Fatma Mujgan Sonmez

Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjögren syndrome

Marinesco-Sjögren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjögren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjögren syndrome triad (ataxia, cataracts, myopathy) whereas the detection rate in the group of patients with more variable phenotypic presentation was below 3% (1/37). We report 16 unrelated families with a total of 19 different SIL1 mutations. Among these mutations are 15 previously unreported changes, including single- and multi-exon deletions. Based on data from our screening cohort and data compiled from the literature we found that SIL1 mutations are invariably associated with the combination of a cerebellar syndrome and chronic myopathy. Cataracts were observed in all patients beyond the age of 7 years, but might be missing in infants. Six patients with SIL1 mutations had no intellectual disability, extending the known wide range of cognitive capabilities in Marinesco-Sjögren syndrome to include normal intelligence. Modestly constant features were somatic growth retardation, skeletal abnormalities and pyramidal tract signs. Examination of mutant SIL1 expression in cultured patient lymphoblasts suggested that SIL1 mutations result in severely reduced SIL1 protein levels irrespective of the type and position of mutations. Our data broaden the SIL1 mutation spectrum and confirm that SIL1 is the major Marinesco-Sjögren syndrome gene. SIL1 patients usually present with the characteristic triad but cataracts might be missing in young children. As cognitive impairment is not obligatory, patients without intellectual disability but a Marinesco-Sjögren syndrome-compatible phenotype should receive SIL1 mutation analysis. Despite allelic heterogeneity and many families with private mutations, the phenotype related to SIL1 mutations is relatively homogenous. Based on SIL1 expression studies we speculate that this may arise from a uniform effect of different mutations on protein expression.

Parental-reported drug allergy in 6-to 9-yr-old urban schoolchildren

Epidemiologic studies about the prevalence of adverse drug reactions in children are scarce compared to reports in adults. To assess the prevalence of parental‐reported drug allergy in 6‐ to 9‐yr‐old urban school children, we performed a cross‐sectional study of 6‐ to 9‐yr‐old urban children from the eastern Black Sea region of Turkey during the year 2004, using a self‐administered questionnaire by parents. Response rate was 81.6% (2855/3500). The prevalence of parental‐reported drug allergy was 2.8% (81/2855). The most common parental‐reported drugs were penicillins and other β‐lactams (59.3%), trimethoprim–sulfamethoxazole (11.1%), and acetylsalicylic acid and other non‐steroidal anti‐inflammatory drugs (NSAIDs) (9.9%). The most commonly reported clinical manifestations were cutaneous (n = 76, 93.8%) followed by gastrointestinal (n = 17, 21%) symptoms. In 19 (23.5%) children, the reaction involved more than one organ system. Of these 19 children, 14 used β‐lactams. Systemic reactions were not reported with NSAIDs. Medications were taken by mouth in 88.9% of the reactions. Most of the reported allergic reactions occurred in the first day of treatment (61.7%). The reported time to reaction after the last intake of the drug was <2 h in 35 (43.2%) children and 2–24 h in 45 (55.6%). Oral reactions occurred later than reactions to parentally administered drugs. Parents of 58 children (71.6%) reported that they completely avoided the suspected culprit drug following the reaction. Relapse occurred after re‐administration of the drug in 21 (25.9%) children. A diagnostic approach for drug allergy was not undertaken in any of the children. This study may provide some information about the prevalence of drug allergy, although it is based on parental perception and results are unlikely to conform well to true prevalence.

Methylphenidate-Induced Acute Orofacial and Extremity Dyskinesia

Methylphenidate is a short-acting stimulant. In this article, the authors report a 7-year-old male patient who presented with orofacial and limb dyskinesia after his first dose of methylphenidate treatment for a diagnosis of attention-deficit/hyperactivity disorder; he was also receiving sodium valproate treatment for epilepsy. Orofacial dyskinesia appeared 5 hours after methylphenidate administration, persisted for 10 hours, and had completely resolved within 2 days. Although limb dyskinesia after methylphenidate is a commonly reported side effect, to the authors’ knowledge this is only the second reported case to develop both orofacial and limb dyskinesia in the acute period after the first dose of methylphenidate. This case is reported to emphasize the potential side effects of methylphenidate, individual differences in drug sensitivities, and drug–receptor interactions via different mechanisms.

Vitamin D Deficiency in Children With Newly Diagnosed Idiopathic Epilepsy

Several studies have shown a link between vitamin D deficiency and epilepsy. This study includes 60 newly diagnosed idiopathic epilepsy patients and 101 healthy controls (between the ages of 5 and 16). Each group was also divided into two subgroups according to seasonal changes in terms of months of longer versus shorter daylight. We retrospectively evaluated the levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone, and 25-OH vitamin-D3 in the study participants. Levels below 20 ng/ml were defined as vitamin D deficiency and levels of 20-30 ng/ml as insufficiency. There were no significant differences in age, gender distribution and levels of calcium, phosphorus, alkaline phosphatase and parathyroid hormone between the groups. The level of 25-OH vitamin-D3 in the patient group was significantly lower when compared to the control group (p < 0.05) (14.07 ± 8.12 and 23.38 ± 12.80 ng/ml, respectively). This difference also held true when evaluation was made according to seasonal evaluation (12.38 ± 6.53 and 17.64 ± 1.14 in shorter daylight and 18.71 ± 9.87 and 30.82 ± 1.04 in longer daylight).

The effects of topiramate and valproate therapy on insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin, and resistin levels in children with epilepsy

PURPOSE Antiepileptic drugs may affect the endocrine system. We investigated the effects of valproic acid and topiramate on the levels of insulin, c-peptide and adipocytokines in pre-pubertal patients with idiopathic partial and generalized epilepsy. METHODS Forty-one children with epilepsy were included. The patients were divided into two groups (valproic acid; n = 21, topiramate; n = 20). The weight, height, body mass index and homeostasis model assessment of insulin resistance (HOMA-IR) were recorded and insulin, c-peptide, leptin, neuropeptide Y, adiponectin, visfatin and resistin levels were determined at 0, 6 and 12 months of therapy. RESULTS In the valproate group, weight and height increased significantly. Seven of 21 patients were overweight at the end of one year. Leptin was higher in the overweight subgroup. Although insulin and HOMA-IR increased (p < 0.05), none of the patients showed hyperinsulinism or IR. Resistin had decreased at the 6th and 12th months (p < 0.05). In the topiramate group, some statistically nonsignificant changes were demonstrated. CONCLUSION The mechanisms behind valproate and topiramate-related weight control are still unclear, especially in children. Valproate and topiramate affect the weight, BMI, and insulin, leptin and adipocytokine levels in prepubertal children. We suggest that further studies including more patients with a long follow-up period are necessary to draw a firm conclusion regarding an association between the treatment with these drugs and the levels of leptin, insulin and adipocytokines.

Blood levels of cytokines in children with idiopathic partial and generalized epilepsy

PURPOSE Antiepileptic drugs have been reported to reduce the levels of serum immunoglobulins and affect the production and levels of certain cytokines. We investigated the effects of valproic acid (VPA) and topiramate (TPM) on the blood levels of interleukin (IL)-1α, IL-1β, IL-6, IL-10, and TNF-α in children with idiopathic generalized and partial epilepsy. METHODS Forty prepubertal children aged 6-12 (mean 8.3±1.7) years, 19/40 (47.5%) female and 21/40 (52.5%) male, with idiopathic generalized or partial epilepsy diagnosed in the child neurology outpatient clinic were included. The patients were divided into two treatment groups: 20 were treated with VPA and 20 with TPM. The plasma levels of IL-1α, IL-1β, IL-6, IL-10, TNF-α were measured using ELISA method before the initiation of treatment and at the 6th and 12th months of the treatment. The Chi-square test was used to compare qualitative data. To compare the periods, recurrence measurements were done using variance analysis and Freidman 2-sided variance analysis. p<0.05 was considered as statistically significant. RESULTS In the VPA group, the levels of IL-1α significantly increased at 12 months while the levels of IL-10 decreased at 6 months of treatment compared to values before treatment (p<0.05). There was no significant difference in levels of IL-1β, IL-6, TNF-α (p>0.05). In the TPM group, lower levels of IL-10 were observed at 6th and 12th months compared to the onset of treatment (p<0.05). CONCLUSION The results of this study demonstrated that VPA and TPM might lead to changes in the levels of cytokines in epileptic patients. The next step would be to investigate the relation of these findings to the outcome of epilepsy and response to treatment.

Benign Acute Childhood Myositis

Objective: To evaluate the clinical and laboratory findings of benign acute childhood myositis. Subjects andMethods: Six children, 1 girl and 5 boys, aged 3–9 years, were admitted to Karadeniz Technical University Paediatric Neurology Department in Trabzon, Turkey, with the diagnosis of benign acute childhood myositis in January and February 2002. The clinical and laboratory findings on the patients were analysed. Results: Serum creatine kinase and aspartate aminotransferase levels were increased in all cases. Two patients had leucopenia. Viral studies were negative. All the patients had a good outcome, and full recovery was achieved within 12 h to 3 days. Conclusion: Benign acute childhood myositis is a self-limiting disease with a good prognosis. Pediatricians and pediatric neurologists must be aware of this condition to avoid unnecessary investigations and to differentiate this condition from other causes of acute onset of inability to walk. It may occur in epidemics mainly in the wintertime, suggesting a viral aetiology.

The Very Low Density Lipoprotein Receptor–Associated Pontocerebellar Hypoplasia and Dysmorphic Features in Three Turkish Patients

Pontocerebellar hypoplasia consists of a rare heterogeneous group of congenital neurodevelopmental disorders characterized by hypoplasia and atrophy of the cerebellar cortex, dentate and pontine nuclei, and inferior olives. The very low density lipoprotein receptor protein is an integral part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. Mutations in this receptor cause nonprogressive cerebellar ataxia, mental retardation, and cerebellar hypoplasia. In this report, we present 3 patients from 2 different families displaying very low density lipoprotein receptor–associated pontocerebellar hypoplasia, cortical dysplasia, mental retardation, and bipedal gait. One of the siblings has also displayed dysmorphic features, as we previously reported before the identification of the genetic defect in this family.

Cerebral sinovenous thrombosis associated with MTHFR A1298C mutation in the newborn: a case report

Although cerebral sinovenous thrombosis (CSVT) is a rare condition in the neonatal period, high rates of morbidity and mortality necessitate the establishment of an early diagnosis. Methylenetetrahydrofolate reductase (MTHFR) plays a central role in the folate cycle and mutations of MTHFR are associated with vascular disease. While the C677T common missense mutation is the most well-defined MTHFR polymorphism, another common missense mutation, A1298C also exists. There has been no reported case of CSVT associated with MTHFR A1298C mutation in the neonatal period. Herein, we report a neonate with CSVT who was found to have MTHFR A1298C homozygosity.