Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study.

BACKGROUND: Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses. METHODS: In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. RESULTS: Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively. CONCLUSION: Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

A novel INPP4A mutation with pontocerebellar hypoplasia, myoclonic epilepsy, microcephaly, and severe developmental delay.

BACKGROUND: The inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological illnesses with clinically significant pons and cerebellum involvement. CASE REPORTS: A seven-year-old girl with pontocerebellar hypoplasia, resistant myoclonic epilepsy with axial hypotonia, microcephaly, atypical facial appearance, nystagmus, ophthalmoplegia, hyperactive tendon reflexes, spasticity, clonus, extensor plantar response, contractures in wrists and ankles and growth retardation, whole-exome sequencing was performed and a homozygous "NM_001134225.2:c.646C > T, p.(Arg216Ter)" variant was found in the INPP4A gene. CONCLUSION: INPP4A mutations should be kept in mind in cases with severely delayed psychomotor development, progressive microcephaly, resistant myoclonic epilepsy, isolated cerebellum, and pons involvement.

Wernicke`s encephalopathy manifesting with diplopia after ileojejunostomy: report of a pediatric case with Hirschsprung disease.

BACKGROUND: Wernicke`s encephalopathy (WE) is a coenzyme-induced disease with acute neuropsychiatric symptoms leading to high mortality and morbidity due to thiamine deficiency. WE is mostly caused by alcoholism in adult populations; however, it is often associated with gastrointestinal surgical procedures, recurrent vomiting, chronic diarrhea, cancer and chemotherapy treatment, systemic diseases, drugs, magnesium deficiency, and malnutrition in children. Although these predisposing factors are considered to be uncommon in children, they are actually highly frequent and can be fatal if not treated promptly. CASE: In this report, we present a patient who developed diplopia during total parenteral nutrition following surgical resection and was diagnosed with WE. The findings of the patient's cranial magnetic resonance imaging (MRI) findings were consistent with those of WE and the ocular findings of the patient resolved completely after thiamine treatment. CONCLUSION: Although WE is rare in children it can be prevented by early diagnosis and treatment and oculomotor findings such as diplopia can be a warning sign.

HMGB-1, TLR4, IL-1R1, TNF-α, and IL-1ß: novel epilepsy markers?

The purpose of this study was to compare HMGB-1, TLR4, IL-1ß, IL-1R1, and TNF-α levels in patients with mild and severe epilepsy with those in a healthy control group. Children aged 4-17 years, diagnosed with epilepsy for at least three years and with no progressive neurological disease, metabolic disease or infection, were selected for the study. The severe epilepsy group consisted of 28 children with at least one episode a week despite receiving three or more antiepileptic drugs. The mild epilepsy group consisted of 29 children with no seizures in the previous year, receiving only one antiepileptic drug, while 27 healthy children were selected as the control group. HMGB-1, TLR4, IL-1R1, TNF-α and IL-1ß levels were investigated in these three groups. The MRI findings and clinical characteristics of the patients in the epilepsy group were also compared with these markers. HMGB-1, TLR4, TNF-α, and IL-1ß levels in the severe epilepsy group were higher than in the control group and the mild epilepsy group (p<0.05), and were higher in the mild epilepsy group than in the control group (p<0.05). IL-1R1 was also higher in the severe epilepsy group than in the control group (p<0.05). In this first report to identity a possible correlation between HMGB-1, TLR4, IL-1ß, IL-1R1, and TNF-α levels and severity of epilepsy, our data demonstrates that the serum level of these cytokines is higher in cases of drug-refractory epilepsy.

Cerebral neoplasm in L-2-hydroxyglutaric aciduria: two different presentations.

BACKGROUND: L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder characterized by a slowly progressive clinical course, psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings. The diagnosis depends on the presentation of increased levels of L-2-hydroxyglutaric acid in the urine, plasma, and cerebrospinal fluids. Patients with L2HGA have an increased risk for the development of cerebral neoplasms which, though rarely, can be the initial presentation of the disease. Moreover, patients with L2HGA have an increased risk for the development of cerebral neoplasms. CASES PRESENTATION: Although psychomotor and mental retardation, macrocephaly, dysarthria, seizures, and cerebellar and extrapyramidal findings are the most common characteristics of the disease, we present two rare cases admitted with tumoral symptoms. CONCLUSION: Patients with L2HGA have an increased risk for the development of cerebral neoplasms.

Vitamin D protects against hippocampal apoptosis related with seizures induced by kainic acid and pentylenetetrazol in rats.

OBJECTIVES: The hippocampus is susceptible to damage in patients with epilepsy and in animals with seizures caused by excitotoxic agents. The effect of vitamin D on hippocampal apoptosis related with seizures has not been reported. However, epileptic patients have an increased risk of hypovitaminosis D which is most likely due to the effects of antiepileptic drugs. Therefore, in this study, it was aimed to evaluate the effects of vitamin D on hippocampal apoptosis related with seizures by using pentylenetetrazol (PTZ) and kainic acid (KA) in rats. METHODS: Male Sprague Dawley rats, aged 5.5 weeks, were randomly divided into six groups: control, vitamin D, PTZ, KA, PTZ + vitamin D and KA + vitamin D groups. The groups that received vitamin D were given 500 IU/kg of vitamin D daily for two weeks in addition to a standard diet. At the end of this period, PTZ and KA were applied to trigger seizures in the rats in the seizure groups. 24 h after the administration of PTZ and KA, the rats were decapitated. In the hippocampal region, apoptosis was assessed by TUNEL and brain-derived neurotrophic factor (BDNF), Bax, caspase-3 and c-fos activation were evaluated by immunohistochemical method. RESULTS: BDNF level increased while c-fos, Bax and caspase-3 levels decreased (p < 0.0001, in all) in the hippocampal neurons of the groups that were pre-treated with vitamin D before the administration of PTZ and KA, in comparison with the PTZ and KA groups. Vitamin D significantly decreased the number of apoptotic cells in these rats in comparison with the PTZ and KA groups (p < 0.0001). CONCLUSION: This study indicates that vitamin D has neuroprotective effects on hippocampal apoptosis induced by PTZ and KA in rats. With this study it is suggested that keeping vitamin D levels within normal limits may be beneficial for patients with epilepsy, especially children.

A Case of Wernicke Encephalopathy Developing After Ileal Bypass Surgery.

Wernicke encephalopathy is an acute neurological problem resulting from thiamine deficiency and manifesting with mental confusion, oculomotor dysfunction, and ataxia. It is associated with alcohol dependence in adults. Preparatory factors include hyperemesis gravidarum, prolonged diarrhea, prolonged parental nutrition without vitamin support, absorption disorders, anorexia, cancer, and chemotherapy. Failure to consider the clinical findings and preparatory factors of this disease, which is rare in children, can delay diagnosis. This report describes a case of Wernicke encephalopathy developing in a patient with brid ileus and receiving total parenteral nutrition after partial ileal bypass surgery. The patient's clinical and cranial magnetic resonance findings were compatible with Wernicke encephalopathy. Although these are not widespread, typical ocular findings for Wernicke encephalopathy were present. Dramatic improvements were observed in clinical, ocular, and cranial magnetic resonance findings after treatment.

Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy.

Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.

Cardiac echinococcosis associated with cerebrovascular occlusive disease and subcutaneous bullous eruptions and ulcers.

Cardiac involvement is an uncommon complication of echinococcosis. It is usually asymptomatic and may only be diagnosed incidentally. A 7-year-old boy was admitted with acute stroke and bullous and ulcerated skin lesions. He was diagnosed with cardiac echinococcosis complicated by systemic emboli to the central nervous system and superficial cutaneous arteries. In endemic areas, echinococcosis should be considered in the differential diagnosis of cardiac disease and unexplained cerebral embolism.

Methylphenidate has dose-dependent negative effects on rat spermatogenesis: decreased round spermatids and testicular weight and increased p53 expression and apoptosis.

In the present study, we aimed to evaluate the possible effects of methylphenidate on rat testes. Forty-two Wistar rats were randomly distributed into three experimental groups of 14 rats each. For 90 days, each group via gavage received the following: group 1 = tap water (control group), group 2 = 5 mg/kg/day of ritalin (methylphenidate, MPH), and group 3 = 10 mg/kg/day of ritalin. After sacrificing the animals, the body weights as well as the absolute and relative testicular weights were measured. Testes were sampled, fixed, and processed and, by histopathological examination, quantitative morphometric analysis of Sertoli cells, spermatocytes, and spermatids was performed in stages II, V, and XII. Immunohistochemistry was performed for transforming growth factor (TGF)-ß1 and p53, and the apoptotic index was assessed through the TUNEL method. Group 2 had a reduction of round spermatids in stage II. Group 3 had reduction in both stage II and stage V spermatids, as well as lower testicular weight. The p53 expression was increased in group 3. In groups 2 and 3, the TGF-ß1 expression was reduced and the apoptotic index by TUNEL was increased. Body weights remained stable on either group. Our results showed that methylphenidate might negatively affect spermatogenesis not only by reducing testicular weight and amount of round spermatids but also by increasing apoptotic death and p53 activation. The findings of the study, however, must be cautiously interpreted.

Effects of chronic treatment with valproate and oxcarbazepine on testicular development in rats.

PURPOSE: The aim of this study was to examine the potential effects of valproate (VPA) and oxcarbazepine (OXC) on testicular development in rats. METHODS: Forty-two Wistar rats were randomly divided into three groups of 14 rats each. Each group received the following via gavage over 90 days: group 1, tap water (control group); group 2, VPA (300mg/kg/day); group 3, OXC (100mg/kg/day). After sacrifice, body, testicular and epididymidis weights were measured. Testes were sampled, fixed and processed, and quantitative morphometric analysis of Sertoli cells, spermatocytes and spermatids was performed in stages II, V and XII by histopathological examination. Immunohistochemical staining was performed to transform growth factor beta 1 (TGF-ß1) and p53, and the apoptotic index was assessed using the TUNEL method. RESULTS: Testis and relative testis weights were significantly lower in the VPA group compared to the control group (p<0.05). Spermatogonia, pachytene spermatocyte and round spermatocyte numbers decreased in all stages in both the VPA and OXC groups compared to the control group, though this was not statistically significant (p>0.05). Apoptotic cell counts and p53 immunoreaction were significantly high and TGF-ß1 expression was significantly lower in the VPA group compared to that of the control group (p<0.05). In the OXC group, p53 immunoreaction and TGF-ß1 expression decreased compared to the control group, but this difference did not attain statistical significance (p>0.05). CONCLUSIONS: Our results show that VPA treatment from prepuberty to adulthood significantly negatively affects spermatogenesis, not only by reducing testicular weight, but also by increasing apoptotic death and p53 and decreasing TGF-ß1 activation. OXC has a minimal side effect on testicular development.

Histologic and morphologic effects of valproic acid and oxcarbazepine on rat uterine and ovarian cells.

PURPOSE: To determine the histologic and morphologic effects of valproic acid (VPA) and oxcarbazepine (OXC) on rat uterine and ovarian cells. METHODS: Fifty-six female prepubertal Wistar rats (21-24 days old and weighing between 47.5 and 58.1 g) were divided equally into four groups, which were given drinking water (controls), 300 mg/kg/day of VPA, 100 mg/kg/day of OXC or VPA + OXC via gavage, for 90 days. Ovaries and uteri of rats on proestrous and diestrous phases of estrous cycle were extirpated and placed in a fixation solution. The tissue specimens were assessed with apoptosis (TUNEL) staining protocols, eosinophil counting, and electron microscopic techniques. RESULTS: In uteri, apoptosis in stroma, mitochondrial swelling, and cristolysis were observed in the VPA group, and OXC led to negative effects on epithelial cell and intracellular edema. In ovaries, both drugs increased apoptosis and intracytoplasmic edema. Organelle structure disruption was also observed in the OXC group. More conspicuous degenerative modifications were determined in the VPA + OXC group. In uteri, the number of TUNEL-positive luminal epithelial cells was 7.20 +/- 1.32 in controls, and significantly increased to 29.60 +/- 1.58, 34.20 +/- 2.53, and 54.80 +/- 2.04 in VPA, OXC, and VPA + OXC groups, respectively (p < 0.001). The highest number of TUNEL-positive glandular epithelium cells was observed in the VPA + OXC group; however, the number of TUNEL-positive stroma cells was highest in the VPA group. The highest number of eosinophils in stroma was in the VPA group. CONCLUSION: VPA and OXC trigger apoptotic and degenerative effects on rat uterine and ovarian cells. VPA also prevents implantation of embryo to the uterus and causes abortion via endometrial eosinophil infiltration.

Prophylactic drugs and cytokine and leptin levels in children with migraine.

The study objective was to evaluate levels of the cytokines tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 and of leptin, and then to determine the relationship between these levels and clinical responses in children with migraine after prophylactic therapy with one of four drugs. In all, 77 children who needed prophylactic drugs were treated with cyproheptadine, amitriptyline, propranolol, or flunarizine. Serum levels of the cytokines and leptin were measured before and 4 months after the treatment. Results were compared by drug for headache frequency, severity, and duration, the PedMIDAS score, and levels of each cytokine and of leptin. Each of the four drugs not only decreased the frequency and duration but also the severity of headache, and the PedMIDAS score. None of the drugs was found to be superior to others in terms of reduction in cytokine levels (P > 0.05). Both cyproheptadine and flunarizine (but not amitriptyline and propranolol) caused an increase in leptin levels (P < 0.05). These data suggest that cytokine levels are related to clinical responses, and might help in objective evaluation of clinical response in migraine. To our knowledge, the present study is the first trial to compare the effects of prophylactic drugs, cytokine levels, and leptin levels in children with migraine.

A focal cortical dysplasia case whose seizure focuses were detected using interhemispheric grid electrode: a technical case report.

We report an 18-year-old boy who presented with seizures at the age of 12 years. He had 3 different kinds of seizures, occurring 4 to 5 times a week, despite adequate antiepileptic treatment. Magnetic resonance imaging (MRI) showed deep paramedian focal cortical dysplasia in the left parietal lobe. Ictal video-EEG demonstrated 5 seizures originating from the left parietal lobe, left hemisphere and right hemisphere. He was submitted to invasive recordings with two frontal strips and an interhemispherical grid that was advanced to the corpus callosum. The lesion and other seizure focuses were resected subpially down to the corpus callosum approximately 1 cm posterior to the motor area. His seizures resumed after three years of quiescence. Postoperative MRI investigation revealed remnants of dysplastic tissue deep in the interhemispheric region, which were silent during the invasive EEG monitorization. We want to re-emphasize that each patient with cortical dysplasia who is a candidate for epilepsy surgery should undergo detailed neuroradiological investigations as well as EEG monitorization, whereas complete resection of the lesion on the basis of findings that are obtained from neuroradiological examination might have a superior effect on the postoperative seizure outcome compared to the findings obtained from EEG recordings.

A case with a ring chromosome 22.

Ring chromosome 22, a rare cytogenetic finding, was first described in 1968, and since then about 60 patients have been reported. We describe a new patient with ring chromosome 22 syndrome and discuss the common features of the previously reported cases. Our patient had the major features of this syndrome including mental retardation, hypotonia, motor delay, microcephaly, dysplastic large ears, lack of speech, and hyperactivity disorder. Magnetic resonance imaging findings also revealed an arachnoid cyst, found in the posterior cerebellum. In patients with ring chromosome 22, variable clinical manifestations may be seen due to the size of lost sequences near the telomere. By fluorescent in situ hybridization (FISH) technique, LSI DiGeorge/VCFS/ ARSA locus-specific probes are used to detect deleted sequences. We found that 22q11.2 regions were intact on both chromosomes 22, but 22q13.3 (Arylsulfatase A; ARSA region) was absent in the ring chromosome. As far as we know this is the first reported Turkish patient in the literature.

Effects of chronic treatment with valproate and oxcarbazepine on ovarian folliculogenesis in rats.

PURPOSE: We aimed to define the morphologic effects of valproate (VPA) and oxcarbazepine (OXC) on ovarian folliculogenesis in rats. METHODS: Forty female wistar rats (21-24 days old and weighted between 46.4 and 55.3 g) were divided equally into 4 experimental groups, which were applied tap water (control group), 300 mg/kg/day VPA, 100 mg/kg/day OXC, and both VPA and OXC via gavage for 90 days. Ovaries of the rats on proestrous and diesterous phase of estrous cycle according to daily vaginal smear were taken out and placed in a fixation solution. Immunohistochemical and apoptosis (TUNEL) staining protocols were applied. RESULTS: The number of follicles decreased and that of corpora lutea increased significantly in OXC, VPA, and OXC+VPA treated groups compared with control group (p < 0.05). The number of TUNEL positive ovarian follicles was 1.40 +/- 0.52 in control group, but it significantly increased to 3.50 +/- 0.53, 3.50 +/- 0.53, and 4.90 +/- 0.88 in VPA, OXC, and VPA+OXC groups (p < 0.0001). The increase in the number of TUNEL positive granulosa cells was also significant for OXC and VPA+OXC groups (p < 0.0001). Immunohistochemical HSCORE decreased for TGF beta 1 and IGF1 staining and increased for P53 staining in all drug groups compared with control group (p < 0.001). Intensity of P53 labeling increased, while intensity of TGF beta 1, IGF-1, and GDF-9 immunoreactivity decreased significantly in all drug groups compared with control group (p < 0.001). CONCLUSION: Long-term treatment with VPA or OXC from prepuberty to adulthood causes apoptosis and deterioration of folliculogenesis in rat ovarian follicles.

Vincristine-induced peripheral neuropathy and urinary bladder paralysis in a child with rhabdomyosarcoma.

Vincristine commonly induces peripheral neuropathy but rarely causes voiding dysfunction. In this report, we describe a case of neurogenic bladder and peripheral neuropathy caused by the neurotoxic effect of vincristine and documented by urodynamic testing and electromyography. Neurologic evaluation aided in monitoring and understanding this problem.