Voltage-gated sodium channel epilepsies in a tertiary care center: Phenotypic spectrum with correlation to predicted functional effects.

BACKGROUND: Variants in sodium channel genes (SCN) are strongly associated with epilepsy phenotypes. Our aim in this study to evaluate the genotype and phenotype correlation of patients with SCN variants in our tertiary care center. METHODS: In this retrospective study, patients with SCN variants and epilepsy who were followed up at our clinic between 2018 and 2022 were evaluated. Our study discussed the demographics of the patients, the seizure types, the age of seizure onset, the SCN variants, the domains and the functions of the variants, the magnetic resonance imaging findings, the motor, cognitive, and psychiatric comorbidities, and the response to anti-seizure medication. Genetic testing was conducted using a next-generation sequencing gene panel (epilepsy panel) or a whole-exome sequencing. For evaluating variant function, we used a prediction tool (https://funnc.shinyapps.io/shinyappweb/ site). To assess protein domains, we used the PER viewer (http://per.broadinstitute.org/). RESULTS: Twenty-three patients with SCN variants and epilepsy have been identified. Sixteen patients had variants in the SCN1A, six patients had variants in the SCN2A, and one patient had a variant in the SCN3A. Two novel SCN1A variants and two novel SCN2A variants were identified. The analysis revealed 14/23 missense, 6/23 nonsense, 2/23 frameshift, and 1/23 splice site variants in the SCN. There are seven variants predicted to be gain-of-function and 13 predicted to be loss-of-function. Among 23 patients; 11 had Dravet Syndrome, 6 had early infantile developmental and epileptic encephalopathy, three had genetic epilepsy with febrile seizures plus spectrum disorder, one had self-limited familial neonatal-infantile epilepsy, one had self-limited infantile epilepsy and one had infantile childhood development epileptic encephalopathy. CONCLUSION: Our cohort consists of mainly SCN1 variants, most of them were predicted to be loss of function. Dravet syndrome was the most common phenotype. The prediction tool used in our study demonstrated overall compatibility with clinical findings. Due to the diverse clinical manifestations of variant functions, it may assist in guiding medication selection and predicting outcomes. We believe that such a tool will help the clinician in both prognosis prediction and solving therapeutic challenges in this group where refractory seizures are common.

Diagnostic yield of muscle biopsy in infants: Retrospective analysis of clinical and histopathologic findings.

The aim was to define the clinical and histopathologic findings of infants who underwent muscle biopsy and identify the diagnostic yield of muscle biopsy in this cohort. Infants who underwent muscle biopsy from January 2010 to March 2017 at a tertiary hospital were included in the study (N = 87; 64 boys (73.6%), 23 girls (26.4%); age range 0 - 2 years; mean age 9.73 ± 7.04 months). Clinical and histopathologic data were obtained from medical records. Developmental delay (64.4%) and hypotonia (59.8%) were the most frequent clinical findings, and mitochondrial disease (61%) was the most frequent clinical diagnosis, followed by muscular dystrophy (15.9%) and congenital myopathy (11.5%). Creatine kinase level was normal in 65.9% and > 1,000 U/L in 17.1%. Specific pathologic findings were identified from 38 biopsies (43.7%). The most frequent pathologic findings were features compatible with mitochondrial/metabolic myopathy (14 patients, 16.1%) and muscular dystrophy (12 patients, 13.8%). Myopathic changes were present in 7 biopsy samples (8.0%) and neurogenic changes in 5 (5.7%). The clinical and pathologic diagnoses were compatible in 24 patients (63.2%). The diagnostic yield of muscle biopsy remains significant, especially in this age group. Mitochondrial disease is a major diagnostic challenge, and muscle biopsy helps to support the clinical diagnosis and guide further studies.

Vanishing white matter disease with different faces.

PURPOSE: The goal of this study was to better understand vanishing white matter (VWM) disease, which is one of the most common hereditary white matter disorders, and its relationship to radiologic features, genetic analyses, and clinical findings. METHODS: We performed a study on 11 patients to describe the clinical and neuroimaging features of VWM. Patients were grouped into "infantile," "early childhood," and "juvenile" based on their onset age. EIF2B1-5 genes encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B) were analyzed in all patients with clinically suspected VWM disease. RESULTS: In brain magnetic resonance imaging (MRI), all patients showed white matter abnormalities with various degrees. The initial clinical presentation in five of patients was ataxia, with severe refractory epilepsy in three patients. In children with infantile-onset VWM, a rapid deterioration of motor function was detected, and the frequency of epilepsy was higher. Two patients showed manifestations of end-stage VWM disease, and one of them had chronic subdural hematoma. One of our patients and his father were diagnosed with Brugada syndrome. Sequencing of the exons and exon-intron boundaries of the EIF2B1-5 genes revealed mutations in the genes EIF2B5 (5 cases), EIF2B3 (3 cases), and EIF2B4 (2 cases). We also found a novel mutation in one patient: c.323_325delGAA in the EIF2B1 gene. CONCLUSIONS: In this study, in addition to classical clinical and radiological findings, we wanted to emphasize that we may be confronted with refractory epilepsy (early infancy), cardiac problems, and intracranial complications that may occur in advanced stages.

BEND4 as a Candidate Gene for an Infection-Induced Acute Encephalopathy Characterized by a Cyst and Calcification of the Pons and Cerebellar Atrophy.

Three siblings born to Turkish parents from the same village had normal brain development until acute neurological deterioration between 12 months and 8 years of age. Consequent loss of all acquired motor, social, and language functions following infections was associated with a pontine cyst, calcification, and cerebellar atrophy. Exome sequencing revealed a homozygous c.1297G>A (p.Gly433Ser) alteration in BEND4, which was predicted to be deleterious in in silico analysis tools and segregated in multiple affected individuals in the family. BEND4 has not been associated with any existing disease. Immunofluorescence microscopy analysis of wild-type and mutant BEND4 expressing Vero cells showed nuclear and cytoplasmic localization. Wild-type BEND4 displayed a network-like distribution, whereas mutant BEND4 showed a juxtanuclear distribution pattern. Differential proteome analysis of Vero cells expressing BEND4 revealed that mutant BEND4 expression caused selective increase in reticulocalbin-1 and endoplasmic reticulum resident protein-29. Both proteins are associated with the endoplasmic reticulum and are primarily involved in protein processing and folding pathways. Any defect or stress in protein folding creates stress on cells and may cause chronic damage. This is the first study showing that pathogenic BEND4 variants may lead to an infection-induced acute necrotizing encephalopathy as demonstrated in characteristic neuroimaging findings.

Proteomic Analysis of m.8296A>G Variation in the Mitochondrial tRNA Lys Gene.

Variation in the mitochondrial tRNA Lys gene at position 8296 was previously found to be associated with maternally inherited diabetes mellitus and deafness, hypertrophic cardiomyopathy, myoclonic epilepsy with ragged-red fibers and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The pathogenicity of the m.8296A>G variation is unclear. In this study, we aimed to analyze the mitochondrial proteome in a patient with m.8296A>G variation to elucidate the effects of this mutation at the protein level. Whole-exome sequencing and mitochondrial genome analysis were performed in a patient with sensorineural hearing impairment, cognitive impairment, leukodystrophy, migraine-like headaches, and gastrointestinal dysmotility. Mitochondrial genome analysis identified a homoplasmic m.8296A>G variation in the mitochondrial tRNA Lys gene in the proband and unaffected mother. Global mitochondrial proteome analysis was carried out in the muscle mitochondria of the index patient and a control subject. Comparative muscle mitochondrial proteome analysis revealed a total of 13 nuclear-encoded mitochondrial proteins differently expressed with respect to the control. Ten of the 13 proteins were downregulated. Most of the proteins were involved in ATP synthesis and Krebs cycle and have strong interactions with each other. We considered the m.8296A>G variation to be pathogenic with variable penetrance for our patient's phenotype, and this variation led to different expressions of nuclear-encoded proteins involved in energy metabolism.

Cytotoxic lesions of the corpus callosum in children: Etiology, clinical and radiological features, and prognosis.

OBJECTIVES: Cytotoxic lesions of the corpus callosum (CLOCCs) are secondary lesions associated with entities like infection manifested by restricted diffusion on diffusion-weighted cranial magnetic resonance imaging. Our objectives are to evaluate the clinic-radiological spectrum of pediatric patients with cytotoxic lesions of the corpus callosum (CC). METHODS: Children (0-18 years) admitted between February 2017 and May 2020 with splenial lesions showing diffusion restriction on MRI, either isolated or within involvement of other parts of the brain, were included retrospectively. The primary lesions of the CC (e.g. acute disseminated encephalomyelitis, acute ischemic infarction, and glioblastoma multiforme) were excluded. CLOCCs were divided into infection-associated, metabolic disorder-associated, and trauma-associated lesions, as well as CLOCCs involving other entities. Data were collected from the medical databases. RESULTS: Forty-one patients were determined to have CLOCCs. Twenty-five (61%) were infection-associated, nine (22%) were trauma-associated, and three (7%) were metabolic disorder-associated cases, including 2 inherited disorders of metabolism. There were four (10%) patients with other entities, three with epilepsy, and one had an apparent life-threatening event. Six patients had a known etiology among the infection-associated group; one had multisystem inflammatory syndrome caused by COVID-19 and one had been infected by COVID-19 without any complications. All the infection-associated patients with isolated splenial lesions recovered totally, although six patients required intensive care hospitalization. Four trauma-associated patients had sequela lesions. CONCLUSIONS: CLOCCs are associated with a spectrum of diseases, including the new coronavirus, COVID-19 infection. Infection-associated CLOCCs has the best prognosis, although severe cases may occur. Sequelae are possible based on the etiology.

Mild encephalitis/encephalopathy with a reversible splenial lesion in children.

PURPOSE: We aimed to present clinical and radiologic characteristics of mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) in children. METHODS: Eight children (5 boys and 3 girls; median age, 5.9 years; age range, 8 months to 14.1 years) diagnosed with MERS between September 2015 and June 2017 were included in the study. We reviewed the patient's data, including demographic characteristics, prodromal and neurologic symptoms, neurologic examination, magnetic resonance imaging and electroencephalography findings, laboratory findings, treatment, and prognosis. RESULTS: Prodromal symptoms were nausea and vomiting (n=6), diarrhea (n=6), and fever (n=3). Initial neurologic symptoms were seizures (n=4), delirious behavior (n=1), drowsiness (n=1), ataxia (n=1), transient blindness (n=2), abnormal speech (n=2), and headache (n=1). Two patients had a suspected infective agent: urinary tract infection caused by Escherichia coli and gastroenteritis caused by rotavirus. Seven patients had type I lesions, comprising characteristic symmetric ovoid (n=6) and band-shaped (n=1) T2-weighted hyperintense lesions at the spenium of corpus callosum, and one patient had type II lesion with additional symmetric posterior periventricular lesions. The lesions were isointense to mildly hypointense on T1-weighted imaging and did not show enhancement. All lesions displayed restricted diffusion. In all patients, neurologic symptoms completely normalized < 48 hours from the onset of symptoms without any sequelae. CONCLUSION: MERS has characteristic imaging features and favorable outcome.

Long-term clinical and radiologic follow-up of Schilder's disease.

BACKGROUND: Schilder's disease is a rare, subacute, or chronic demyelinating disorder that mainly affects children and generally shows a monophasic course. CASE: Here, we present three boys diagnosed with Schilder's disease, age at onset 10-14 years, and followed up for 4-8 years. All of them presented with headache, two with encephalopathy and vomiting, and one with diplopia and vertigo. Cranial magnetic resonance imaging (MRI) showed two large demyelinating lesions, asymmetric in two patients and symmetric in the other. They were treated with steroid therapy. There were no radiologic relapses after discontinuation of corticosteroid therapy in all patients, but clinical attack without objective clinical findings was observed in one patient. Mild memory deficits and decline in school performance were the only neurologic sequelae in two patients. Cranial MRI findings showed significant shrinkage, but persistent T2-weighted hyperintensity of white matter lesions and loss of ring contrast enhancement at the end of the steroid therapy. There were no differences between the radiologic findings at the end of the steroid therapy and subsequent follow-ups. CONCLUSION: Although Schilder's disease is considered to be a variant of MS, it behaves more like ADEM with its monophasic course, and low recurrence rates. Radiologic features include shrinkage of mass lesions after steroid therapy, but sequel lesions remain same at the subacute and chronic stage.

Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.

In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic evidence and functional verification indicated that both variants were deleterious, segregation with the patient phenotype established that the POLR1A defect underlies the disease, as a clinically unaffected sister also was homozygous for the OSBPL11 variant. Decreased nucleolar RPA194 was observed in the skin fibroblasts of only the affected brothers, whereas intracellular cholesterol accumulation was observed in the skin biopsies of the patients and the sister homozygous for the OSBPL11 variant. Our findings provide the first report showing a complex leukodystrophy associated with POLR1A. Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset. Of those, POLR1C is also implicated in a mandibulofacial dysostosis syndrome without leukodystrophy as POLR1A is. This syndrome is absent in the family we present.

Clinical outcomes in children with herpes simplex encephalitis receiving steroid therapy.

BACKGROUND: Herpes simplex virus encephalitis (HSE) is a significant cause of morbidity and mortality. Neurologic sequelae are common even after early initiation of acyclovir treatment. The host immune response during HSE can also lead to brain damage. There are an increasing number of reports favoring steroid use in HSE. OBJECTIVES: We aimed to compare the prognosis of children with HSE with and without steroid therapy. STUDY DESIGN: We retrospectively screened our hospital archive from 2009 to 2014 for patients diagnosed with HSE with a positive result for herpes simplex virus polymerase chain reaction in cerebrospinal fluid. Patients ≥1 month and ≤18 years at diagnosis were included in the study. Clinical outcomes in terms of cognitive function, motor function, electroencephalographic findings, seizure frequency, and radiologic findings were compared in patients who received adjuvant steroid therapy with those who did not. RESULTS: Six patients (1 boy, 5 girls; aged 4 months to 10 years) were included. Overall symptom duration before hospital admission was ≤5days. Patients received acyclovir treatment for 21-28days. Three received steroid therapy early during the disease and three patients did not. No adverse effects related to steroids were observed. Follow-up duration was 6 months to 5 years. All patients had radiologic sequelae of encephalitis. Cognition, motor function, and seizure control were better in patients who received steroid therapy. CONCLUSIONS: Adjuvant steroid therapy seems to be effective in decreasing morbidity in children with HSE but the radiologic sequelae were the same in both groups.

Head Circumference Charts for Turkish Children Aged Five to Eighteen Years.

INTRODUCTION: Most head circumference growth references are useful during the first years of life, but they are also useful for older children when screening for developmental, neurological, and genetic disorders. We aimed to develop head circumference growth reference charts for age, height, and waist circumference for Turkish children aged 5-18 years. METHODS: Head circumference, height, and waist circumference measurements were obtained from 5079 students aged 5-18 years from Izmit, Kocaeli Province, Turkey. The LMS method was used to construct reference centile curves. RESULTS: Head circumference measurements were strongly correlated with height (r=0.74), weight (r=0.76), and waist circumference (r=0.68). The mean head circumference values for boys were larger than those for girls at all ages. Compared with data from the United States, the World Health Organization, and other studies from Turkey, our data showed a decrease in head circumference at all ages for both sexes. CONCLUSION: Local growth charts can be used to evaluate head circumference growth in older Turkish children and adolescents.

Clinical and neuroradiologic variability of Aicardi-Goutiéres syndrome: Two siblings with RNASEH2C mutation and a boy with TREX1 mutation.

Aicardi-Goutières syndrome (AGS) is a rare, autosomal recessively inherited, immune-mediated neurodevelopmental disorder. The syndrome causes infantile-onset progressive encephalopathy characterized by the neuroradiologic features of basal ganglia and periventricular white matter calcification, leucodystrophy and cerebral atrophy. Lymphocytosis and elevated levels of interferon alpha (IFN-alpha) in the cerebrospinal fluid are supplementary findings of AGS. It is frequently misdiagnosed as sequelae of congenital infection (pseudo-TORCH) and mostly recognized later. We describe three AGS cases with different clinical presentation, two male siblings with RNASEH2C mutation and a boy with TREX1 mutation. These cases highlight the importance of considering AGS in the differential diagnosis of unexplained leukoencephalopathy and developmental delay. We suggest to search for intracranial calcification, especially if there are more than one affected cases in a family.

TSEN54 gene-related pontocerebellar hypoplasia type 2 presenting with exaggerated startle response: report of two cases in a family.

The pontocerebellar hypoplasias (PCHs) are a heterogeneous group of autosomal recessive disorders characterized by hypoplasia of the ventral pons and cerebellum, with variable cerebral involvement and severe psychomotor retardation. Eight different subtypes (PCH1-8) have been reported up to now. PCH2 is the most common type, generally caused by homozygous mutations in the TSEN54 gene and characterized by cerebellar hypoplasia that affects the hemispheres more severely than the vermis, progressive cerebral atrophy, microcephaly, dyskinesia, seizures and death in early childhood. We present two cousins with PCH2. Both patients presented with exaggerated startle response in the newborn period. Here we discuss the clinical and neuroradiological findings of PCH2, and its differentiation from familial startle disease or hereditary hyperekplexia.