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.

Clinical and Genetic Spectrum of Myotonia Congenita in Turkish Children.

BACKGROUND: Myotonia congenita is the most common form of nondystrophic myotonia and is caused by Mendelian inherited mutations in the CLCN1 gene encoding the voltage-gated chloride channel of skeletal muscle. OBJECTIVE: The study aimed to describe the clinical and genetic spectrum of Myotonia congenita in a large pediatric cohort. METHODS: Demographic, genetic, and clinical data of the patients aged under 18 years at time of first clinical attendance from 11 centers in different geographical regions of Türkiye were retrospectively investigated. RESULTS: Fifty-four patients (mean age:15.2 years (±5.5), 76% males, with 85% Becker, 15% Thomsen form) from 40 families were included. Consanguineous marriage rate was 67%. 70.5% of patients had a family member with Myotonia congenita. The mean age of disease onset was 5.7 (±4.9) years. Overall 23 different mutations (2/23 were novel) were detected in 52 patients, and large exon deletions were identified in two siblings. Thomsen and Becker forms were observed concomitantly in one family. Carbamazepine (46.3%), mexiletine (27.8%), phenytoin (9.3%) were preferred for treatment. CONCLUSIONS: The clinical and genetic heterogeneity, as well as the limited response to current treatment options, constitutes an ongoing challenge. In our cohort, recessive Myotonia congenita was more frequent and novel mutations will contribute to the literature.

Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome.

OBJECTIVE: Joubert syndrome is a neurodevelopmental disorder with a distinctive hindbrain malformation called molar tooth sign, causing motor and cognitive impairments. More than 40 genes have been associated with Joubert syndrome. We aim to describe a group of Joubert syndrome patients clinically and genetically emphasizing organ involvement. METHODS: We retrospectively collected clinical information and molecular diagnosis data of 22 patients with Joubert syndrome from multiple facilities. Clinical exome or whole-exome sequencing were performed to identify causal variations in genes. RESULTS: The most common variants were in the CPLANE1, CEP290, and TMEM67 genes, and other causative genes were AHI1, ARMC9, CEP41, CSPP1, HYLS1, KATNIP, KIAA0586, KIF7, RPGRIP1L, including some previously unreported variants in these genes. Multi-systemic organ involvement was observed in nine (40%) patients, with the eye being the most common, including Leber's congenital amaurosis, ptosis, and optic nerve coloboma. Portal hypertension and esophageal varices as liver and polycystic kidney disease and nephronophthisis as kidney involvement was encountered in our patients. The HYLS1 gene, which commonly causes hydrolethalus syndrome 1, was also associated with Joubert syndrome in one of our patients. A mild phenotype with hypophyseal hormone deficiencies without the classical molar tooth sign was observed with compound heterozygous and likely pathogenic variants not reported before in the KATNIP gene. CONCLUSION: Some rare variants that display prominent genetic heterogeneity with variable severity are first reported in our patients. In our study of 22 Joubert syndrome patients, CPLANE1 is the most affected gene, and Joubert syndrome as a ciliopathy is possible without a classical molar tooth sign, like in the KATNIP gene-affected patients.

Effects of Inspiratory Muscle and Balance Training in Children with Hemiplegic Cerebral Palsy: A Randomized Controlled Trial.

The aim of the study was to investigate the effects of inspiratory muscle and balance training on pulmonary function, respiratory muscle strength (RMS), functional capacity, and balance in children with hemiplegic cerebral palsy (CP). Thirty children with hemiplegic CP (Gross Motor Function Classification System I-II) included in this study. The control group (n = 15) underwent conventional physiotherapy rehabilitation program (CPRP) that included balance exercises, and the training group's (n = 15) program included inspiratory muscle training (IMT) in addition to CPRP for 8 weeks. The outcome measures were pulmonary function test, RMS measurement, the six-minute walk test (6MWT), and balance tests. There were no significant differences in the score changes of pulmonary function, balance, and 6MWT distance between groups (p > .05), whereas maximum inspiratory and expiratory pressure further increased in the training group (p > .05). RMS assessment and the identification of children who need it, and adding IMT to CPRP will contribute greatly to the rehabilitative approach of children with CP.

First Case of MELAS Syndrome Presenting with Local Brain Edema Requiring Decompressive Craniectomy.

Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes (MELAS) syndrome is a rare but one of the most common maternally inherited multisystem disorder. Although patients with MELAS present a variable clinical profile, strokelike lesions have been detected in 90% of cases, with stroke being the first presenting symptom in 25% of cases. However, cases of local brain edema requiring decompressive craniectomy has not been reported. A 12-year-old male patient was admitted to our pediatric intensive care unit with altered mental status, seizures, and vision loss. The patient was stuporous and presented neck stiffness. Complete blood count, serum electrolytes, biochemistry (including lactate level), acute phase reactants, and repeated blood gas analysis were unremarkable. Brain magnetic resonance imaging (MRI) revealed an edematous stroke-like lesion in the right occipital lobe accompanied by brain swelling. Intravenous ceftriaxone, acyclovir, intravenous immunoglobulin (IVIG), and pulse steroid therapy were started for possible diagnosis of viral/bacterial/autoimmune encephalitis; levetiracetam, phenytoin, and an infusion of sodium thiopental were started for refractory status epilepticus; and a 3% NaCl infusion was started for local brain edema. The results of serum autoimmune encephalitis panel were negative. Further investigations for rheumatic, vascular, and metabolic disorders were unremarkable. Despite these supportive treatments, the patient was clinically decompensated due to brain swelling that progressed to the left midline shift, and he underwent decompressive craniectomy. Histologic examination of brain biopsy specimen revealed non-specific encephalitis findings. A pathogenic variant of the MT-TL1 gene (m.3243A > T), responsible for MELAS, was detected. The patient?s condition dramatically improved after specific treatment for MELAS. If the diagnosis and treatment are delayed, MELAS syndrome can cause serious brain edema, which may ultimately require decompressive craniectomy.

Expanding the Phenotype of Homozygous KCNMA1 Mutations; Dyskinesia, Epilepsy, Intellectual Disability, Cerebellar and Corticospinal Tract Atrophy

BACKGROUND: The KCNMA1 gene encodes the α-subunit of the large conductance, voltage, and calcium-sensitive potassium channel (BK channels) that plays a critical role in neuronal excitability. Heterozygous mutations in KCNMA1 were first illustrated in a large family with generalized epilepsy and paroxysmal nonkinesigenic dyskinesia. Recent research has established homozygous KCNMA1 mutations accountable for the phenotype of cerebellar atrophy, developmental delay, and seizures. CASE REPORT: Here, we report the case of a patient with a novel homozygous truncating mutation in KCNMA1 (p.Arg458Ter) presenting with both the loss- and gain-of-function phenotype with paroxysmal dyskinesia, epilepsy, intellectual delay, and corticospinal­cerebellar tract atrophy. CONCLUSION: This report extends the KNCMA1 mutation phenotype with a patient who carries a novel frameshift variant, presenting with both the gain- and loss-of-function phenotypes along with spinal tract involvement as a novel characteristic.

A Severe Congenital Neutropenia Type 4 Case (G6PC3 Mutation) Presented With Large Platelets in the Peripheral Smear.

Severe congenital neutropenia type 4 is a disorder of the hematopoietic system associated with mutations in the glucose-6-phosphatase catabolic 3 (G6PC3) gene. This disorder is characterized by neutropenia, congenital heart defects, urogenital malformations, and prominent superficial veins. To our knowledge, although intermittent thrombocytopenia is observed in this mutation, the coexistence of large thrombocytes is rarely seen. Here we present a case of severe congenital neutropenia type 4 with G6PC3 mutation and large platelets in the peripheral smear.

The role of heparan sulphate in pathogenesis of Crimean-Congo hemorrhagic fever disease.

BACKGROUND & OBJECTIVES: Crimean-Congo hemorrhagic fever (CCHF) is a viral infection typically transmitted by tick bite. This study is to define the level of heparan sulphate (HS) in serum/urine since HS may play a role in the pathogenesis of hemorrhagic events in the patients with CCHF. METHODS: In this study, the patient group consisted of 79 cases with a positive diagnosis of CCHF according to PCR/ELISA outcome among the patients referred to Cumhuriyet University, School of Medicine in 2010. A total of 81 volunteers who had not any viral or metabolic disease were enrolled as the control group. The blood samples were centrifuged, and the serum and urine samples obtained were stored at - 80°C until they were studied. Then, these samples were simultaneously dissolved, and HS level was spectrophotometrically measured using glycosaminoglycans specific 1- 9, dimethyl-methylene blue (DMMB) stain. RESULTS: A statistically significant increase in the HSserum values was found both in the individuals under and above 16 yr old in the patient groups compared to the controls (p <0.05). Also there was a statistically significant increase in the urine levels of HS in the cases >16 yr old compared to the controls (p <0.05). INTERPRETATIONS & CONCLUSION: Increase of the serum/urine levels of HS was though to be due to vascular endothelium damage and to liver injury as well as vascular endothelium damage in the patients who died. Further, comprehensive studies are needed to demonstrate whether the serum/urine levels of HS are correlated to liver and vascular endothelium damage and prognosis of the disease.

Anterior rhinomanometry and determination of nasal mucociliary clearance time with the saccharin test in children with Crimean-Congo hemorrhagic fever.

OBJECTIVES: Crimean-Congo hemorrhagic fever (CCHF), like other viral infections, may prolong mucociliary clearance time and increase nasal resistance in children. The aim of the present prospective case-control study was to study, using saccharin and anterior rhinomanometry tests, whether CCHF infections caused any change in nasal physiology. METHODS: Overall, 40 subjects, 20 of whom had CCHF (group 1) and 20 of whom were healthy controls (group 2), were enrolled in this study. The definitive diagnosis of CCHF infection was made based on typical clinical and epidemiological findings and detection of CCHF virus-specific IgM by ELISA or of genomic segments of the CCHF virus by reverse transcription-polymerase chain reaction. Anterior rhinomanometry was performed in all participants according to current recommendations of the Committee Report on Standardization of Rhinomanometry. A saccharin test was used to evaluate mucociliary clearance, and nasal mucociliary clearance time was assessed with the saccharin test as described previously. RESULTS: In our patients, the mean time from the application of saccharin crystals to the first feeling of a sweet taste was 6.77 ± 3.25 minutes (range 2-16 min). In terms of the mean time from the application of saccharin crystals to the first feeling of a sweet taste, there was no difference between two groups. The mean total air flow was 637.60 ± 76.18 mL/s (range 490-760 mL/s). The mean total nasal airway resistance was 0.24 ± 0.03 Pa/mL s (range 0.20-0.31 Pa/mL s). In terms of the degree of nasal air flow and nasal airway resistance and the total air flow and total nasal airway resistance of each nostril, there was no difference between the 2 groups. CONCLUSIONS: The results obtained in anterior rhinomanometry and saccharin test showed that there was no statistically significant difference between CCHF (+) patients and controls. These results suggest us that CCHF virus infection does not affect nasal physiology. However, this is the first study performed on this issue and further studies on larger series need to be performed.

The prevalence and outcomes of thrombocytopenia in a neonatal intensive care unit: a three-year report.

Neonatal thrombocytopenia is one of the most common hematologic disorders in neonatal intensive care units (NICUs). The purpose of this study was to determine the prevalence of thrombocytopenia and whether thrombocytopenia has an effect on the occurrence of intraventricular hemorrhage (IVH) ≥ grade 2 and on mortality rate. This study was carried out retrospectively in neonates admitted to NICU of Cumhuriyet University in Sivas, Turkey, between 2009 and 2012. Among 2218 neonates evaluated, 208 (9.4%) developed thrombocytopenia. The prevalence of IVH ≥ grade 2 was more in infants with thrombocytopenia (7.2%) than in those without thrombocytopenia (4.4%), although this was not statistically significant (P = .08). In univariate analysis, IVH ≥ grade 2 was higher in cases with very severe thrombocytopenia (35.7%, n = 5) than in those with mild (2.1%, n = 2), moderate (4.7%, n = 3), and severe thrombocytopenia (15.2%, n = 5) (P = .04). Multivariate logistic regression analysis showed that birth weight <1500 g (OR 6.2, 95% CI 3.4-9.8; P = .0001), gram-negative sepsis (OR 2.5, 95% CI 1.8-4.2; P = .01), very severe thrombocytopenia (OR 1.3, 95% CI 1.1-2.1; P = .03), and platelet transfusion ≥2 (OR 7.3, 95% CI 4.1-12.1; P = .001) were significant risk factors for mortality. The results of our study suggest that outcomes of neonates with thrombocytopenia depend not only on platelet count but also on decreased gestational age or birth weight, prenatal factors, and sepsis.

Prevalence of known mutations in the MEFV gene in a population screening with high rate of carriers.

The Familial Mediterranean Fever (FMF) shows an autosomal recessive pattern of inheritance and affects certain ethnic groups. Disease is caused by mutations in MEFV gene and more than 180 mutations have been defined in affected individuals. Current study aimed to determine the frequency-type of the mutations for MEFV gene in Sivas-middle Anatolian city. The cohort was composed of 3340 patients. MEFV gene mutations were studied by multiplex PCR based reverse hybridization stripAssay method. Patients' clinical features were; family history: 68%, erysipelas-like erythema: 17.6%, fever: 89.9%, abdominal pain: 84.2%, peritonitis: 90.2%, arthritis: 33%, pleuritis: 14.2%, parental consanguinity: 21.2%. Current results revealed that M694V is the most frequent mutation (43.12%), followed by E148Q (20.18), M680I(G/C) (15.00%) and V726A (11.32%). The study population has a high rate of carriers and the E148Q mutation frequency was found to be highest when compared to the other regions of Turkey and other Mediterranean groups.

Cerebral hemiatrophy (Dyke-Davidoff-Masson syndrome) in childhood: clinicoradiological analysis of 19 cases.

BACKGROUND: The purpose of this study was to emphasize the clinical and imaging findings of 19 child cases of cerebral hemiatrophy. METHODS: A total of 11 male and eight female patients underwent assessment with computed tomography and magnetic resonance imaging. The patients ranged from 1 to 17 years in age. The evaluated parameters were: location of the lesions, midline structural shift effect, ipsilateral calvarial and parenchymal changes. RESULTS: Left cerebral hemiatrophy was seen in 14 of the cases while right cerebral hemiatrophy was observed in five cases. Unilateral calvarial thickening was seen in 11 cases, hyperpneumatization of paranasal sinuses in five, and hypoplasia of the middle frontal cranial fossa in three patients. Cerebral peduncle atrophy was noted in seven cases. In total, 11 patients had thalamic atrophy and lentiform nucleus hypoplasia. In one case, cerebral hemiatrophy was associated with ipsilateral large schizencephalic cleft and absence of the septum pellucidum, whereas in another case, there was diffuse cerebellar atrophy associated with cerebral hemiatrophy. CONCLUSION: Computed tomography and, in particular, magnetic resonance imaging are the procedures of choice with respect to assessment of the etiology and extent of cerebral parenchymal involvement in cerebral hemiatrophy.

Serum leptin levels in children receiving long-term carbamazepine.

In this article we studied serum leptin levels in children receiving long-term carbamazepine (CBZ) therapy (mean 3.4 years) to determine whether or not there was a relationship between serum leptin level and CBZ therapy. The study includes 14 patients followed with the diagnosis of epilepsy and treated long term CBZ, and 19 healthy children. Only two (14%) patients complained about overeating and weight gain. We did not find any significant difference for age, sex, body mass index and serum leptin levels between the study and control groups (p > 0.05). If a markedly weight gain was seen in the study group, a higher levels of serum leptin could be expected. Additionally, there was not a relationship between serum leptin and CBZ levels (r: 0.48; p > 0.05). Our preliminary findings showed that long-term use of CBZ did not cause markedly weight gain in childhood and serum leptin levels did not differ from the control subjects. We think that more extensive studies should be performed about this subject.

An adrenal cyst in a newborn.

Adrenal cysts (AC) are rare, particularly in the newborn period. Almost all ACs in newborns were diagnosed on exploratory laparotomy or at autopsy. We report a newborn with an AC that was diagnosed after an exploratory laparotomy due to its rare presentation. This case shows that ACs should be considered in the differential diagnosis of an abdominal mass in the newborn period.

Effect of long-term carbamazepine therapy on serum lipids, vitamin B12 and folic acid levels in children.

Serum triglycerides, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), vitamin B12 and folic acid levels were studied in 16 children with epilepsy who had been receiving carbamazepine (CBZ), and in 16 healthy children. Our purpose was to determine whether there was any effect of CBZ therapy on serum lipids, vitamin B12 and folic acid levels. Age ranged from 5 to 19 years (12.25 +/- 3.79 years) and 5.5 to 18 years (12.16 +/- 3.53 years) in the study and control groups, respectively. The duration of CBZ therapy in the patients was between 1 and 4.5 years (3.01 +/- 1.04 years). Serum CBZ level varied between 4 and 12 microg/ml (6.26 +/- 2.07 microg/ml). There was no statistically significant difference in serum triglycerides, TC, HDL-C, LDL-C, VLDL-C or vitamin B12. However, mean folic acid level was found to be lower in the study group than that of the control group (p < 0.05). Nonetheless, serum folic acid levels were within the normal range in all patients. Our study demonstrated that CBZ therapy does not affect serum lipids, vitamin B12 and folic acid levels, and may safely be used with regard to these parameters in children.

Combined genetic defects in a child with ischemic stroke: case report.

A 10-year-old Turkish boy was admitted with mild right spastic hermiplegia. First, he experienced sudden numbness and weakness in the right extremities at the age of 2 years and was diagnosed with right hemiparesis. His parents were generally healthy and non-consanguineous. His mother suffered from deep vein thrombosis of the left lower extremity during pregnancy and had recurrent fetal loss. At the age of 10 years, a thrombophilia marker examination revealed that plasma-free protein S was 49.3% (normal range = 70-123%), and factor VIII level was found to be 470 IU/dL (normal = 150 IU/dL). The patient and his two siblings were found to be heterozygous for factor V Leiden mutation. His mother was also heterozygous for factor V Leiden mutation and had protein S deficiency. A combination of protein S deficiency, factor V Leiden mutation, and a high level of factor VIII was detected in our patient. After his first attack at the age of 2 years, in spite of no prophylaxis, he did not experience any other ischemic insult. To our knowledge, this is the first patient with these combinations of genetic defects and ischemic stroke to be reported in the literature.

Serum C-reactive protein and interleukin6 levels in neonatal sepsis.

In this article, we studied complete blood count, serum C-reactive protein (CRP) and interleukin (IL-6) levels in 30 newborn infants with sepsis at admission, in the 24th hour of admission and at the end of the treatment. Our purpose was to determine the relationship among these parameters in the early diagnosis of neonatal sepsis. In our study, there was not a significant difference in white blood cell (WBC) and thrombocyte count among the values of the first, 24th hour and end of therapy in the study group (P > 0.05). However, there was not a significant difference in B/N ratio among the values at admission, 24th hour and end of therapy in the study group (P > 0.05). Both serum CRP and IL-6 levels were found to be significantly higher than those of control subjects at the beginning (P < 0.05). Similarly, the values obtained on the 24th hour were also elevated. However, at the end of therapy both decreased to normal level (P < 0.05). Based on these data, we think that serum CRP levels only which is a simple method may be used in the diagnosis of neonatal sepsis. However, WBC and serum IL-6 levels may be useful to establish mortality, because there was a statistically significant difference for these parameters between the survivors and deaths (P < 0.05).