Prediction and assessment of acute encephalopathy syndromes immediately after febrile status epilepticus.

OBJECTIVE: This study aimed to predict occurrence of acute encephalopathy syndromes (AES) immediately after febrile status epilepticus in children and to explore the usefulness of electroencephalogram (EEG) in the early diagnosis of AES. METHODS: We reviewed data from 120 children who had febrile status epilepticus lasting >30 min and were admitted to our hospital between 2012 and 2019. AES with reduced diffusion on brain magnetic resonance imaging was diagnosed in 11 of these patients. EEG and serum cytokines were analyzed in AES patients. Clinical symptoms and laboratory data were compared between AES and non-AES patients. Logistic regression analysis was used to identify early predictors of AES. RESULTS: Multivariate logistic regression identified serum creatinine as a risk factor for developing AES. A scoring model to predict AES in the post-ictal phase that included serum creatinine, sodium, aspartate aminotransferase, and glucose was developed, and a score of 2 or more predicted AES with sensitivity of 90.9% and specificity of 71.6%. Post-ictus EEG revealed non-convulsive status epilepticus in four of the seven AES patients. CONCLUSION: Children with febrile status epilepticus may be at risk of developing severe AES with reduced diffusion. Post-ictus EEG and laboratory data can predict the occurrence of severe AES.

Immunodeficiency in a patient with microcephalic osteodysplastic primordial dwarfism type I as compared to Roifman syndrome.

BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.

TUBB3 E410K syndrome with osteoporosis and cough syncope in a patient previously diagnosed with atypical Moebius syndrome.

BACKGROUND: A heterozygous c.1228G > A p.E410K mutation in TUBB3 encoding neuronal-specific ß-tubulin isotype 3 causes TUBB3 E410K syndrome, which exhibits a wide range of neurological and endocrinological abnormalities. CASE DESCRIPTION: The patient is a 31-year-old Japanese woman who was diagnosed with atypical Moebius syndrome because of congenital facial weakness and extraocular ophthalmoplegia sparing abduction. She suffered a femoral neck fracture at 23 years of age, and radiological and endocrinological studies revealed osteoporosis because of hypogonadotropic hypogonadism. She also had borderline intellectual disability, cyclic vomiting, syncope with cough, and decreased sense of smell since childhood. Brain magnetic resonance imaging revealed abnormal morphology of the corpus callosum and pontine. Hypoplastic bilateral oculomotor and facial nerves were evident. Based on these symptoms, we analyzed the TUBB3 gene and identified a heterozygous c.1228G > A (p.E410K) mutation that confirmed the diagnosis of TUBB3 E410K syndrome. CONCLUSION: TUBB3 E410K syndrome may be diagnosed as atypical Moebius syndrome because of overlapping clinical symptoms. Genetic analysis of c.1228G > A in TUBB3 is useful to differentiate TUBB3 E410K syndrome from other disorders presenting congenital external ophthalmoplegia and facial nerve palsy.

A case of Dravet syndrome complicated by human herpesvirus-6 infection-associated acute encephalopathy and choreoathetosis.

We report the case of a 14-month-old girl with Dravet syndrome carrying a splice-site mutation of c. 1170+1G>A on neuronal sodium channel alpha 1 subunit (SCN1A). She had a history of recurrent febrile or afebrile seizures since 4 months of age and developed acute encephalopathy due to infection with human herpesvirus-6, which presented with high grade fever, severe consciousness disturbances, and prolonged and clustered seizures. Electroencephalography showed a generalized slow activity. Intensive treatments, including mechanical ventilation, continuous thiopental infusion, and high-dose steroid therapy were initiated, and she gradually recovered. During the recovery phase, choreoathetosis-like involuntary movements appeared on the face and limbs, which were treated successfully with haloperidol. MRI findings during the acute phase were normal; however, diffuse cerebral atrophy became evident during the recovery phase. Single photon emission computed tomography (SPECT) of the brain revealed decreased cerebral perfusion over bilateral frontal and temporal lobes; however, perfusion of the occipital lobes, basal ganglia, and cerebellum remained normal. The patient showed serious developmental regression at discharge, with the loss of head control and meaningful words. Patient's clinical course and the findings of SPECT resembled those of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), with the exception of lack of reduced diffusion of the subcortical white matter on the acute phase MRI and the prolonged and severe clinical symptoms. It has been reported that patients with Dravet syndrome are prone to complications, including various types of acute encephalopathies. Therefore, clinicians should carefully manage prolonged febrile seizures in patients with Dravet syndrome.

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

Chromosome 9q33q34 microdeletion with early infantile epileptic encephalopathy, severe dystonia, abnormal eye movements, and nephroureteral malformations.

BACKGROUND: Microdeletion of chromosome 9q33q34 is an emerging disease disorder associated with early infantile epileptic encephalopathy, intellectual disability, and a variety of movement disorders. PATIENT: We describe a male infant with early infantile epileptic encephalopathy with suppression-burst (Ohtahara syndrome) who carried a de novo 2.0-Mb microdeletion in chromosome 9q33q34, including STXBP1. The previously reported examples of 9q33q34 microdeletion including STXBP1 are reviewed. RESULTS: The patient developed infantile spasms at 4 months of age, and these were refractory to multiple antiepileptic drugs. He also developed severe dystonia during infancy, rotatory nystagmus, and nephroureteral malformations. Immunoglobulin and clobazam administered at 11 months were effective for the spasms, but profound psychomotor retardation remained. A comparative genomic hybridization array analysis and the fluorescence in situ hybridization analysis revealed a de novo 2.0-Mb microdeletion in chromosome 9q33q34, which encompasses STXBP1, ENG, SPTAN1, and 52 other genes. A total of 14 patients (13 from the literature) with a 9q33q24 microdeletion including STXBP1 were reviewed, five of them displayed early infantile epileptic encephalopathy with suppression-burst, and six of them had early-onset epilepsy but not early infantile epileptic encephalopathy. Dystonia has been previously described in 9q33q34 deletions involving TOR1A but not STXBP1. Neither abnormal eye movements nor nephroureteral malformations has been previously described. CONCLUSIONS: This patient adds unique clinical presentations of neurological and nephroureteral abnormalities to the features of 9q33q34 microdeletion.