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Dear Editor, Neuromuscular disorders still keep their mystery 1. Considering that cases with very mild symptoms cannot be diagnosed at all, it is almost impossible to know the true prevalence of these diseases 2. Relatively little information about the exact prevalence of neuromuscular disorders (NMDs) has been published 1-4. It has been reported that NMDs affect approximately one in 3500 children worldwide and X-linked dystrophinopathies have the highest incidence among them 4. Knowledge of NMDs has expanded dramatically during the last four decades thanks to advances in modern pathological techniques and genetic tests. Currently, the dystrophinopathies and most cases of limb-girdle dystrophies (LGMDs) can be diagnosed with immunohistochemical analysis of muscle tissues 4-7. It must be kept in mind that diagnoses may be suggested by the histopathological evaluation, but definitive diagnosis mostly relies on genetic analyses 5-7. It can be thought that the evaluation by molecular techniques of comprehensive panels, each aimed at identifying genetic changes in a separate disease group, reduces the importance of pathological examination of muscle tissue 6. However, the evaluation of muscle biopsy specimens is an irreplaceable approach in some cases. For example, dystrophinopathy, the most common muscular disease, has two clinically and significantly different entities: Duchenne (DMD) and Becker muscular dystrophy (BMD). Among these two diseases that start in childhood, patients with DMD die in the second decade of their lives, and patients with BMD can reach their 50s thanks to close surveillance. Interestingly, genetic changes are similar in both diseases and cannot be distinguished by genetic analyses 4. The only way to differentiate the two diseases is to show the complete loss of dystrophin as in DMD or the presence of partially functional dystrophin protein as in BMD. Therefore, demonstration of sarcolemmal dystrophin in muscle biopsy tissue specimens has vital diagnostic importance 5. Similarly, the immunohistochemical examination of muscle biopsy specimens with commercially available primary antibodies is helpful in the diagnosis of many muscular dystrophies. In addition, staining of muscle biopsy specimens with combined succinate dehydrogenasecytochrome oxidase (SDH-COX) enzyme stain is the most reliable way to diagnose mitochondrial myopathy in mitochondrial diseases with muscle involvement. Oil red O and PAS stains are also helpful for differential diagnosis of muscle involvement in metabolic diseases. In this way, unnecessary treatments can be avoided in many myopathies considered in the differential diagnosis 5-7. Histopathologic evaluation of muscle biopsy specimens is an important step in the diagnosis of a neuromuscular disease. An experienced pathologist can provide very useful clues to the clinician for differential diagnosis. Presence of inflammatory cells or regenerated fibers, group atrophy, ragged red fiber, core or targets, increase in the number of central nuclei, accumulation of glycogen or lipid and fibrosis-like pathologies can be determined in neuromuscular disease. These findings discriminate against the disease group and determine the most useful genetic analysis that may be preferred for further examination. Especially in children older than 6-8 weeks, the presence of muscle fibers showing neonatal myosin expression in immunohistochemical analysis provides further evidence for a muscle disease 5-7. Single muscle biopsy is almost always sufficient. For additional diagnostic approaches, the biopsy material stored at -80 oC should be re-evaluated by an experienced muscle pathologist with new dyes that have not been applied before. Repeat biopsy examination may be required only in newborn infants. In many muscle diseases, including DMD, recurrent biopsies only show a progression to an end-stage muscle disease and eventually the muscle tissue is replaced by fibroadipose tissue. There are few muscle diseases in which histopathologic examination of repeat biopsy specimens has diagnostic value. For example, in centronuclear myopathy, the nuclei in the muscle fibers are located peripherally at birth but migrate to the center in the following years, which is considered as a kind of dedifferentiation. Diagnosis cannot be made based on the histopathologic examination of the first biopsy specimens obtained in early childhood, and the diagnosis is usually established based on the examination of biopsy specimens harvested around the age of 4 1-3. A muscle biopsy specimen of a 10-month-old boy was evaluated histopathologically nearly five years ago. He was a hypotonic infant and had respiratory distress. There was no consanguinity between his parents. In the histopathologic examination of the first biopsy material, the presence of an increased number of central nuclei and myofibers of various sizes were detected. The patient was evaluated as a case of congenital myopathy such as centronuclear myopathy, myofiber-type disproportion and so on. In the first biopsy, there were mild differences in the size and shape of fibers. Numerous internal nuclei were not observed (Figure 1A-C). A repeat biopsy was suggested at a later date. Two years later, a new biopsy material was available. Interestingly, in the histopathologic examination of the second biopsy specimens, greater differences were seen in the sizes of fibers. Small fibers were of type1 and all fibers always had internal nuclei. Muscle injury had deteriorated to muscular dystrophy (Figure 2A-C). As the centronuclear myopathy must not have dystrophic features, and exaggerated differences in fiber sizes as seen in this case, the slides were consulted with an expert muscle pathologist, Professor Caroline Sewry, Ph.D., FRCPath, about the biopsy results who suggested a genetic evaluation. She wrote that central nuclei and small slow fibers seemed to be the main features, so a panel of congenital myopathy including MTM1, Titin (TTN), and RYR1 genes must be evaluated. Nearly a year later, we genetically evaluated these three genes and determined a homozygous MTM1 gene mutation (c.731C>T p.R241C). This variant was previously reported as pathogenic. Finally, the patient was diagnosed as a case of centronuclear myopathy caused by the mutation of the MTM1 gene on Xq28 6. In conclusion, unlike many other diseases, the histopathologic examination does not form the basis of the diagnosis of neuromuscular diseases. As in many parts of the world, a limited number of centers and a scarce number of trained pathologists are performing special muscle and nerve biopsy examinations in our country. Nevertheless, as observed in the present case, histopathologic examination, and more importantly, repeat biopsy is invaluable in the differential diagnosis. For this reason, it is very important to be able to perform the histopathologic examination of muscle and nerve biopsy specimens at least in some large centers and to provide the relevant training to the pathologists interested in this subject.

Limb-girdle muscular dystrophy type 2D (LGMD-2D) is caused by autosomal recessive defects in the alpha-sarcoglycan gene located on chromosome 17q21. In this study, we present a child with alpha-sarcoglycanopathy and describe a novel deletion in the alpha-sarcoglycan gene. A 5-year-old boy had a very high serum creatinine phosphokinase level, which was determined incidentally, and a negative molecular test for the dystrophin gene. Muscle biopsy showed dystrophic features. Immunohistochemistry showed that there was diminished expression of alpha- and gamma-sarcoglycans. DNA analysis revealed a novel 7 bp homozygous deletion in exon 3 of the alpha-sarcoglycan gene. His parents were consanguineous heterozygous carriers of the same deletion. We believe this is the first confirmed case of primary alpha-sarcoglycanopathy with a novel deletion in Turkey. In addition, this study demonstrated that both muscle biopsy and DNA analysis remain important methods for the differential diagnosis of muscular dystrophies because dystrophinopathies and sarcoglycanopathies are so similar.

Aim:To evaluate the association of etiology, continuous electroencephalography (cEEG) findings and neuroimaging findings with short-term outcomes for patients admitted to a pediatric intensive care unit (PICU) for acute encephalopathy.Materials and Methods:A total of 24 children admitted to a PICU for acute encephalopathy were enrolled into this study. The etiology, treatment, duration of stay in the PICU, their demographic information and their past medical history were recorded. cEEG was initiated as quickly as possible following admission to the PICU and continued for at least 24 hours. Their short-term prognosis was evaluated by the Pediatric Cerebral Performance Category score (PCPC) at PICU discharge.Results:The most common cause was traumatic brain injury comprising 25% (n=6) of all cases. Other common causes were asphyxia (hanging, foreign body aspiration, drowning) (n=4, 16.67%) and intoxication (n=3, 12.5%). Twenty-two patients underwent cranial imaging. The most common findings in CT were hemorrhage (n=6, 30%) and ischemia/edema (n=6, 30%). Fourteen patients had unfavorable PCPC outcome scores. There was a tendency for poorer outcomes in those patients with hemorrhage/fracture or ischemia/edema in the imaging and for those patients who needed either pre-hospital CPR or had non-convulsive seizures but without statistical significance.Conclusion:cEEG in critically ill children is useful for detecting both epileptic and non-epileptic events. The use of cEEG in PICUs can be helpful for the better management of cases.

Objective: Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome. TSC arises from mutations in either TSC1, at 9q34, or TSC2, at 16p13.3. Skin lesions, such as hypomelanotic macules, facial angiofibromas, shagreen patches, and ungual fibromas, are frequently seen in these patients. The present study aims to investigate clinical manifestations, molecular findings and phenotype-genotype correlations in 17 patients with TSC. Materials and Methods: TSC1 and TSC2 molecular analyses were performed on a next-generation sequencing platform (Illumina MiSeq). Variant interpretation was made in accordance with the American College of Medical Genetics 2015 recommendations. Results: Four patients carried a heterozygous mutation in TSC1, while the remaining seven carried mutations in TSC2. Three novel variants in TSC2 were defined. Sequencing failed to detect a mutation in six patients. In only one of these patients, multiplex ligation-dependent probe amplification (MLPA®) could be performed, and a large deletion in the TSC1 gene was detected. A wide spectrum of phenotypic features was noted throughout the study group. Dermatological findings were observed in almost all patients. Conclusion: In this study, in addition to the three novel mutations reported herein, the spectrum of TSC1 and TSC2 gene mutations and their phenotypes were reported.

Aim:A brief resolved unexplained event (BRUE) is characterized by sudden alterations in an infant’s breathing, color, tone, or responsiveness. The aim of this study was to evaluate the necessity of electroencephalography (EEG) in high-risk BRUE cases.Materials and Methods:Fifty-one patients’ cases were analyzed retrospectively. All of these patients were younger than 1 month so considered to be a high-risk group. The gestational week, the age of the patient, the duration of the event, the conditions related to the event, whether or not any intervention was needed, the type of intervention if done, if the event recurred, the number of recurrences, the state of consciousness during the event, respiratory pattern, muscle tone, sleeping position, suspicion of trauma, use of medication by mother and/or baby and smoking exposure were evaluated in detail.Results:The mean age of the patients was 15.74±14.96 days, 31 (60.78%) were male and 20 (39.21%) were female. The mean gestational age was 37.64±2.35 weeks. The neurological examinations of the patients were evaluated as normal. EEG was performed in 36 (70.58%) of the 51 patients and only one patient had sharp waves in the left hemisphere central region. In 11 patients hospitalized with a preliminary diagnosis of BRUE, final diagnoses were found as congenital pyloric stenosis, dehydration, fetal myocarditis, patent ductus arteriosus, lower respiratory tract infection and gastroesophageal reflux.Conclusion:It would be more appropriate to plan the tests to be carried out in the high-risk BRUE group by evaluating many factors such as recurrence of the event, family history, and neurological examination findings. As a result, even in the high-risk BRUE group, it would be cost effective to perform an EEG if only the clinical cues are strongly suggestive for the diagnosis of epilepsy.

INTRODUCTION: Acquired demyelinating syndromes are immune-mediated demyelinating disorders of the central nervous system. Clinical spectrum includes acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, clinically isolated syndrome, and neuromyelitis optica. Aim of this study is to present the clinical features of patients demyelinating disease other than multiple sclerosis and our therapeutic experience. METHODS: Data of 30 patients with acquired demyelinating disease followed up in Ege University Department of Child Neurology between January 2013 and January 2018 were evaluated retrospectively. Demographic data, complaints, clinical and neuroimaging findings, laboratory results, ophthalmologic findings and treatment were recorded. RESULTS: The age of the patients ranged between 3-15 years and mean age was 8.76 +- 3.59 years. The most common diagnosis was acute disseminated encephalomyelitis. The most common complaints were ataxia, headache, encephalopathy, pleome (mono + paraplegia), blurred vision and visual loss respectively. Tests were negative for oligoclonal banding in all patients. Anti-myelin oligodendrocyte antibody was positive in seven patients. One of these patients was double positive for both anti-aquaporin 4 and anti-myelin oligodendrocyte antibodies. Neuroimaging revealed findings consistent with cerebral white matter, spinal cord and optic nerve involvement. All patients were given intravenous pulse methylprednisolone therapy for the acute period DISCUSSION AND CONCLUSION: Since childhood acquired demyelinating diseases may be the first episode of multiple sclerosis, it is important to perform detailed serological tests and CSF examinations for follow-up and differential diagnosis.

Aim: The aim of this study is to determine the risk factors of epilepsy development in children with cerebral palsy. Materials and Methods: Data of 234 cerebral palsy patients treated at Ege University Pediatrics Department, Child Neurology Division between January 2008 and December 2015 were evaluated retrospectively. All patients were classified into two groups; Group I: cerebral palsy without epilepsy (n=116) and Group II: cerebral palsy with epilepsy (n=118). The clinical and laboratory findings of the groups were compared to each other, a p value of less than 0.05 was considered as statistically significant. Results: There was no significant difference between the two groups in terms of gender, gestastional age, birth type, birth weight, risk factors for cerebral palsy development (pre-/peri-/postnatal), duration of neonatal intensive care stay and the need for mechanical ventilation (p>0.05). The risk factors of epilepsy were determined as the following; the presence of neonatal convulsions, focal clonic and generalized tonic neonatal seizures, an abnormal baseline rhythm on neonatal electroencephalography (EEG), discharge from neonatal intensive care unit with at least one antiepileptic drug, spastic bilateral (tetraplegic) cerebral palsy, epileptic activity on the sixth month EEG, abnormal cranial magnetic resonance imaging findings, mental retardation, microcephaly and visual problems. Conclusion: Epilepsy is a common problem in children with cerebral palsy. Therefore, cases of cerebral palsy, especially those with the determined risk factors should be closely monitored for epilepsy in order to ensure a timely diagnosis and proper treatment.

Congenital myasthenic syndromes (CMS) are neuromuscular hereditary diseases with the symptoms of fatigue, weakness, ptosis, ophthalmoparesis and respiratory problems. This disease group is classified as CMS originating from the presynaptic region, synaptic gap and postsynaptic region according to the origin of the neuromuscular junction. Most of these patients are affected by receptor defects originating from the postsynaptic gap. Here, we present a case who was thirteen years old and had a CHRNE genotype p.Y124 *(c.372C> G) homozygous mutation, which is associated with weakness, low voice, ophthalmoparesis and frequent respiratory infection since birth. Our patient has been diagnosed with non-kinetic AChR deficiency and the case is important with the detection of a new mutation.

Hereditary neuropathy with a liability to pressure palsies (HNPP) represented by recurrent focal pressure neuropathies is rare in childhood. Here we present a 10-year-old girl admitted to our hospital with a recurrent weakness in her foot and diagnosed as HNPP with a quick Multiplex Ligation-dependent Probe Amplification test revealing PMP22 deletion.

Ring chromosome 20 (r[20]) syndrome is characterized by mild to moderate learning disability, behavioural disorders, epilepsy, and various dysmorphic features. Although still considered rare, r(20) syndrome is being increasingly diagnosed. More than 30 cases have been described in the literature since 1976. Here we report an additional case of a 14-year-old male with r(20). He had moderate to severe learning disability and epileptic seizures manifesting at about 18 months of age. During the 13 years' follow-up period he showed intractable epileptic seizures, behavioural disorders, and mild dysmorphological features including microcephaly, strabismus, micrognathia, down-slanting eyelids, and ear abnormalities. Frequent episodes of atypical absence or non-convulsive status associated with electroencephalogram changes were seen in follow-up. He was treated with several classical and new antiepileptic drugs, including intravenous immunoglobulin, corticotropin, and vagal nerve stimulation, with unsuccessful control of seizures. Finally, surgical treatment (corpus callosotomy) was performed at the age of 13 years; severity of tonic seizures was diminished, but frequency was unchanged. Although his behavioural problems, e.g. hyperactivity, were mild in early childhood they became more severe when he was 11 years old. Aggressiveness, compulsiveness with self-injury, and panic attacks developed at the age of 13 years, and were more pronounced after callosotomy. This case report provides the first description of deterioration in psychological situation in patients with r(20) intractable epilepsy. The patient was diagnosed with r(20) syndrome after 13 years of clinical follow-up. Karyotype analysis should, therefore, be performed in every patient with intractable epilepsy of unknown aetiology. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the value of vagal nerve stimulation (VNS) in improving the quality of life, seizure frequency and mood in children with pharmacoresistant epilepsy. Materials and Methods: Eleven pharmacoresistant epileptic children implanted with the VNS therapy device between 2010-2014 were included in this prospective longitudinal study. Clinical assessment for the Diagnostic and Statistical Manual of Mental Disorders-IV psychiatric disorders, schedule for affective disorders, and schizophrenia for school children were applied. Childhood Depression Inventory (CDI), Beck Depression Inventory (BDI) were filled. Child Behavior Checklist (CBCL) and the Pediatric Quality of Life Inventory (PedsQL) were filled in by parents before the implantation. All of these tests were repeated in the first and second year of implantation. Results: Mean age at the first implantation of the VNS therapy device was 11.5 (2.5-16). Mean age was 13.9 (2.5-18) years. Mean duration of epilepsy prior to VNS implantation was 6.6 years, and VNS usage period was 30.4 months (10-96). International League Against Epilepsy classification of predominant seizure type was partial in seven, and generalized in four patients. Decrease in the number of seizures was 42% and 43% in the first and the second year respectively. While four of 11 patients had no psychopathology, different problems were determined in seven patients. There was no statistically significant difference between the scores of CDI/BDI, scores of CBCL and PedsQL prior to implantation, and also did not differ 1 year and 2 years after implantation. Conclusion: VNS is partially effective in controlling drug-resistant epilepsy. Although a positive effect on depression and quality of life is reported in literature, the results of this study were not statistically significant. We think that the scores of depression inventory should gradually decrease in years as it is reported for seizure frequency.

Sturge-Weber syndrome (SWS) is a neurogenetic disease with an incidence of 1 in 20.000-50.000 live births. The less common form, which can be difficult to diagnose and only involves leptomeningeal angioma, has been defined as Type III SWS. A 5.5-month-old male patient with normal neuromotor development presented with right sided partial seizures, which had been occurring frequently for the previous two days and could not be controlled. A cranial magnetic resonance imaging showed pathological contrasts in the cortical regions involving the left hemisphere and in the leptomeningeal structures. We aim to present the case of an infant with SWS, which unlike the classical form was unidentifiable in physical examination and diagnosed using imaging methods.

Today rapidly increasing obesity causes significant morbidity and mortality. Gastric by-pass is frequently used for the treatment of morbid obesity, which cannot be controlled with diet and exercise. Although this treatment modality achieves rapid success, it also has several complications such as nutritional deficiency and its clinical results. We aimed to present a patient with polyneuropathy after having undergone gastric by-pass surgery for morbid obesity.

The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881C>A (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined. [ABSTRACT FROM AUTHOR]