A novel heterozygous ATP1A2 pathogenic variant in a Chinese child with MELAS-like alternating hemiplegia.

BACKGROUND: Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura. METHODS: The patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES). RESULTS: WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic. CONCLUSION: At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.

Protective effects of naloxone in two-hit seizure model.

PURPOSE: Early life status epilepticus (SE) could enhance the vulnerability of the immature brain to a second SE in adulthood (two-hit seizure model). Naloxone has been proved to possess inflammation inhibitory effects in nervous system. This study was designed to evaluate the dose-dependent protective effects of naloxone in kainic acid (KA)-induced two-hit seizure model. METHODS: After KA-induced SE at postnatal day 15 (P15), Sprague-Dawley rats were infused with either saline or different doses (1.92, 3.84, 5.76, and 7.68 mg/kg) of naloxone continuously for 12 h. De novo synthesis of cytokines (interleukin-1 beta [IL-1 beta], S100B) was assessed by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) at 12 h after P15 SE. Glial activation states were analyzed by western blotting of glial markers (glial fibrillary acidic protein [GFAP], S100B, Iba1) both at 12 h after P15 SE and at P45. After a second SE at P45, cognitive deteriorations were evaluated by Morris water tests and neuron injuries were evaluated by TdT-mediated dUTP nick end labeling (TUNEL) assays. RESULTS: Naloxone reduced IL-1 beta synthesis and microglial activation most potently at a dose of 3.84 mg/kg. Attenuation of S100B synthesis and astrocyte activation were achieved most dramatically by naloxone at a dose of 5.76 mg/kg, which is equal to the most powerful dose in ameliorating cognitive injuries and neuron apoptosis after second SE. CONCLUSIONS: Naloxone treatment immediately after early life SE could dose-dependently reduce cytokine production, glial activation, and further lower the vulnerability of immature brains to a second hit in adulthood.

Astrocyte activation and memory impairment in the repetitive febrile seizures model.

Frequently repetitive febrile seizures (FRFS) in immature brain could impair long-term memory without obvious pathological alteration. Although astrocyte activation has been implicated in many seizure models, it has never been examined in febrile seizure models. We investigated astrocyte activation states after FRFS in postnatal-10-day (P10) rats by western blot and immunohistochemical analysis of GFAP and S100beta, two protein markers for activated astrocytes, at three time points (P25, P35, P45). The levels of GFAP and S100beta increased significantly at all the time examined. Furthermore, we administered propentofylline, an astrocyte modulator, to verify the relationship between the activated astrocytes and memory injury. After propentofylline treatment for 10 consecutive days following P10 frequently repetitive FS, rats exhibited improved performances in Morris water maze at P36 and inhibitory avoidance task at P45, along with markedly suppressed overexpression of GFAP and S100beta. This research suggests that modulation of astrocyte activation might be a potential therapeutic target to improve memory outcomes after frequently repetitive febrile seizures.