Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

High diagnostic rate of trio exome sequencing in consanguineous families with neurogenetic diseases.

Consanguineous marriages have a prevalence rate of 24% in Turkey. These carry an increased risk of autosomal recessive genetic conditions, leading to severe disability or premature death, with a significant health and economic burden. A definitive molecular diagnosis could not be achieved in these children previously, as infrastructures and access to sophisticated diagnostic options were limited. We studied the cause of neurogenetic disease in 246 children from 190 consanguineous families recruited in three Turkish hospitals between 2016 and 2020. All patients underwent deep phenotyping and trio whole exome sequencing, and data were integrated in advanced international bioinformatics platforms. We detected causative variants in 119 known disease genes in 72% of families. Due to overlapping phenotypes 52% of the confirmed genetic diagnoses would have been missed on targeted diagnostic gene panels. Likely pathogenic variants in 27 novel genes in 14% of the families increased the diagnostic yield to 86%. Eighty-two per cent of causative variants (141/172) were homozygous, 11 of which were detected in genes previously only associated with autosomal dominant inheritance. Eight families carried two pathogenic variants in different disease genes. De novo (9.3%), X-linked recessive (5.2%) and compound heterozygous (3.5%) variants were less frequent compared to non-consanguineous populations. This cohort provided a unique opportunity to better understand the genetic characteristics of neurogenetic diseases in a consanguineous population. Contrary to what may be expected, causative variants were often not on the longest run of homozygosity and the diagnostic yield was lower in families with the highest degree of consanguinity, due to the high number of homozygous variants in these patients. Pathway analysis highlighted that protein synthesis/degradation defects and metabolic diseases are the most common pathways underlying paediatric neurogenetic disease. In our cohort 164 families (86%) received a diagnosis, enabling prevention of transmission and targeted treatments in 24 patients (10%). We generated an important body of genomic data with lasting impacts on the health and wellbeing of consanguineous families and economic benefit for the healthcare system in Turkey and elsewhere. We demonstrate that an untargeted next generation sequencing approach is far superior to a more targeted gene panel approach, and can be performed without specialized bioinformatics knowledge by clinicians using established pipelines in populations with high rates of consanguinity.

Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Sural Sparing Pattern and Sensory Ratio as Electrodiagnostic and Prognostic Markers in Pediatric Guillain-Barré Syndrome.

BACKGROUND: We aimed to evaluate the presence of sural sparing pattern (SSP) and sensory ratio in pediatric Guillain-Barré syndrome (GBS), their distribution to subtypes, and their relationship with demographic and clinical features with a focus on the disability and muscle strength. METHODS: This single-center retrospective study was conducted on pediatric GBS patients of both sexes with 2 years follow-up and two nerve conduction studies in which SSP and sensory ratio were calculated. Three subgroups of SSP were formed by separate calculation of median (SSP-m) and ulnar (SSP-u) and both median and ulnar sensory nerve action potentials (SNAPs; SSP-total). Muscle strength and disability were evaluated with the Medical Research Council (MRC) sum score and Hughes functional grading scale (HFGS), respectively. RESULTS: SSP total was identified in 70.6% (n: 24) of the patients, while sensory ratio >1 was observed in 20 (66.7%) patients. Patients with SSP-m, SSP-u, SSP-total, or sensory ratio >1 had higher HFGS scores, while patients with SSP-m, SSP-u, or SSP-total had lower MRC sum scores. SSP parameters were significantly associated with muscle strength and disability scores in acute motor axonal neuropathy patients. CONCLUSION: Both SSP and sensory ratio can be used for diagnostic and prognostic purposes. Disability and muscle strength are associated with SSP and sensory ratio in pediatric GBS.

The Effect of Nusinersen Therapy on Laboratory Parameters of Patients with Spinal Muscular Atrophy.

INTRODUCTION: We evaluated the effect of nusinersen on clinical and laboratory parameters and presented its safety and effect on laboratory parameters. METHODS: Two groups were formed from among patients with spinal muscular atrophy (SMA) followed up between September 2017 and June 2021: group 1, SMA type 1; group 2, SMA type 2 and 3. The laboratory parameters were evaluated in groups 1 and 2 between doses. Motor scale tests were performed on patients before each dose of nusinersen. RESULTS: Twenty seven patients (group 1; n = 13, group 2; n = 14) were included. The mean age (±standard deviation) at the onset of symptoms was 3 ± 1.21 (range, 1.5-6) months in group 1 and 12 ± 4.27 (range, 8-24) months in group 2. No significant laboratory treatment-related abnormalities and adverse effects were observed. The cerebrospinal fluid protein levels and the frequency of conventional LP were higher in group 1. Serum creatinine (Cr) levels were higher in group 1 before the first dose and higher in group 2 before the fifth dose (p < 0.05). With treatment, the Cr levels of group 1 decreased and group 2 remained constant or increased. We observed that the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and Hammersmith Functional Motor Scale-Expand scores increased as our patients received treatment (p < 0.05). CONCLUSION: Our results support the safety and efficacy of nusinersen. However, changes in Cr levels according to the clinical type and treatment suggested that serum Cr could be a candidate marker for treatment follow-up.

Inflammation and endothelial dysfunction in pediatric migraine patients.

BACKGROUND: Inflammation and endothelial dysfunction are the suggested underlying mechanisms in migraine. Pentraxins, C-reactive protein, erythrocyte sedimentation rate, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio are good indicators of inflammation. Alterations in insulin levels and insulin sensitivity may trigger endothelial dysfunction. This study evaluates the association between migraine and serum biomarkers of inflammation and endothelial dysfunction in children. METHODS: Children with migraine and healthy subjects were recruited. Serum samples were obtained in an attack-free period. We collected data on serum levels of complete blood cell count, C-reactive protein, erythrocyte sedimentation rate, pentraxin-3, and data from biochemical investigations. We compared these with clinical data such as age, sex, disease duration, attack frequency, attack duration, analgesic use, family history, and Pediatric Migraine Disability Assessment Questionnaire scores. RESULTS: We assessed samples from 32 children (11 boys, 21 girls) with migraine and 19 healthy controls (8 boys, 11 girls). We found significantly higher pentraxin-3, insulin, and insulin resistance in patients with migraine (P = 0.001, P = 0.032, and P = 0.008, respectively). A positive directional correlation is found between pentraxin-3 and Pediatric Migraine Disability Assessment Questionnaire scores. The best cut-off values for pentraxin-3 is determined between 12.75 pg/mL to 15 pg/mL in migraineurs. CONCLUSIONS: In conclusion increased pentraxin-3 levels support the suggestions that inflammation plays a role in pediatric migraine. The vascular endothelial dysfunction is observed by a rise in insulin and insulin resistance levels. Our findings support the idea that ongoing inflammation and vascular endothelial dysfunction between attacks may play a role in migraine pathogenesis in children.

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263.

Risk Factors of Post-Stroke Epilepsy in Children; Experience from a Tertiary Center and a Brief Review of the Literature.

OBJECTIVES: Acute seizures and post-stroke epilepsy have been reported more frequently in patients with pediatric stroke than adults. Acute seizures in the first days of a stroke may deteriorate stroke and ischemia-related neurodegeneration and contribute to the development of post-stroke epilepsy. In this study, we aimed to investigate risk factors for the development of post-stroke epilepsy in children with arterial ischemic stroke. MATERIALS AND METHODS: We recruited 86 children with arterial ischemic stroke. We analyzed variables, including age at admission, gender, complaints at presentation, focal or diffuse neurologic signs, neurologic examination findings, laboratory investigations that were conducted at admission with stroke (complete blood cell count, biochemical-infectious-metabolic-immunological investigations, vitamin B12 levels, vitamin D levels), neuroimaging results, etiologies, time of the first seizure, time of remote seizures, and development of neurologic deficit retrospectively. Seizures during the first six hours after stroke onset were defined as 'very early seizures'. 'Early seizures' were referred to seizures during the first 48 h. Patients who experienced two or more seizures that occurred after the acute phase of seizures were classified as 'epileptic.' A binary logistic regression analysis was used to estimate risk factors. RESULTS: An acute seizure was detected in 59% and post-stroke epilepsy developed in 41% of our cohort. Binary logistic regression analysis demonstrated that 'very early seizures' increased epilepsy risk six-fold. Epilepsy was 16 times higher in patients with 'early seizures'. Low vitamin D levels were defined as a risk factor for post-stroke epilepsy. CONCLUSION: Seizures in the very early period (within the first six hours) are the most significant risk factors for the development of post-stroke epilepsy Further studies regarding seizure prevention and neuroprotective therapies are needed because post-stroke epilepsy will affect long term prognosis in patients with pediatric stroke.

Neuroprotective Effects of Lacosamide and Memantine on Hyperoxic Brain Injury in Rats.

In neonates supraphysiological oxygen therapy has been demonstrated to cause neuronal death in hippocampus, prefrontal cortex, parietal cortex, and retrosplenial cortex. There is a need for the detection of novel neuroprotective drugs. Neuroprotective effects of lacosamide or memantine have been demonstrated in adult patients with ischemia, trauma and status epilepticus. The effects in immature brains may be different. This study aimed to evaluate neuroprotective effects of lacosamide and memantine treatment in a hyperoxia-induced brain injury model in immature rats. This study was performed in the Animal Experiments Laboratory of Dokuz Eylul University Faculty of Medicine. Neonatal Wistar strain rat pups were exposed to hyperoxia (80% oxygen + 20% nitrogen) for five days postnatally. They were divided into five groups; hyperoxia + lacosamide, hyperoxia + memantine, hyperoxia + lacosamide and memantine, hyperoxia + saline, control groups. After termination of the experiment, brain tissues were examined. Neuron counting in examined regions were found to be higher in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups than hyperoxia + saline group. The presence of apoptotic cells evaluated with TUNEL and active Caspase-3 in hyperoxia + memantine and hyperoxia + lacosamide and memantine groups were found to be lower compared to hyperoxia + saline group. This study demonstrates that neuron death and apoptosis in newborn rat brains after hyperoxia is reduced upon memantine treatment. This is the first study to show the effects of memantine and lacosamide on hyperoxia-induced damage in neonatal rat brains.

A Multinational Survey on Actual Diagnostics and Treatment of Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a chronic infection of the central nervous system caused by the measles virus (MV). Its prevalence remains high in resource poor countries and is likely to increase in the Northern Europe as vaccination rates decrease. Clinical knowledge of this devastating condition, however, is limited. We therefore conducted this multinational survey summarizing experience obtained from more than 500 patients treated by 24 physicians in seven countries. SSPE should be considered in all patients presenting with otherwise unexplained acquired neurological symptoms. In most patients, the diagnosis will be established by the combination of typical clinical symptoms (characteristic repetitive myoclonic jerks), a strong intrathecal synthesis of antibodies to MV and typical electroencephalogram findings (Radermecker complexes). Whereas the therapeutic use of different antiviral (amantadine, ribavirin) and immunomodulatory drugs (isoprinosine, interferons) and of immunoglobulins has been reported repeatedly, optimum application regimen of these drugs has not been established. This is partly due to the absence of common diagnostic and clinical standards focusing on neurological and psychosocial aspects. Carbamazepine, levetiracetam, and clobazam are the drugs most frequently used to control myoclonic jerks. We have established a consensus on essential laboratory and clinical parameters that should facilitate collaborative studies. Those are urgently needed to improve outcome.

Comparison of cranial magnetic resonance imaging findings and clinical features in patients with corpus callosum abnormalities.

AIM: The aim of this study was to evaluate the relationship between clinical and cranial magnetic resonance imaging findings in patients with corpus callosum (CC) abnormalities. PATIENTS AND METHODS: Between September 2010 and March 2012, patients with developmental CC abnormalities were included in the study. CC abnormalities were classified as total agenesis, partial agenesis, and callosal hypoplasia. Regarding the groups, the association between radiological abnormalities and clinical findings were evaluated. RESULTS: A total of 62 patients (32 females [51.6%] and 30 males [48.4%]) with a mean age of 18.0 ± 32.1 months were enrolled in the study. Of them, 20 patients (32.3%) had total agenesis, 9 patients (14.5%) had partial agenesis, and 33 (53.2%) patients had hypoplasia of the CC. Thirty-five cases (56.7%) had abnormal physical examination, 47 cases (75.8%) had abnormal neurological examination, and 42 cases (67.7%) had psychomotor retardation. There were no significant differences between groups regarding physical examination, psychomotor retardation, seizures, or microcephaly. Seizures, psychomotor retardation, and neurological abnormalities were significantly more frequent in patients with associated other radiological abnormalities. Posterior segment of the CC was significantly thinner in patients with psychomotor retardation and the anterior part of the CC thinner in patients with abnormal physical examination. Patients with total agenesis were more prone to seizures at an early age than patients with partial agenesis or hypoplasia. CONCLUSION: The neurological prognosis of patients with CC abnormalities is poorer in patients with an associated neuroradiological abnormality. Early development of seizures may be observed in cases with total agenesis of the CC.

Zonisamide attenuates hyperoxia-induced apoptosis in the developing rat brain.

Oxygen therapy used in the treatment of perinatal hypoxia induces neurodegeneration in babies with immature antioxidant mechanisms. Zonisamide is a new antiepileptic drug used in childhood intractable seizures. Many studies demonstrated its neuroprotective effects. There is no study evaluating its effect on hyperoxic brain injury. The aim of this study was to investigate the neuroprotective effect of zonisamide on hyperoxia-induced neonatal brain injury. A total of 21 Wistar rat pups were used. The animals were divided into three groups: control group, hyperoxia group, and zonisamide-treated group. The zonisamide-treated group received an intraperitoneal injection of zonisamide. Zonisamide significantly preserved the number of neurons in CA1 and dentate gyrus parts of hippocampus, prefrontal, and parietal cortex. Zonisamide treatment also decreased the number of apoptotic neurons in all examined parts of hippocampus, prefrontal, and parietal cortex. We suggest that zonisamide treatment may be used as a neuroprotective agent in hyperoxic brain injury.

The Paediatric migraine disability assessment score is a useful tool for evaluating prophylactic migraine treatment.

AIM: There is a need for an objective assessment scoring system to evaluate the effectiveness of prophylactic drugs in paediatric migraine, and the aim of this study was to evaluate the Paediatric Migraine Disability Assessment Score (PedMIDAS). METHODS: We recruited 88 children aged between 6 and 17 years of age with migraine. The 53 children in the treatment group were divided into three groups according to the prophylactic drug they received topiramate, flunarizine and propranolol and assessed using PedMIDAS before the start of treatment and 3 and 6 months after treatment. The 35 patients in the control group did not receive prophylactic treatment and were assessed with PedMIDAS on three occasions, 3 months apart. RESULTS: Topiramate, propranolol and flunarizine treatments significantly decreased PedMIDASs and were shown to be effective in improving the patients' quality of life. Topiramate and propranolol were more effective than flunarizine. The number of days on analgesic treatment significantly decreased in the patients who had received topiramate and propranolol treatments (p < 0.05), but remained unchanged in the flunarizine prophylaxis group (p > 0.05). CONCLUSION: The PedMIDAS scoring system is useful in evaluating the efficacy of prophylactic therapy in paediatric migraine. Topiramate and propranolol lowered the PedMIDASs better than flunarizine.

Capillary malformation-arteriovenous malformation syndrome with spinal involvement.

Capillary malformation-arteriovenous malformation (CM-AVM) is a recently identified autosomal dominant disorder. Arteriovenous lesions have been reported in the brain, limbs, and face. We report a 7-year-old patient with CM-AVM with spinal AVM, which is a rarely reported association.

Carnitine palmitoyl transferase II deficiency in an adolescent presenting with rhabdomyolysis and acute renal failure.

The most common cause of recurrent rhabdomyolysis in childhood is inherited metabolic disorders. Carnitine palmitoyl transferase II (CPT II) deficiency is a lipidosis and is a common cause of inherited recurrent myoglobinuria. The disease is inherited in autosomal recessive trait, and the clinical phenotype ranges from a severe and multisystemic infantile form to a milder muscle form, which is characterized with rhabdomyolysis and myoglobinuria. Exercise, infection, fasting, and cold are the most important triggering factors of rhabdomyolysis in CPT II deficiency. The severity of attacks is highly variable and some of these attacks may be complicated by acute renal failure. We report a case of a 13-year-old girl with recurrent rhabdomyolysis due to CPT II deficiency whose last attack was complicated by acute renal failure.

Molecular Diagnosis of Limb-Girdle Muscular Dystrophy Using Next-Generation Sequencing Panels.

Introduction: Limb-girdle muscular dystrophies (LGMDs) are clinically and genetically heterogeneous muscle disorders. We aimed to share the diagnostic yield of an NGS gene panel containing LGMD-related genes and our experience with LGMD. Methods: Between February 2019 and October 2022, patients with a suspicion of LGMD and their relatives were reviewed in terms of demographic, clinical, and individual genetic data, age of symptom onset, sex, clinical features, LGMD types, cardiac involvement, muscle biopsy results, family history, and consanguinity. Our NGS gene panel consisted of ANO5, CAPN3, CAV3, DAG1, DES, DNAJB6, DYSF, FKTN, FLNC, FRKP, GAA, GMPPB, HNRNPDL, ISPD, LIMS2, LMNA, MYOT, PLEC, POMGNT1, POMK, POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, TCAP, TNPO3, TRAPPC11, TRIM32, and TTN genes. Results: The diagnosis rate was 61.1% (11/18). Twelve (80%) patients with LGMD were male and three (20%) were female. The median age was 15.9 (range, 1.5-39) years. Our patient collective was drawn up out of patients with the following variants: LGMDR1 (n = 6; 40%), LGMDR2 (n = 4; 26.6%), LGMDR3 (n = 4; 26.6%), and LGMDR12 (n = 1; 6.7%). Conclusion: The present study showed that the NGS panel has a high success rate in the diagnosis of LGMD and contributes to early diagnosis.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study.

BACKGROUND: Various etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. METHODS: Cases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. RESULTS: The study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1-12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others". The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. CONCLUSION: Our results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri­ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Biallelic NAA60 variants with impaired n-terminal acetylation capacity cause autosomal recessive primary familial brain calcifications.

Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Incidental white matter lesions in children presenting with headache.

AIM: We aimed to describe the prevalence and significance of white matter lesions detected on magnetic resonance imaging (MRI) in children with headache. MATERIAL AND METHODS: Children who were admitted with the complaint of headache and had neuroimaging between December 2007 and June 2012 were included in the study. The clinical and neuroimaging data of the patients were retrospectively evaluated. MRI results of the patients were documented in detail. The patients with non-specific white matter lesions were called for a control visit, and current status of headache and neurological findings were determined. RESULTS: A total of 941 patients were included in the study. Sixty-one percent of the patients received cranial neuroimaging. 8.2% had only cranial computed tomography (CT), 7.5% had cranial CT and cranial MRI, and 84.3% had only cranial MRI. 22.1% of the patients had abnormal cranial MRI findings. The rate of incidental non-specific white matter changes detected in our study group was 23/527 (4.4%). Among the 23 patients, 12 (52.2%) were male and 11 (47.8%) were female. Fourteen (60.9%) had migraine without aura, 8 (34.8%) had tension-type headache, and 1 (4.3%) had migraine with aura. Mean age of patients at the time of imaging was 12.1 ± 3.4 years (range 4.0-16.0 years). All patients with non-specific white matter changes on MRI showed normal psychomotor development, and there was no history of seizures or head trauma. The physical and neurological examinations of all patients were normal. The mean clinical follow-up period of the patients was 16.8 ± 17.3 months (range 6-80 months). No patients showed neurological deterioration during the follow up. The white matter lesions were supratentorial in all patients. The mean size of the lesions was 5.1 ± 4.5 mm (minimum, 2 mm; maximum, 24 mm). Repeated radiological evaluations were performed in 11 (47.8%) of the patients. No new white matter lesions were detected in control MRI during follow up. CONCLUSION: Non-specific incidental white matter changes may be seen in children with headache. For normal clinical follow up, in the absence of evident benefits from repeated imaging studies, we suggest that repeated imaging studies are not warranted in every patient and should be tailored according to clinical course.

Caffeic acid phenethyl ester prevents apoptotic cell death in the developing rat brain after pentylenetetrazole-induced status epilepticus.

Population-based studies suggest that seizure incidence is highest during the first year of life, and early-life seizures frequently result in the development of epilepsy and behavioral alterations later in life. The early-life insults like status epilepticus often lead to epileptogenesis, a process in which initial brain injury triggers cascades of molecular, cellular, and network changes and eventually spontaneous seizures. Caffeic acid phenethyl ester is an active component of propolis obtained from honeybees and has neuroprotective properties. The aim of this study was to investigate whether caffeic acid phenethyl ester exerts neuroprotective effects on the developing rat brain after status epilepticus. Twenty-one dams reared Wistar male rats, and 21-day-old rats were divided into three groups: control group, pentylenetetrazole-induced status epilepticus group, and caffeic acid phenethyl ester-treated group. Status epilepticus was induced on the first day of experiment. Caffeic acid phenethyl ester injections (30 mg/kg intraperitoneally) started 40 min after the tonic phase of status epilepticus was reached, and the injections of caffeic acid phenethyl ester were repeated over 5 days. Rats were sacrificed, and brain tissues were collected on the 5th day of experiment after the last injection of caffeic acid phenethyl ester. Apoptotic cell death was evaluated. Histopathological examination showed that caffeic acid phenethyl ester significantly preserved the number of neurons in the CA1, CA3, and dentate gyrus regions of the hippocampus and the prefrontal cortex. It also diminished apoptosis in the hippocampus and the prefrontal cortex. In conclusion, this experimental study suggests that caffeic acid phenethyl ester administration may be neuroprotective in status epilepticus in the developing rat brain.