ObjectiveRett Syndrome is a progressive neurodevelopmental disorder caused mainly by mutations in the gene encoding methyl-CpG-binding protein 2. The relevance of MeCP2 for GABAergic function was previously documented in animal models. In these models, animals show deficits in brain-derived neurotrophic factor, which is thought to contribute to the pathogenesis of this disease. Neuronal Cation Chloride Cotransporters (CCCs) play a key role in GABAergic neuronal maturation, and brain-derived neurotrophic factor is implicated in the regulation of CCCs expression during development. Our aim was to analyse the expression of two relevant CCCs, NKCC1 and KCC2, in the cerebrospinal fluid of Rett syndrome patients and compare it with a normal control group.MethodsThe presence of bumetanide sensitive NKCC1 and KCC2 was analysed in cerebrospinal fluid samples from a control pediatric population (1 day to 14 years of life) and from Rett syndrome patients (2 to 19 years of life), by immunoblot analysis.ResultsBoth proteins were detected in the cerebrospinal fluid and their levels are higher in the early postnatal period. However, Rett syndrome patients showed significantly reduced levels of KCC2 and KCC2/NKCC1 ratio when compared to the control group.ConclusionsReduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective.

SUMMARYPurpose: To validate the use of 18F-fluorodeoxyglucosepositron emission tomography/magnetic resonance imaging (FDG-PET/MRI) coregistration for epileptogenic zone detection in children with MRI nonlesional refractory epilepsy and to assess its ability to guide a second interpretation of the MRI studies. Methods: Thirty-one children with refractory epilepsy whose MRI results were nonlesional were included prospectively. All patients underwent presurgical evaluation following the standard protocol of our epilepsy unit, which included FDG-PET and FDG-PET/MRI coregistration. Cerebral areas of decreased uptake in PET and PET/MRI fusion images were compared visually and then contrasted with presumed epileptogenic zone localization, which had been obtained from other clinical data. A second interpretation of MRI studies was carried out, focusing on the exact anatomic region in which hypometabolism was located in FDG-PET/MRI fusion images.Key Findings: Both FDG-PET and FDG-PET/MRI detected hypometabolism in 67.8% of patients, with good concordance on a subject basis and on the cerebral region involved (j statistic = 0.83 and 0.79, respectively). Hypometabolism detected by single PET, as well as by PET/MRI fusion images, was located in the same hemisphere, as indicated by electroclinical data in 58% of patients, and at the same place in 39% of cases. Of the patients who showed hypometabolism on PET/MRI, 43% also experienced changes in the guided second MRI interpretation, from nonlesional to subtlelesional. Significance: PET/MRI coregistration is an imaging variant that is at least as accurate as PET alone in detecting epileptogenic zone in pediatric nonlesional patients, and can guide a second look at MRI studies previously reported as nonlesional, turning a meaningful percentage into subtle-lesional.

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Summary:Purpose: Seizures with ictal laughter (also termed gelastic seizures) have been associated with hypothalamic hamartomas and precocious puberty. It is not known, however, where in the brain such seizures originate. We describe a child with gelastic seizures and a hypothalamic lesion (probably a hamartoma) in whom two dysfunctional phenomena were observed.Results: First, there was a hyperperfusion in the hypothalamopituitary areas shown by ictal [99m]Tc hexamethylpropyleneamine oxime (HM-PAO) single photon-emission computed tomography (SPECT). Second, there was an ictal pulse of gonadotropins, 17P-estradiol, and growth hormone well above the normal limits in one of the seizures.Conclusion: These findings suggest that gelastic seizures associated with hypothalamic hamartomas are generated in the hypothalamus or in its neighboring regions and that these seizures may cause paroxysmal dysfunction of the hypothalamopitutary axis.

Several unrelated disorders can lead to 5-methyltetrahydrofolate (5MTHF) depletion in the cerobrospinal fluid (CSF), including primary genetic disorders in folate-related pathways or those causing defective transport across the blood-CSF barrier. We report a case of cerebral folate transport deficiency due to a novel homozygous mutation in the FOLR1 gene, in an effort to clarify phenotype-genotype correlation in this newly identified neurometabolic disorder. A previously healthy infant developed an ataxic syndrome in the second year of life, followed by choreic movements and progressive myoclonic epilepsy. At the age of 26 months, we analyzed CSF 5MTHF by HPLC with fluorescence detection and conducted magnetic resonance (MR) imaging and spectroscopy studies. Finally, we performed mutational screening in the coding region of the FOLR1 gene. MR showed a diffuse abnormal signal of the cerebral white matter, cerebellar atrophy and a reduced peak of choline in spectroscopy. A profound deficiency of CSF 5MTHF (2 nmol/L; NV 48-127) with reduced CSF/plasma folate ratio (0.4; NV 1.5-3.5) was highly suggestive of defective brain folate-specific transport across the blood-CSF/brain barrier. Mutation screening of FOLR1 revealed a new homozygous missense mutation (p.Cys105Arg) that is predicted to abolish a disulfide bond, probably necessary for the correct folding of the protein. Both parents were heterozygous carriers of the same variant. Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. Progressive ataxia and myoclonic epilepsy, together with impaired brain myelination, are clinical hallmarks of the disease.

A precise assessment of the drug-resistant epileptic pediatric population for surgical candidacy is often challenging, and to date there are no evidence-based guidelines for presurgical identification of the epileptogenic zone. To evaluate the usefulness of radionuclide imaging techniques for presurgical evaluation of epileptic pediatric patients, we compared the results of video-electroencephalography (EEG), brain MR imaging, interictal SPECT, ictal SPECT, subtraction ictal SPECT coregistered to MR imaging (SISCOM), and interictal PET with 18 F-FDG. Methods: Fifty-four children with drug-resistant epilepsy who had undergone video-EEG monitoring, brain MR imaging, interictal and ictal brain perfusion SPECT, SISCOM, and 18 F-FDG PET were included in this study. All abnormal findings revealed by these neuroimaging techniques were compared with the presumed location of the epileptogenic zone (PEZ) as determined by video-EEG and clinical data. The proportion of localizing studies for each technique was statistically compared. In the 18 patients who underwent resective brain surgery, neuroimaging results were compared with histopathology results and surgical outcome. Results: SISCOM and 18 F-FDG PET concordance with the PEZ was significantly higher than MR imaging (P , 0.05). MR imaging showed localizing results in 21 of 54 cases (39%), SISCOM in 36 of 54 cases (67%), and 18 F-FDG PET in 31 of 54 cases (57%). If we consider SISCOM and 18 F-FDG PET results together, nuclear medicine imaging techniques showed coinciding video-EEG results in 76% of patients (41/54). In those cases in which MR imaging failed to identify any epileptogenic lesion (61% [33/54]), SISCOM or 18 F-FDG PET findings matched PEZ in 67% (22/33) of cases. Conclusion: SISCOM and 18 F-FDG PET provide complementary presurgical information that matched video-EEG results and clinical data in three fourths of our sample. SISCOM was particularly useful in those cases in which MR imaging findings were abnormal but no epileptogenic lesion was identified. Radionuclide imaging techniques are both useful and reliable, extending the possibility of surgical treatment to patients who may have been discouraged without a nuclear medicine approach.

Although patients with low cerebrospinal fluid (CSF) serotonin metabolite levels have been reported, inborn errors of the rate-limiting enzyme of serotonin synthesis (tryptophan hydroxylase, TPH) have not been described so far. In this study we aimed to evaluate CSF alterations of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in patients with neurological disorders and to explore a possible TPH deficiency in some of them. A total of 606 patients (286 males, 320 females, mean age 4 years and 6 months, SD 5 years and 7 months) underwent CSF analysis of neurotransmitter metabolites by reverse phase high performance liquid chromatography. Results were compared with values established in a control population. Patients' medical records were reviewed to determine diagnosis and clinical features. A primary defect of biogenic amines was genetically investigated in indicated patients. Low 5-HIAA was seen in 19.3%. Of these, 22.2% showed inborn errors of metabolism (mitochondrial disorders being the most frequent at 10.2% of low 5-HIAA patients) and neurogenetic conditions. Other relatively frequent conditions were pontocerebellar hypoplasia (4.3%), Rett syndrome (4.3%), and among congenital nonetiologically determined conditions, epilepsy including epileptic encephalopathies (26.4%), leukodystrophies (6.8%), and neuropsychiatric disturbances (4.2%). Mutational analysis of the TPH2 gene, performed in five candidate patients, was negative. Although frequency of secondary alteration of 5-HIAA was relatively high in patients with neurological disorders, this finding was more frequently associated with some neurometabolic disorders, epileptic encephalopathies, and neuropsychiatric disturbances. No inborn errors of TPH were found. Due to serotonin's neurotrophic role and to ameliorate symptoms, a supplementary treatment with 5-hydroxytriptophan would seem advisable in these patients.

Glucosylceramide lipidosis results from a defective lysosomal degradation of this glycolipid. Lipid degradation is controlled by two components, the enzyme beta-glucocerebrosidase and a sphingolipid activator protein. While most Gaucher cases are due to mutations within the gene that codes for the lysosomal enzyme, only two patients have been described with normal enzyme levels and mutations in the gene for the sphingolipid activator protein C (sap-C). Here we present the detailed neurological manifestations, neuropathological findings and brain lipid composition in one sap-C-deficient patient. The patient was an 8-year-old boy who presented with transient losses of consciousness, myoclonic jerks and generalized seizures resistant to all antiepileptic drugs. He developed progressive horizontal ophthalmoplegia, pyramidal and cerebellar signs, and died at the age of 15.5 years. Neuropathological studies demonstrated neuronal cell loss and neuronophagia, massive intraneuronal lipid storage and lack of perivascular Gaucher cells. Electron microscopy examination showed different types of storage including lipofuscin granules as well as the cytosomes with parallel arrays of bilayers that are assumed to be formed by stored lipids. General brain lipid composition did not show a remarkable increase or loss of any of the major lipid fractions but the glucosylceramide concentration in the cortex of several anatomical regions showed a striking increase. Fatty acid composition of the ceramide moiety clearly suggests that gangliosides are the main precursors in the cerebral cortex, while it implies an additional and distinct source in the cerebellum. Studying the phenotypic consequences of mutant sphingolipid activator proteins is critical to a better understanding of the physiological significance of these proteins.