Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

What is the safe observation period for seizure recurrence in pediatric emergency departments?

BACKGROUND: Afebrile seizures are the common causes of emergency department (ED) admissions in childhood, and there is limited data on the observation period in emergency service follow-up of these patients in terms of seizure recurrence in the literature. This study aims to determine the seizure recurrence time in afebrile seizures and the risk factors that determine it. METHODS: Patients aged between 1 month and 18 years with afebrile seizures were included in the study. Seizure recurrence times, demographic data, diagnosis of epilepsy, use of antiseizure medications, Electroencephalography (EEG) and imaging results, structural abnormalities, hospitalizations, and treatments were recorded. RESULTS: The median age of 623 patients included in the study was 42 months (16.0-94.0 months) and 59.9% were male. Epilepsy was diagnosed in 372 (59.7%) of the patients. Short-acting benzodiazepine was administered in 249 of the cases. The mean observation time of the patients was 36 hours (24-98 hours). Electroencephalography (EEG) was applied in 437 (70.1%) of the patients and abnormality was detected in 53.5%. Seizure recurrence was observed in 149 patients (23.9%). The median time of seizure recurrence was 1.0 hour (0.5-4.0 hours). Eighty-six percent of the seizure recurrences (n = 129) occurred within the first six hours and 95.3% (n = 142) within the first 12 hours. Risk factors included a history of febrile seizures (p = 0.001, OR = 2.7), not receiving short-acting benzodiazepine therapy (p = 0.026, OR 1.7), previous structural abnormalities (p = 0.018, OR 1.8), and cluster seizures (p = 0.001, OR 6.7) for all patients and also EEG abnormalities in pediatric ED for first seizure (p = 0.012, OR 2.4). CONCLUSION: Patients with a history of febrile seizure, previous structural abnormalities, cluster seizures, EEG abnormalities in pediatric ED, and patients who didn't receive BZD treatment were at risk for seizure recurrence in the early period. Since most seizure recurrences occur within the first 6 hours, this period is the most critical time for recurrence risk.

Blood neurofilament light chain and thrombospondin-1 levels of patients with autism spectrum disorder.

BACKGROUND: Neurofilaments are intermediary filaments associated with neurodegenerative processes. Thrombospondin-1 (TSP-1) is a biological marker playing a role in synaptogenesis. This study aimed to investigate serum neurofilament light chain (NFL), and TSP1 levels of patients with autism spectrum disorder (ASD) compared to typically developing (TD) children. METHODS: Forty-three patients with ASD and forty-five TD children were included. Serum biomarker levels were measured using the sandwich ELISA technique. The Childhood Autism Rating Scale (CARS) was implemented to measure the severity of ASD. RESULTS: NFL and TSP1 levels did not differ between study groups (For NFL, ASD = 47.8 ± 11.4 vs. TD = 48.2 ± 15.3 pg/mL, p = 0.785; for TSP1, ASD = 224.4 ± 53.7 vs. TD = 224.7 ± 69.0 ng/mL, p = 0.828). Stereotyped behavior and sensory sensitivity domain of the CARS scale was negatively correlated with serum TSP-1 (r = -0.390, p = 0.010) and NFL (r = -0.377, p = 0.013) levels. Age was also positively correlated with NFL levels (r = 0.332, p = 0.030) in the ASD groups but not in the TD group. DISCUSSION: Our results did not support the neurodegenerative process of ASD. Future studies are needed to investigate neuroprogression in a longitudinal follow-up.

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice.

BACKGROUND: The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. OBJECTIVE: To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. METHODS: Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. RESULTS: Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. CONCLUSION: With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. © 2021 International Parkinson and Movement Disorder Society.

Clinical predictors of drug-resistant epilepsy in children

Background/aim: In up to 20% of epilepsy patients, seizures may not be controlled despite the use of antiepileptic drugs, either alone or in combination. These individuals are considered to have drug-resistant epilepsy. Drug-resistant epilepsy is usually associated with intellectual disability, psychiatric comorbidity, physical injury, sudden unexpected death, and low quality of life. Early detection and prediction of drug-resistant epilepsy are essential in determining the patient's most appropriate treatment option. This retrospective study aimed to determine the clinical, electroencephalographic, and radiological factors associated with medically intractable childhood seizures. Materials and methods: Data regarding 177 patients diagnosed with drug-resistant epilepsy were compared with 281 patients with drug-responsive epilepsy. Results: Univariate analysis showed that age at seizure onset, having mixed seizure types, history of status epilepticus, history of neonatal seizures, history of both having febrile and afebrile seizures, daily seizures at the onset, abnormality on the first electroencephalogram, generalized epileptic abnormality on electroencephalogram, abnormal neurodevelopmental status, abnormal neuroimaging, and having symptomatic etiology were significant risk factors for the development of drug-resistant epilepsy (p < 0.05). In multivariable analysis, having mixed seizure types, history of status epilepticus, having multiple seizures in a day, intellectual disability, symptomatic etiology, and neuroimaging abnormality remained significant predictors for developing drug-resistant epilepsy. Conclusions: In the course of childhood epilepsy, some clinical features may predict the outcome. Early identification of patients with high risk for drug-resistant epilepsy will help plan the appropriate treatment option. Further prospective studies should confirm these findings.

Herpes simplex virus-1 as a rare etiology of isolated acute cerebellitis: case report and literature review.

Acute cerebellitis is one of the most common cerebellar disorders and occurs due to para-infectious, post-infectious, or post-vaccination cerebellar inflammation. Herpes simplex virus-1 (HSV-1) is known as a common infectious cause of sporadic encephalitis. Cerebellar involvement of HSV-1 is rare and almost always associated with meningoencephalitis. To date, HSV-1 has been identified as the cause of acute isolated cerebellitis in only two patients. Here we report another case of isolated acute cerebellitis caused by HSV-1 in a 20-month-old boy.

A novel mutation in the glycine decarboxylase gene in patient with non-ketotic hyperglycinemia.

Non-ketotic hyperglycinemia (NKH) is a rare inborn error of metabolism and is caused by a glycine cleavage system deficiency. Eighty-five percent of patients present with the neonatal type of NKH, the infants initially develop lethargy, seizures, and episodes of apnea, and most often death. Between 60-90% of cases are caused by mutations in the glycine decarboxylase (GLDC). We believed that more mutation reports especially for rare disease as NKH help to evaluate the genotype-phenotype relationship in patients with GLDC. In this study, we describe a case of a neonate admitted to intensive care unit with hypotonia, respiratory failure, lethargy, poor feeding. Due to the history of 2 non-ketotic hyperglycinemia diagnosed male siblings, molecular prenatal diagnosis in patient was performed and a novel c.2963G>A (Arg998Gln) homozygous mutation within the GLDC gene has been detected. We aimed to contribute to mutation knowledge pool of GLDC gene with a novel mutation.

Assessment of neuropsychological late effects in survivors of childhood leukemia.

The neurologic dysfunctions caused by treatment may affect health and quality of life in survivors of childhood leukemia. The objective of this study was to identify the neuropsychological late effects of leukemia treatment to provide an assessment about the degree and incidence of these late effects. Neurological and ophtalmological examination, cranial magnetic resonance imaging (MRI), auditory and neurocognitive tests, and questionnaires of quality of life were performed to 44 acute leukemia survivors at least 5 years after diagnosis. Median time since completion of chemotherapy was 7.5 years (2-18) and median age at the time of the study was 16.4 years (8-31). At least one or more late effects detected by physical examination (PE), neurological tests, or neurocognitive tests encountered in 80% of the patients, and 64% of the patients specified at least one complaint in the quality of life questionnaire. MRI revealed pathological findings in 18% and electroencephalogram (EEG) abnormalities were present in 9% of the patients. Evaluation of total intelligence scores revealed that 30% of patients' IQ scores were <80 and 70% of the patients' scores demonstrated neurocognitive dysfunctions. The patients >6 years at the time of diagnosis were found to have more psychological problems and higher rates of smoking and alcohol consumption. The most frequent complaint was headache and the most common problem in school was denoted as difficulty in concentration. Our study demonstrated that most of the survivors of childhood leukemia are at risk of developing neuropsycological late effects.

Acute cervical dystonia after the first dose of butamirate citrate.

Butamirate citrate is a central-acting antitussive drug and is widely used in clinical practice in childhood. It is thought that to be centrally active antitussive drugs act through receptors in the brainstem to inhibit cough, and these findings were based on the evidence of animal models. Central nervous system adverse effects of cough suppressants are rare and include irritability, lethargy, hallucinations, and dystonic reactions. In this report, we present the first patient who developed cervical dystonia shortly after the first dose of butamirate citrate, and the patient's symptoms improved immediately after a single intramuscular dosage of biperiden.

Phrenic nerve palsy associated with brachial plexus avulsion in a pediatric patient with multitrauma.

Although brachial plexus injury occurring during multitrauma is frequent in adults, it is rarely observed in childhood. The most common cause of pediatric traumatic brachial palsy is motor vehicle accidents followed by pedestrian struck. Generally, phrenic nerve palsy accompanying brachial plexus trauma is observed in 10% to 20% of cases, but it is overlooked because unilateral injuries are frequently asymptomatic. Severe unilateral phrenic nerve palsy accompanying brachial plexus avulsion is very rare. Here, we present a pediatric case of unilateral phrenic nerve palsy associated with respiratory distress and brachial plexus avulsion due to multitrauma.

Cefixime-induced oculogyric crisis.

Oculogyric crisis is a neurologic adverse event characterized by bilateral dystonic, usually upward, conjugate eye deviations. Cefixime is a third-generation cephalosporin and is widely used in clinical practice in childhood. Confusion, encephalopathy, coma, myoclonus, nonconvulsive status epilepticus, and seizures have been described with the use of cephalosporins. We presented a cefixime-induced oculogyric crisis in a 7-year-old boy during the treatment of urinary tract infection, and this is the first case of cefixime-induced oculogyric crisis whose ocular symptoms gradually disappeared within 48 hours after the drug was discontinued.

Novel insights into PORCN mutations, associated phenotypes and pathophysiological aspects.

BACKGROUND: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants. RESULTS: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes. CONCLUSIONS: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS.

VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain.

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.

The effectiveness and tolerability of clobazam in the pediatric population: Adjunctive therapy and monotherapy in a large-cohort multicenter study.

OBJECTIVE: To evaluate the effectiveness and tolerability of clobazam therapy in the pediatric population in terms of seizure semiology, epileptic syndromes, and etiological subgroups. METHODS: A retrospective cohort study was conducted consisting of 1710 epileptic children from eight centers in seven geographic regions of Turkey. The initial efficacy of clobazam therapy was evaluated after three months of treatment. The long-term effectiveness of the drug, overall seizure outcomes, and overall therapeutic outcomes were evaluated during 12 months of therapy. RESULTS: Analysis of initial efficacy after the first three months of clobazam therapy showed that 320 (18.7 %) patients were seizure-free, 683 (39.9 %) had > 50 % seizure reductions, and 297 (17.4 %) had < 50 % seizure reductions. A positive response (seizure-free and >50 % seizure reduction) was determined for focal-onset (62.3 %) seizures, epileptic spasms (61.5 %), and generalized onset seisures (57.4). The highest positive response rate among the epileptic syndromes was for self-limited epilepsy with centrotemporal spikes (SeLECTS). The highest negative response rate was for developmental and/or epileptic encephalopathies (DEEs). Magnetic resonance imaging (MRI) revealed a structural etiological diagnosis in 25.8 % of the cohort. A higher positive response rate was observed at MRI in patients with sequelae lesions than in those with congenital lesions. The seizure recurrence rate was higher in the patient group with epilepsy with genetic and metabolic causes, in individuals with more than one seizure type, and in those using three or more antiseizure drugs. CONCLUSIONS: This cohort study provides additional evidence that clobazam is an effective and well-tolerable drug with a high seizure-free rate (18.7 %), a significant seizure reduction rate (57.3 %), and with excellent overall therapeutic outcomes with a low seizure relapse rate and considerable reversible benefits in the pediatric population.

Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy.

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.

Brain abscess caused by Lactococcus lactis cremoris in a child.

Lactococcus lactis cremoris infections are very rare in humans. It is recognized as a commensal organism of mucocutaneous surfaces of cattle, and is occasionally isolated from human mucocutaneous surfaces. We report a brain abscess caused by L. lactis cremoris in an immunocompetent child. A 19-month-old female patient was admitted with fever and vomiting. Brain computed tomography (CT) revealed brain abscess. L. lactis cremoris was isolated from culture of the abscess material. The patient was treated with pus drainage from brain abscess and antibiotics including vancomycin and meropenem. The patient recovered completely. To our knowledge, this is the first report of a L. lactis cremoris infection in children.

A rare complication of intrathecal methotrexate in a child with acute lymphoblastic leukemia.

Methotrexate (MTX) is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (ALL). Both intravenous and most commonly intrathecal routes of MTX have been implicated in acute, subacute, and chronic neurotoxicity syndromes. Subacute MTX neurotoxicity occurs within days to weeks after the intravenous or intrathecal therapy and characterized by a distinct presentation with remarkable clinical resemblance to stroke, including hemiparesis, hemisensory deficits, aphasia, dysarthria, dysphagia, and diplopia. Herein the authors describe the clinical and typical neuroimaging features of a female patient with ALL who presented with subacute MTX neurotoxicity that rapidly progressed to a severe clinical condition in a few hours but eventually resolved completely with dexamethasone and folinic acid. Subacute MTX neurotoxicity is a transient neurological dysfunction that should be considered in patients presenting with stroke-like and various neurological symptoms 10 to 14 days after intrathecal therapy and diffusion-weighted magnetic resonance imaging should be undertaken for the correct diagnosis and exclusion of possible ischemic infarct. Discontinuation of subsequent intrathecal MTX therapies should be considered in severe cases and treatment with dexamethasone and folinic acid may help to resolve the symptoms.