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.

Extreme delta brush activity: Could it be a marker for early diagnosis and prognosis of anti- NMDA (N-methyl-D-aspartate) encephalitis?

Autoimmune encephalitis should be excluded in unexplained encephalitis. A significant portion of autoimmune encephalitis in childhood is anti- NMDA encephalitis. However, neuroimaging and routine diagnostic tests are inadequate, diagnosis sholud be confirmed by the demonstration of autoantibodies. The treatment may be delay in this process. Extreme delta brush waves are unique electroencephalography pattern, seen in some of Anti-NMDA encephalitis, useful for early diagnosis. Extreme delta brush activity is associated with prolonged hospitalization and illness. Despite of these, the specificity and sensitivity of this pattern is not-known clearly. We present a five years old boy with the loss of consciousness, involuntary movements, intermittant generalized tonic clonic seizures and extreme delta brush activity in electroencephalography.

Açiklanamayan ensefalit klinigi ile basvuran hastalarda otoimmun ensefalitler dislanmalidir. Çocukluk çaginda otoimmun ensefalitlerin önemli kismi anti-NMDA (N-metil-D-aspartat) ensefalitidir. Ancak nörogörüntüleme ve rutin tetkikler tanida yetersiz kalmakta, kesin tani otoantikorlarin gösterilmesi ile konulmaktadir. Bu süreçte tedavide gecikme olabilmektedir. Anti-NMDA ensefalitli olgularinin bir kisminda erken dönemde elektroensefalogramda saptanan özgül bir örnegi olan asiri delta 'brush' tanida gecikmeyi önlemektedir. Asiri delta 'brush' aktivitesi, uzamis hastalik ve hastanede kalma süresi ile iliskilendirilmistir. Tüm bu bilinenlere ragmen bu örnegin özgüllügü ve duyarliligi tam olarak bilinmemektedir. Bu yazida bilinç kaybi, istemsiz hareketler ve sik jeneralize tonik klonik nöbetler ile basvuran, elektroensefalografisinde asiri delta 'brush' gözlenen bes yasinda erkek bir hasta sunuldu.

Prevalence and severity of malnutrition in pediatric neurology outpatients with respect to underlying diagnosis and comorbid nutrition and feeding related problems.

Tekin H, Tekgül H, Yilmaz S, Arslangiray D, Reyhan H, Serdaroglu G, Gökben S. Prevalence and severity of malnutrition in pediatric neurology outpatients with respect to underlying diagnosis and co-morbid nutrition and feeding related problems. Turk J Pediatr 2018; 60: 709-717. This study aimed to determine prevalence and severity of malnutrition with respect to underlying diagnosis and co-morbid nutrition and feeding related problems in pediatric neurology outpatients. A total of 1,057 pediatric neurology outpatients (7.2±5.4 years, 56.9% males) were included. Data on patient demographics, neurological diagnosis, anthropometrics and Nutritional Questionnaire (NQ) for co-morbid feeding difficulties and nutritional problems were recorded. Epilepsy (45.2%) was the most common diagnosis, while prevalence of acute malnutrition was 17.7%. Nutritional support resulted in a significant decrease in the percentage of malnourished patients (from 17.1% to 6.7%, p˂0.001) and significant improvement in weight for height scores (increased to 81.42±8.17, p=0.045). In NQ-10 item assessment, at least one item was positive in 66.0% (gastrointestinal in 54.3%) of acutely malnourished patients, more commonly in severe acute malnutrition. NQ 4- item set of `red flags` revealed that prolonged meal time, meal time stressful to child or parent, lack of weight gain not just weight loss and cough during feeding were evident in 45.2%, 46.8%, 36.7% and 14.8% of patients with acute malnutrition, respectively; and more common in patients with severe malnutrition. NQ 4-item set of `red flags` was associated with high sensitivity (95%) and specificity (88%) in detection of malnutrition. In conclusion, our findings in a cohort of pediatric neurology outpatients revealed that 17.1% of overall patients were acutely malnourished along with higher prevalence of malnutrition in underlying diagnosis of cerebral palsy and higher likelihood of nutritional problems and feeding difficulties in severe malnutrition. Given the association of 6-month nutritional support with improved anthropometrics and decreased percentage of malnourished patients, our findings indicate that increased awareness of nutritional status and nutritional support is essential for the care of neurologically impaired children with potential benefit of identifying early feeding/swallowing related signs of malnutrition.

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights.

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis. Here, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, referred over a 5-year period (2011-2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven congenital myasthenic syndromes originating from Turkey. In total, the authors identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n = 15; 35%) were the most common type, followed by synaptic basal-lamina associated (n = 14; 33%) and presynaptic syndromes (n = 10; 23%). The authors had only 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n = 1; 2%). Knowledge on congenital myasthenic syndromes and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.

A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.

Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.

Targeted next generation sequencing: the diagnostic value in early-onset epileptic encephalopathy.

We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one. Five mutations had been previously detected (SCN1A c.842C > T (p.P281L), SCN1A c.4907G > C (p.A1636P), PCDH19 c.1091dupC (p.Y366LfsX10), CNTNAP2 c.416A > G (p.N139S), MBD5 c.3595G > A(p.Y1199R) while other seven were novel (SCN1A c.4907G > C (p.A1636P), SCN2A c.4633A > G (p.M1545 V), CDKL5 c.197_198delCT (p.L67QfsX23), FOXG1 c.*6C > T, KCNQ2 c.560c > A (p.S187Y), KCNQ2 c.835G > A (p.G279S), STXBP1 c.1105G > T (p.E369X)). Eight of 12 mutations were de novo. While the overall mutation detection rate was found 40 %, this ratio was 55.5 % (10 out of 18) and 16.6 % (2 out of 12) in patients born to nonconsanguineous parents and consanguineous parents, respectively. In conclusion, a selected gene panel approach including mainly de novo and channel-encoding genes will result in the detection of variants in isolated patients and support the channelopathy theory underlying epilepsy, while consanguineous families will remain less diagnosed. Targeted next generation sequencing approach is an efficient diagnostic tool in the detection of the genetic basis of early-onset EE.

Evaluation of ten prognostic factors affecting the outcome of West syndrome.

The aim of this study is to assess the seizure and developmental outcome and to determine the prognostic factors affecting the outcome of West syndrome in an etiologically well-defined large cohort. Demographic features, treatment modalities, etiology, seizure and developmental outcome of 216 cases with West syndrome were recorded retrospectively. Ten prognostic factors possibly affecting the outcome of West syndrome including (1) gender, (2) age at the onset (3) presence of seizures prior to spasms, (4) presence of asymmetric spasm, (5) presence of abnormal neurological signs, (6) treatment lag, (7) etiology, (8) drug chosen as the initial treatment, (9) response to initial treatment regardless of the kind, (10) development of other seizure types after spasms were evaluated in terms of seizure and developmental outcome. Twelve percent of the cases were developmentally normal at the end of 2-year follow-up. Ongoing seizures requiring antiepileptic drug medication at the last follow-up were noted in 90 % of the cases. Hypoxia (29 %), metabolic disorders (11 %), infectious diseases (9 %) and cerebral developmental disorders (8 %) were the most frequent etiological factors. Five of the ten prognostic factors (presence of seizures prior to spasms, presence of abnormal neurological signs, response to initial treatment regardless of the kind, etiology and development of other seizure types after spasms) were found to be statistically significant prognostic factors predicting the outcome. In conclusion, West syndrome is still a catastrophic epileptic encephalopathy. Preventable causes still constitute a substantial portion of the etiological causes of West syndrome. Therefore, the prevention of avoidable causes is at least as important as the treatment.

Different Neurologic Aspects of Nutritional B12 Deficiency in Infancy.

The objective of this study is to evaluate neurologic problems caused by nutritional vitamin B12 deficiency in infancy. Twenty-four cases between 2 and 18 months of age with neurologic symptoms and/or signs and diagnosed as nutritional vitamin B12 deficiency were analyzed. The most common symptoms were developmental retardation, afebrile seizures, and involuntary movements. The mean vitamin B12 levels were lower in patients with both neurologic and extraneurologic involvement when compared to those with only neurologic symptoms. All of the cases were treated with vitamin B12. In patients with severe deficiencies, involuntary movements were observed during vitamin B12 treatment using cyanocobalamin form. At the 1-year follow-up, all but 3 patients were considered neurodevelopmentally normal. The 3 patients that did not fully recover, on admission, had the lowest vitamin B12 levels. It is of great importance to prevent, diagnose, and treat vitamin B12 deficiency promptly to prevent the long-term neurologic problems.

The expanding phenotypic spectrum of ARFGEF2 gene mutation: Cardiomyopathy and movement disorder.

Mutations in ADP-ribosylation factor guanine nucleotide-exchange factor 2 (ARFGEF2) gene was recently recognized to cause bilateral periventricular nodular heterotopia, putaminal hyperintensity and movement disorder. A ten year-old girl with severe developmental and growth delay, feeding problems and involuntary movements is presented. Bilateral periventricular nodular heterotopia and putaminal hyperintensity were detected in cranial magnetic resonance imaging. Her echocardiographic examination revealed left ventricular non-compaction cardiomyopathy. Sequence analysis of ARFGEF2 gene demonstrated a homozygous c.5126G>A, p.Trp1709(∗) mutation. The mutation is the first nonsense mutation described in ARFGEF2 gene and the case is the second reported case of ARFGEF2 gene mutation with cardiomyopathy. The presented case supports the view that the presence of cardiomyopathy in ARFGEF2 gene mutations is more than a coincidence and thus expands the phenotypic spectrum of ARFGEF2 gene mutations. Mutations in the ARFGEF2 gene must be considered in the presence of bilateral periventricular nodular heterotopia and putaminal hyperintensity in children presenting with movement disorder, severe developmental delay and microcephaly. In case of ARFGEF2 gene mutation, screening for cardiomyopathy may be indicated.

Turkish cases of early infantile epileptic encephalopathy: two novel mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene.

Cyclin-dependent kinase-like 5 gene-related epileptic encephalopathy is gradually becoming better known in child neurology practice. The related gene mutations cause early infantile epileptic encephalopathy characterized by intractable epilepsy, severe mental retardation and, later, the development of Rett syndrome-like features. Herein, we report the first two Turkish cases of cyclin-dependent kinase-like 5 gene-related epileptic encephalopathy with novel mutations in exon 8, which is located in the catalytic domain of the gene.

Ictal urinary urge: localization and lateralization value in a pediatric case.

BACKGROUND: Ictal urinary urge is a rare autonomic symptom usually lateralizing to the non-dominant hemisphere and localizing to the temporal lobe. CASE REPORT: A 12-year-old boy was referred with desire to void and contraction of the left arm. The history of the case revealed tickling and an unpleasant rising feeling in the stomach and sense of fear lasting for 1 year. He had been evaluated and treated several times with the diagnosis of gastroesophageal reflux and cystitis. His cranial MRI displayed an intra-axial mass formation on the right temporal lobe. Pathological findings were consistent with a low-grade glial mass. CONCLUSION: Ictal urinary urge has a considerable value both for localization and lateralization of seizures.

Seizures due to high dose camphor ingestion.

Camphor is a cyclic ketone of the hydro aromatic terpene group. Today it is frequently used as a prescription or non-prescription topical antitussive, analgesic, anesthetic and antipruritic agent. Camphor which is considered an innocent drug by parents and physicians is a common household item which can lead to severe poisoning in children even when taken in small amounts. Neurotoxicity in the form of seizures can ocur soon after ingestion. A two-year old female patient who presented with a complaint of generalized tonic-clonic seizures after oral ingestion of camphor is presented.

Clinical characteristics and outcome of children with electrical status epilepticus during slow wave sleep.

BACKGROUND: Electrical status epilepticus in slow wave sleep (ESES) is a rare, age-related, self-limited disorder characterized as epilepsy with different seizure types, neuropsychological impairment in the form of global or selective regression of cognitive functions, motor impairment, and typical electroencephalographic (EEG) findings of continuous epileptic activity occupying 85% of nonrapid eye movement sleep. AIMS: The aim is to examine the clinical and electrophysiological findings and treatment modalities of children with ESES and to evaluate the outcome of the disorder. MATERIALS AND METHODS: Fourteen patients with a diagnosis of electrical status epilepticus during slow wave sleep and followed-up at least 2 years were included. STATISTICAL ANALYSIS: Pearson correlation test was used in the study. RESULTS: Among the 14 patients, eight of them had normal mental development before ESES. Twelve of the patients mentioned cognitive impairment and decline in school performance during ESES. After ESES, seven patients had mental retardation in different severity. One of these patients was diagnosed with benign partial epilepsy of childhood with centrotemporal spikes and had normal intelligence quotient level prior to ESES. The diagnosis of ESES was made after newly occurred different seizure types in four of the patients while two of the previously known epileptic patients presented with only severe psychiatric impairment. Valproic acid and carbamazepine were the mostly frequently used drugs before the onset of ESES. After at least 2 years of follow-up, seven patients were seizure free, but still taking antiepileptic treatment. Five patients were seizure free, while two of them had ongoing seizures despite antiepileptic therapy. CONCLUSION: ESES should be kept in mind in children with unexplained regression or stagnation of development associated with seizures or not. Sleep EEGs should be performed for timely diagnosis, proper treatment and prevention of permanent cognitive impairment.

Concomitant alpha- and gamma-sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha-sarcoglycan gene.

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.

Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2C.

OBJECTIVE: In this study, it was aimed to describe the clinical, histopathological and genetic features of 20 patients with gamma sarcoglycanopathy confirmed by muscle biopsies and genetic analysis. MATERIAL AND METHOD: We retrospectively reviewed 20 patients from whom muscle biopsy specimens were obtained between 2007 and 2012. All patients were clinically diagnosed as muscular dystrophy and biopsy materials were collected from five different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood samples of patients and genetic tests (mutation analyses for gamma sarcoglycan gene and deletion-duplication analyses for all 4 sarcoglycan genes) were performed. RESULTS: The mean age of the patients was 7.6 years (2 -21 years). Only one case (5%) was older than 14 years. The mean CPK level was 10311 U/L (1311 - 35000 U∕L). There were 4 siblings in these series. Expression defects of gamma sarcoglycan staining were determined in (15 males, and 5 females) all patients with muscle biopsy specimens. But only in 9 of them, disease-causing defects could be determined with genetic analyses. CONCLUSION: The present study has demonstrated that both examination of muscle biopsy specimens and DNA analysis remain important methods in the differential diagnosis of muscular dystrophies. Because dystrophinopathies and sarcoglycanopathies have similar clinical manifestation.

Early-onset acquired myasthenia gravis secondary to anti-muscle-specific kinase autoantibodies.

Autoimmune myasthenia gravis is rarely seen during infancy. Similar to adults, 85% to 90% of generalized pediatric myasthenia gravis cases have acetylcholine receptor antibodies. Approximately 30% of the remaining cases have antibodies against muscle-specific kinase. Information on the clinical course, treatment alternatives, and prognosis of pediatric muscle-specific kinase antibody-positive myasthenia gravis is limited because of the small number of cases. Here, we present a 14-month-old girl with muscle-specific kinase antibody-positive myasthenia gravis as one of the youngest patients described so far in the literature.

Changing views of cerebral palsy over 35 years: the experience of a center.

In this study, it was aimed to evaluate the demographic and clinical characteristics of cerebral palsy (CP) cases over a 35-year period. Findings of 442 patients with CP followed from 1995 to 2006 (Group 2) were compared with 208 patients with CP followed between 1972 and 1994 (Group 1) in the same pediatric neurology division. Ratios of both prematurity (38% vs. 17.7%) and very low birth weight (VLBW) infants (13.8% vs. 1.5%) significantly increased in Group 2. There was also a four-fold increase in cesarean delivery in Group 2 (42.3% vs. 9.6%). A significant increase in the rate of early diagnosis during the first year was also found in this group (56.9% vs. 39.4%). The rate of spastic diparesis cases has significantly increased (33.7% vs. 7.7%), while the rate of spastic tetraparesis cases has significantly decreased (63.5% vs. 37.3%). It was seen that preventable risk factors continue today.

Electrophysiologic assessment of spasticity in children using H-reflex.

We investigated a possible correlation between Hoffmann's reflex (H-reflex) and the Modified Ashworth Scale (MAS) in children with spasticity. H-reflex latencies, amplitudes (H amplitude), Hmax/Mmax amplitude, and MAS were simultaneously measured in 30 children who had bilateral spasticity on the lower extremities. Children with MAS scores of 1 and +1 composed Group I (n=11), and children with MAS scores of 2 and 3 composed Group II (n=26) and Group III (n=23), respectively. The H-reflex latencies were significantly shorter and Hmax/Mmax ratios were significantly higher in patients with cerebral palsy than controls irrespective of the degree of the MAS. The H-reflex latencies in patients with MAS of 1 or +1 were significantly longer than in patients with MAS of 2. Other than between these two groups for H-reflex latencies, no significant differences were revealed among the three different MAS groups for either H-reflex latencies or Hmax/Mmax ratios. There is a positive correlation between spasticity assessed by MAS and H-reflex. We concluded that the H-reflex is a reliable electrophysiologic test for assessment of spasticity in children.