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.

Radiological and Genetic Evaluation in Hypotonic Infants.

OBJECTIVE: To investigate the importance and diagnostic yield of genetic and radiological evaluations in children with hypotonia. STUDY DESIGN: Comparative observational study. Place and Duration of the Study: Department of Pediatrics Neurology, Namik Kemal University, Tekirdag, Turkey, between 2019 and 2022. METHODOLOGY: Patients' medical histories, laboratory results, radiological examinations, and genetic tests, if any, were obtained retrospectively from the patients' clinic files. Children with hypotonia detected since the infantile period and who were on regular follow-up were included in the study. Patients who lost the follow-up were excluded. RESULTS: Out of one hundred and seventy patients, 61.8% (n=105) were boys and 38.2% (n=65) were girls. The admission age of the patients ranged from 1 to 121 months; the mean age at presentation was 13.52±17.35 months. Hypotonia was central in 85.3% (n=145), peripheral in 12.4% (n=21), and mixed in 2.3% (n=4). Cerebral palsy was the predominant, non-genetic clinical cause of hypotonia (n=66, 39%). Brain magnetic resonance imaging (MRI) was normal in 48.2% (n=82). The most common MRI abnormality was periventricular leukomalacia in 15.9% (n=27). Sixty-five (38.2%) patients were diagnosed genetically. More than half of the patients with a genetic diagnosis were diagnosed by whole exome sequencing (WES). CONCLUSION: Brain MRI is the first choice for the patients with central hypotonia. Patients who cannot be diagnosed with clinical findings and brain MRI should undergo WES. This is helpful for the long-term prognosis and management. KEY WORDS: Hypotonia, Whole exome sequencing, Magnetic resonance, Spinal muscular atrophy, Cerebral palsy.

A Retrospective Analysis of the Neurological Evaluation of Cases With Neonatal Hypoglycemia.

Introduction Hypoglycemia is a common treatable metabolic disorder in the neonatal period. It can cause several neurological problems if untreated. In this study, the neurological outcomes of cases with hypoglycemia in the neonatal period were examined retrospectively, and the study aimed to determine risk factors and prognostic factors. Methods In this retrospective study, cases were followed in the pediatric neurology outpatient clinic between 2019 and 2022, and patients with a history of hypoglycemia in the neonatal period were enrolled and analyzed retrospectively. The laboratory studies and clinical findings of the cases were obtained from follow-up records from the pediatric neurology outpatient clinic retrospectively. Physical examination findings, hypoglycemia levels, and symptoms of hypoglycemia, if any, were obtained retrospectively from the discharge files of the patients. Results A total of 70 cases were included in the study. Twenty-eight were girls and 42 were boys. Forty of the cases were preterm. The number of asymptomatic cases was 38, and the number of symptomatic cases was 32. There was no significant difference in regard to the mean lowest serum glucose levels between symptomatic and asymptomatic cases. Thirty-three of the patients had neurological problems such as neuromotor developmental delay, cortical blindness, and epilepsy. Abnormal magnetic resonance imaging (MRI) findings were detected in 30 of the symptomatic cases and eight of the asymptomatic cases. The rate of neurological sequelae in asymptomatic cases was found to be significantly lower than in symptomatic cases. Conclusions Patients who have a symptomatic hypoglycemic period, maternal gestational problems, and abnormal MRI carry a high risk for neurological sequelae, and these findings indicate poor prognosis.

The effectiveness of the ketogenic diet in drug-resistant childhood epilepsy.

BACKGROUND: We aimed to investigate the effectiveness of ketogenic diet (KD) in children with various types of refractory epilepsy. METHODS: A total of 91 children (49 females) aged 3 to 193 months (median, 52 months) with drug resistant epilepsy who received KD treatment for at least 12 months were enrolled in the study. Seizure frequency, adherence to diet, reason for discontinuation of KD, and adverse effects were recorded. Response was defined as ≥50% improvement in seizure frequency compared to baseline. We also searched for influences of different variables on the outcome. RESULTS: Intent-to-treat analysis revealed an improvement in seizure frequency for ≥50% in 73.6%, 80.2%, 75.8%, 73.6%, and 70.3% of patients at month-1, -3, -6, -9, and month-12, respectively. Overall, 32 (35.2%) patients remained seizure-free at month-12. There was no significant differences between responders and nonresponders in terms of age at onset of epilepsy, age at onset of KD, gender, or etiology. Mild hyperlipidemia was associated with a higher response rate. At the last follow-up (median: 20 months), 38 (41.8%) patients were still maintained on KD. While 15.4% of patients completed the diet with a success in seizure control, remainder discontinued KD due to lack of efficacy (23.1%), non-adharence to diet (11%), intercurrent infection (4.4%), adverse effects (3.3%), and death (1.1%). CONCLUSION: Ketogenic diet treatment appears to be effective in about two-thirds of children with various types of drug-resistant epilepsy, including one-third remaining seizure free. Mild hyperlipidemia seems to be associated with a higher response rate. Discontinuation of KD is mostly due to lack of efficacy or nonadherence, and rarely side effects.

Evaluation of immunization status in patients with cerebral palsy: a multicenter CP-VACC study.

Children with chronic neurological diseases, including cerebral palsy (CP), are especially susceptible to vaccine-preventable infections and face an increased risk of severe respiratory infections and decompensation of their disease. This study aims to examine age-appropriate immunization status and related factors in the CP population of our country. This cross-sectional prospective multicentered survey study included 18 pediatric neurology clinics around Turkey, wherein outpatient children with CP were included in the study. Data on patient and CP characteristics, concomitant disorders, vaccination status included in the National Immunization Program (NIP), administration, and influenza vaccine recommendation were collected at a single visit. A total of 1194 patients were enrolled. Regarding immunization records, the most frequently administrated and schedule completed vaccines were BCG (90.8%), hepatitis B (88.9%), and oral poliovirus vaccine (88.5%). MMR was administered to 77.3%, and DTaP-IPV-HiB was administered to 60.5% of patients. For the pneumococcal vaccines, 54.1% of children received PCV in the scope of the NIP, and 15.2% of children were not fully vaccinated for their age. The influenza vaccine was administered only to 3.4% of the patients at any time and was never recommended to 1122 parents (93.9%). In the patients with severe (grades 4 and 5) motor dysfunction, the frequency of incomplete/none vaccination of hepatitis B, BCG, DTaP-IPV-HiB, OPV, and MMR was statistically more common than mild to moderate (grades 1-3) motor dysfunction (p = 0.003, p < 0.001, p < 0.001, p < 0.00, and p < 0.001, respectively). Physicians' influenza vaccine recommendation was higher in the severe motor dysfunction group, and the difference was statistically significant (p = 0.029).Conclusion: Children with CP had lower immunization rates and incomplete immunization programs. Clinicians must ensure children with CP receive the same preventative health measures as healthy children, including vaccines. What is Known: • Health authorities have defined chronic neurological diseases as high-risk conditions for influenza and pneumococcal infections, and they recommend vaccines against these infections. • Children with CP have a high risk of incomplete and delayed immunization, a significant concern given to their increased healthcare needs and vulnerability to infectious diseases. What is New: • Influenza vaccination was recommended for patients hospitalized due to pneumonia at a higher rate, and patients were administered influenza vaccine more commonly. • Children with CP who had higher levels of motor dysfunction (levels 4 and 5) were more likely to be overdue immunizations.

Effect of pyridoxine plus pyridostigmine treatment on vincristine-induced peripheral neuropathy in pediatric patients with acute lymphoblastic leukemia: a single-center experience.

BACKGROUND: Vincristine (VCR), which is a key component of chemotherapy, is important for survival. VCR is associated with a well-known side effect, including neurotoxicity. AIMS: The aim of this study was to evaluate the features of vincristine-induced peripheral neuropathy (VIPN) and the effectiveness of pyridoxine plus pyridostigmine therapy in children with acute lymphoblastic leukemia. METHODS: The WHO and NCI CTCAE neurotoxicity scorings were used to evaluate VIPN at diagnosis, in the first month, and after the third month of the treatment. The clinical features of 23 patients having acute lymphoblastic leukemia with VIPN during the period of July 2013-February 2016 were prospectively evaluated. RESULTS: The mean age was 72.8 ± 51.6 months, and 26.1%, 56.5%, and 17.4% were in standard, moderate, and high-risk groups, respectively. Neuropathy frequently occurred at induction (82.6%) and reinduction (17.4%) of the protocol. Drop foot (82.6%), leg pain (82.6%), and difficulty in walking (82.6%) were observed. The mean total cumulative dose of neuropathy occurrence was 5.6 ± 2.03 mg/m2. Our study showed that both the WHO and NCI CTCAE scorings were significantly improved via pyridoxine plus pyridostigmine therapy. CONCLUSION: The WHO and NCI CTCAE scorings may be used for evaluating neuropathy at diagnosis and follow-up of neurotoxicity with treatment. Pyridoxine plus pyridostigmine therapy may be an effective option in the treatment of VIPN.

Investigation of the most common clinical and imaging findings and the role of tubulin genes in the etiology of malformations of cortical development

Background and aim: The number of reports on the role of tubulin gene mutations (TUBA1A, TUBB2B, and TUBB3) in etiology of malformations of cortical development has peaked in recent years. We aimed to determine tubulin gene defects on a patient population with simple and complex malformations of cortical development, and investigate the relationship between tubulin gene mutations and disease phenotype. Materials and methods: We evaluated 47 patients with simple or complex malformations of cortical development, as determined by radiological examination, for demographic features, clinical findings and mutations on TUBA1A, TUBB2B, and TUBB3 genes. Results: According to the magnetic resonance imaging findings, 19 patients (40.5%) had simple malformations of cortical development and 28 (59.5%) patients had complex malformations of cortical development. Focal cortical dysplasia was the most common simple malformation, lissencephaly was the most common coexisting cortical malformation, and corpus callosum anomalies were the most common coexisting extracortical neurodevelopmental abnormalities. None of the patients had genetic alterations on TUBA1A, TUBB2B, and TUBB3 genes causing protein dysfunction. On the other hand, the frequencies of some polymorphisms were higher when compared to the literature. Conclusion: It is crucial to identify the etiology in patients with malformations of cortical development in order to provide appropriate genetic counseling and prenatal diagnosis. We consider that multicenter studies with higher patient numbers and also including other malformations of cortical development-related genes are required to determine underlying etiological factors of malformations of cortical development patients.

The Importance of Thiopurine S-Methyltransferase Gene Analysis Before Azathioprine Therapy.

Neuromyelitis optica is an inflammatory central nervous system syndrome associated with serum aquaporin-4 IgG antibody. Optic nerve and spinal cord involvement is typical. We report a 9-year-old girl with a diagnosis of neuromyelitis optica, who developed azathioprine-induced pancytopenia that was subsequently found to be caused by thiopurine-methyltransferase mutation.

Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey.

Autosomal recessive ataxias (ARAs) are a heterogeneous group of inherited neurodegenerative disorders that affect the cerebellum, the spinocerebellar tract, and/or the sensory tracts of the spinal cord. This study is aimed at establishing molecular classification and phenotypic correlation of childhood-onset ARAs in Southeast Anatolia of Turkey. Sixty-five children (aged 0 to 18) from 40 unrelated families who were analyzed through hereditary ataxia NGS panel between the years of 2015-2018 were selected for the study. Seventeen different, clinically significant ARA-related pathogenic variants were detected in 33 of 40 families (82.5%), 12 of which were noted to be unreported variants. Among these 33 families, 24 had ATM-related (72.72%), four had SACS-related (12.12%), three had COQ8A-related (9.09%), and two had APTX-related (6.06%) pathogenic variants. The c.3576G>A (p.K1192=) was the most common homozygous pathogenic ATM variant (33.33%) that was associated with milder phenotype of ataxia telangiectasia (AT) with the onset of age of 3. Patients with SACS variants demonstrated developmental delay and progressive ataxia before the age of 3. Slowly progressive ataxia and intellectual disability were the common clinical manifestations of the patients with homozygous c.1396delG (p. E466Rfs*11) pathogenic variant in COQ8A. Homozygous APTX c.689T>G (p.V230G) pathogenic variant was identified in two patients who had chief complaint of ataxic gait onset after puberty. The most common types of ARAs in this region are AT- and Charlevoix-Saguenay-type spastic ataxia. ATM gene analysis should be performed foremost on children presenting early-onset ataxia from Southeastern Anatolia. If there is a concomitant peripheral neuron involvement, SACS gene analysis should be preferred. This valuable data will be a guide for the first step molecular diagnostic approach before requesting the NGS panel for ARA.

Esophageal Atresia and Thenar Hypoplasia Associated with Asymmetric Crying Face.

Asymmetric crying face (ACF) is a minor congenital anomaly that is often associated with a high rate of major malformations and may be considered an indication of a syndromic clinical presentation. Here, we report a 21-month-old male presenting with left- sided ACF, thenar hypoplasia, and esophageal atresia. Ultrasonographic images of the volar surface of the left hand evidenced the absence of muscle tissue around the thenar prominence at the level of the first metacarpal bone. No pathogenic copy number variation was detected on array-comparative genomic hybridization analysis (CGH). The association of esophageal atresia, thenar hypoplasia, and ACF has not been reported before. We discuss the possibility of a distinct association or of a sequence of anomalies associated with ACF.

Iron supplementation should be given in breath-holding spells regardless of anemia

Background/aim: The purpose of this retrospective study was to determine the effectiveness of oral iron therapy in breath-holding spells and evaluation of electrocardiographical changes Materials and methods: Three hundred twelve children aged 1­48 months and diagnosed with breath-holding spells between January 2017 and April 2018 were included. Patients' laboratory findings were compared with 100 patients who had one simple febrile seizure. Results: Cyanotic breath-holding spells were diagnosed in 85.3% (n = 266) of patients, pallid spells in 5.1% (n = 16), and mixed-type spells in 9.6% (n = 30). Sleep electroencephalograms were applied for all patients, 98.2% (n = 306) of which were normal, while slow background rhythm was determined in 1.2% (n = 4). Epileptic activity was observed in only 2 patients (0.6%). The mean hemoglobin (Hb) value in the breath-holding spell group was 10.1 mg/dL. Patients' mean corpuscular volume (MCV) was 73 fL. Patients' Hb and MCV values were statistically significantly lower than those of the control group (P < 0.001). The difference between spell burden was not statistically significant (P = 0.691). Spell burden decreased equally in both groups. Conclusion: Oral iron therapy can be administered in breath-holding seizures irrespective of whether or not the patient is anemic.

Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation.

Gürbüz G, Mutlu Albayrak H. Schwartz Jampel syndrome responding positively to carbamazepine therapy: a case report and a novel mutation. Turk J Pediatr 2019; 61: 967-970. Schwartz Jampel syndrome was first described in 1962. It is an autosomal recessive disease with generalized myotonic myopathy and skeletal dysplasia. A mutation in the HSPG2 gene occurs. Approximately 150 cases have been reported in literature. A 4-year-old girl presented to the pediatric neurology clinic due to difficulty in walking. The patient had difficulty opening her mouth and swallowing. She was unable to eat solid foods and was bottle fed. She was able to stand leaning forward, with her legs open and with one hand supported. Bilateral blepharospasm, posterior cleft palate, microstomia, pursed lips, kyphoscoliosis, contracture in the elbows, long thin fingers and campodactyly in the bilateral 5th fingers were present. Myotonic contraction with thenar percussion was observed. Previously undescribed mutation was determined in HSPG2 gene in the genetic study. Oral carbamazepine therapy was initiated and 1.5 months later the patient`s muscle rigidity had decreased and her motor skills had improved. This report contributes to the literature by defining a new mutation in HSPG2 gene and showing the importance of early diagnosis of the disease.