal and pathological processes, on the other hand. Particular attention is devoted to the functioning of the glutamine-glutamate cycle enzymes during brain ischemia and hypoglycemia and to processes of neuromediator regeneration in neurons. We thoroughly discuss the role of glutamine synthetase in mechanisms of ammonium detoxification and the role of glutamine as a possible factor in astrocyte damage. The analyzed data suggest that the constant maintenance of optimal concentrations and ratio of glutamine to glutamate in nerve tissue is not only critically important for the normal functioning of nervous system, but is also necessary for neuron and astrocyte viability.

Glutamine-mediated protection from neuronal cell death depends on mitochondrial activity.

The specific aim of this study was to elucidate the role of mitochondria in a neuronal death caused by different metabolic effectors and possible role of intracellular calcium ions ([Ca(2+)](i)) and glutamine in mitochondria- and non-mitochondria-mediated cell death. Inhibition of mitochondrial complex I by rotenone was found to cause intensive death of cultured cerebellar granule neurons (CGNs) that was preceded by an increase in intracellular calcium concentration ([Ca(2+)](i)). The neuronal death induced by rotenone was significantly potentiated by glutamine. In addition, inhibition of Na/K-ATPase by ouabain also caused [Ca(2+)](i) increase, but it induced neuronal cell death only in the absence of glucose. Treatment with glutamine prevented the toxic effect of ouabain and decreased [Ca(2+)](i). Blockade of ionotropic glutamate receptors prevented neuronal death and significantly decreased [Ca(2+)](i), demonstrating that toxicity of rotenone and ouabain was at least partially mediated by activation of these receptors. Activation of glutamate receptors by NMDA increased [Ca(2+)](i) and decreased mitochondrial membrane potential leading to markedly decreased neuronal survival under glucose deprivation. Glutamine treatment under these conditions prevented cell death and significantly decreased the disturbances of [Ca(2+)](i) and changes in mitochondrial membrane potential caused by NMDA during hypoglycemia. Our results indicate that glutamine stimulates glutamate-dependent neuronal damage when mitochondrial respiration is impaired. However, when mitochondria are functionally active, glutamine can be used by mitochondria as an alternative substrate to maintain cellular energy levels and promote cell survival.

Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia.

This review collects data on the influence of intracellular and extracellular acidosis on neuronal viability and the effect of acidosis on neuronal damage progressing under brain ischemia/hypoxia. Particular attention is devoted to the involvement of ionotropic glutamic receptors and acid-sensitive ion channel 1a in these processes.