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.

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.

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.

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.

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.

The fate of spikes in self-limited epilepsy with centrotemporal spikes: Are clinical and baseline EEG features effective?

OBJECTIVE: The aim of this study is to evaluate the effects of clinical and electroencephalographic features on spike reduction with a focus on the first EEG characteristics in self-limited epilepsy with centrotemporal spikes (SeLECTS). METHODS: This retrospective study was conducted on SeLECTS patients of with at least five years follow-up and at least two EEG recordings in which spike wave indexes (SWI) were calculated. RESULTS: 136 patients were enrolled. Median SWI in the first and last EEGs were 39% (7.6-89%) and 0 (0-112%). Gender, seizure onset age, psychiatric diseases, seizure characteristics (semiology, duration, and relationship to sleep), last EEG time, and spike lateralization in the first EEG did not have a statistically significant effect on the SWI change. Multinomial logistic regression analysis revealed that presence of phase reversal, interhemispheric generalization, and SWI percentage had a significant effect on spike reduction. The frequency of seizures was also significantly decreased in patients with a greater decrease in SWI. Both valproate and levetiracetam were statistically superior in suppressing SWI, with no significant difference between them. CONCLUSION: Interhemispheric generalization and phase reversal in the first EEG in SeLECTS had negative effects on the spike reduction. The most effective ASMs in reducing spikes were valproate and levetiracetam.

Immunization status of patients with spinal muscular atrophy receiving nusinersen therapy.

BACKGROUND: Children with chronic neurological diseases, including spinal muscular atrophy (SMA), are particularly susceptible to vaccine-preventable infections. We aimed to evaluate the age-appropriate immunization status and its relationship with nusinersen therapy in pediatric patients with SMA. METHODS: Children with SMA who received nusinersen treatment were included in this cross-sectional prospective study. Data were collected on SMA characteristics, nusinersen therapy, vaccination status according to the National Immunization Program (NIP), administration, and influenza vaccination recommendation. RESULTS: A total of 32 patients were enrolled. In patients with SMA type 1, the frequency of under-vaccination of hepatitis B, BCG, DTaP-IPV-HiB, OPV, and MMR was statistically higher than in patients with SMA type 2-3 (p<0.001). The influenza vaccine was administered to only 9.3% of patients and was never recommended to 13 (40.6%) parents. The frequency of under-vaccination of hepatitis B, BCG, DTaP-IPV-HiB, OPV, and MMR was statistically higher in patients receiving nusinersen maintenance therapy than in those with loading doses (p<0.001). Physician recommendations for influenza and pneumococcal vaccines were significantly higher in the nusinersen maintenance group (p = 0.029). There was no statistical significance between the groups in terms of administration of influenza and pneumococcal vaccines (p = 0.470). CONCLUSION: Children with SMA had lower immunization rates and poor compliance with immunization programs. Clinicians should ensure that children with SMA receive the same preventive health measures as healthy children, including vaccinations.

Genetic, serological and clinical evaluation of childhood myasthenia syndromes- single center subgroup analysis experience in Turkey.

BACKGROUND: Congenital myasthenic syndrome is a disease that occurs due to several types such as mutations in different pre-synaptic, synaptic, post-synaptic proteins and, glycosylation defects associated with congenital myopathy. Juvenile myasthenia gravis is an autoimmune condition usually caused by antibodies targeting the acetylcholine receptor. AIMS: Our objective is to conduct an analysis on the subgroup traits exhibited by patients who have been diagnosed with congenital myasthenic syndrome and juvenile myasthenia gravis, with a focus on their long-term monitoring and management. METHODS: This study was conducted on children diagnosed with myasthenia gravis, who were under the care of Dokuz Eylul University's Department of Pediatric Neurology for a period of ten years. RESULTS: A total of 22 (12 congenital myasthenic syndrome, 10 juvenile myasthenia gravis) patients were identified. Defects in the acetylcholine receptor (6/12) were the most common type in the congenital myasthenic syndrome group. Basal-lamina-related defects (5/12) were the second most prevalent. One patient had a GFPT1 gene mutation (1/12). Patients with ocular myasthenia gravis (n = 6) exhibited milder symptoms. In the generalized myasthenia gravis group (n = 4), specifically in postpubertal girls, a more severe clinical progression was observed, leading to the implementation of more aggressive treatment strategies. CONCLUSION: This study highlights that clinical recognition of congenital myasthenic syndrome and knowledge of related genes will aid the rapid diagnosis and treatment of these rare neuromuscular disorders. Findings in the juvenile myasthenia gravis group demonstrate the impact of pubertal development and the need for timely and appropriate active therapy, including thymectomy, to improve prognosis.

DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review of the Literature.

Introduction: Congenital glycosylation disorders are multisystem diseases with heterogeneous clinical manifestations caused by defects in the synthesis of the glycan moiety of glycoproteins or glycolipids or the binding of glycans to proteins and lipids. DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) is an initiating protein in the biosynthetic pathway of dolichol-linked oligosaccharides required for protein N-glycosylation. Pathogenic variants in DPAGT1 (UDP-GlcNAc: dolichol phosphate N-acetylglucosamine-1-phosphotransferase) gene cause a rare type of congenital glycosylation disorder called DPAGT1-CDG (formerly CDG-Ij) (OMIM #608093). It is a rare autosomal recessive disease or a milder version with congenital myasthenic syndrome known as DPAGT1-CMS. A severe disease course with hypotonia, cataracts, skeletal deformities, resistant epilepsy, intellectual disability, global developmental delay, premature death has been described in most patients with DPAGT1-CDG. Patient Presentation: We describe two patients with variants in the DPAGT1 gene: an 8-month-old boy with a homozygous, missense DPAGT1:c.339T>G (p.Phe113Leu) novel variant and a 13-year-old female patient with compound heterozygous variants, DPAGT1:c.466C>T (p.Arg156Cys, R156C) and DPAGT1:c.161+5G>A. While the 8-month-old patient was diagnosed with congenital cataract at the age of 1 month, had dysmorphic findings, and epilepsy, clinical symptoms in the other patient appeared later but with more prominent muscle weakness, behavioral disorder, dysmorphic findings, and no epilepsy. Discussion: Cholinesterase inhibitor therapy was found to be effective in patients against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology. We started pyridostigmine treatment in our patient with more pronounced muscle weakness, and we saw its benefit. We aimed to present our patients diagnosed with DPAGT1-CDG due to different variants in the same gene and different clinical presentations, treatment and to compare them with other patients in the literature.

Pediatric-Onset Chronic Inflammatory Demyelinating Polyneuropathy: A Multicenter Study.

BACKGROUND: To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey. METHODS: The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics. RESULTS: A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 44.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05). CONCLUSIONS: This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response.

Anti-GQ1b-negative Miller Fisher syndrome presented with one-sided horizontal gaze palsy.

Miller Fisher syndrome classically presents with ophthalmoplegia, ataxia and areflexia. The syndrome may present rarely with atypical clinical features. Whether the central or peripheral nervous system is primarily involved remains controversial. Miller Fisher syndrome usually follows an infection, the most likely being Campylobacter jejuni. Mycoplasma pneumoniae has been reported rarely as the antecedent infectious agent in some patients. Herein, we report a 13-year-old girl with positive mycoplasma immunoglobulin (Ig)M and IgG serology who presented with one-sided horizontal gaze palsy, ataxia, areflexia, and bulbar palsy. Her cranial magnetic resonance imaging was normal and blood serum was negative for anti-GQ1b IgG antibodies.

Two cases with megalencephalic leukoencephalopathy with subcortical cysts and MLC1 mutations in the Turkish population.

Megalencephalic leukoencephalopathy with subcortical cysts is a rare leukodystrophy that is characterized by macrocephaly and a slowly progressive clinical course. It is one of the most commonly reported leukoencephalopathies in Turkey. Mutations in the MLC1 gene are the main cause of the disease. We report two patients with megalencephalic leukoencephalopathy with subcortical cysts with confirmed mutations in the MLC1 gene. The mutation in the second patient was novel. We also review identified mutations in the Turkish population.

GPR56 homozygous nonsense mutation p.R271* associated with phenotypic variability in bilateral frontoparietal polymicrogyria.

Öncü-Öner T, Ünalp A, Porsuk-Doru I, Agilkaya S, Güleryüz H, Saraç A, Ergüner B, Yüksel B, Hiz-Kurul S, Cingöz S. GPR56 homozygous nonsense mutation p.R271* associated with phenotypic variability in bilateral frontoparietal polymicrogyria. Turk J Pediatr 2018; 60: 229-237. Polymicrogyria is a disorder of neuronal migration characterized by excessive cortical folding and partially fused gyri separated by shallow sulci. Homozygous mutations in the GPR56 gene, which regulates migration of neural precursor cells, are associated with bilateral frontoparietal polymicrogyria (BFPP) syndrome including white matter changes, brainstem and cerebellar involvement. Herein, we describe three siblings of consanguineous parents with a homozygous germline mutation (p.R271*) located in the seventh exon of the GPR56 gene that was previously detected in only one Portuguese patient. Phenotypic/genotypic relationships were analysed according to the clinical characteristics in only index patient. While earlier reported patient was exhibiting seizures provoked by hot water, macrocephaly, cerebellar/brainstem hypoplasia and corpus callosum abnormalities, the index patient showed only hypoplasia of brainstem, focal onset bilateral tonic clonic seizure. Despite the phenotypic similarities in two patients, the potential causes of the variation in the expression of the p.R271* variant between the two affected families might be genetic or epigenetic factors beyond the GPR56 gene. Consequently, the present findings show that the same mutation in GPR56 gene can have different phenotypic effects. Therefore, additional functional studies are needed to detect the phenotypic spectrum of the p.R271* mutation in GPR56, and provide insight into the mechanism of normal cortical development and regional patterning of the cerebral cortex.

Expanding spectrum of SCN1A-related phenotype with novel mutations.

Mutations in the genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes, with most of the mutations occurring in SCN1A gene. It is one of the most well-researched epilepsy genes. The SCN1A gene, which seems to be a relevant regulator of excitability of the CNS, is implicated in various epilepsy phenotypes through various genetic mechanisms ranging from common variants to rare monogenic variants. It is known that SCN1A gene is tightly linked to severe myoclonic epilepsy of infancy (SMEI). However, its phenotypic spectrum is expanding. Here, we report clinical and genetic findings of 10 patients with SCN1A mutations where two of them were found to have novel mutations. Our findings support understanding and updating knowledge on the correlation between phenotype distribution and location and type of mutations in SCN1A-related disorders.

Occipital cortex dysgenesis with white matter changes due to mutations in Laminin a2.

Yis U, Dixit V, Isikay S, Karakaya M, Baydan F, Diniz G, Polat I, Hiz-Kurul S, Çirak S. Occipital cortex dysgenesis with white matter changes due to mutations in Laminin a2. Turk J Pediatr 2017; 59: 338-341. Laminin α2 related congenital muscular dystrophy is one of the most common congenital muscular dystrophies of childhood with or without clinical evidence of central nervous system involvement. It may be associated with significant white matter abnormalities resembling leukodystrophies. In this study, we elaborated on two cases with laminin α2 related congenital muscular dystrophy who had occipital cortex dysgenesis in addition to characteristic white matter abnormalities. Although laminin α2 related congenital muscular dystrophy with white matter abnormalities is known, the association with occipital cortex dysplasia has been not well recognized by clinical colleagues.