Cognitive stimulation has potential for brain activation in individuals with Rett syndrome.

BACKGROUND: Knowledge regarding neuropsychological training in Rett syndrome (RS) is scarce. The aim of this study was to assess the outcome and the duration of the effect of cognitive stimulation on topographic electroencephalography (EEG) data in RS. METHODS: Twenty female children diagnosed with RS were included in the analysis. Girls with RS conducted a cognitive task using an eye-tracker designed to evaluate access and choice skills. EEG data were acquired during the experimental procedure including two 10-min baseline stages before and after the task. Topographical changes of several EEG spectral markers including absolute and relative powers, Brain Symmetry Index and entropy were assessed. RESULTS: Topographic significance probability maps suggested statistical decreases on delta activity and increases on beta rhythm associated with the cognitive task. Entropy increased during and after the task, likely related to more complex brain activity. A significant positive interaction was obtained between Brain Symmetry Index and age showing that the improvement of interhemispheric symmetry was higher in younger girls (5-10 years). CONCLUSIONS: According to our findings, significant alterations of brain rhythms were observed during and after cognitive stimulation, suggesting that cognitive stimulation may have effects on brain activity beyond the stimulation period. Finally, our promising results also showed an increase brain symmetry that was especially relevant for the younger group. This could suggest an interaction of the eye-tracking cognitive task; however, further studies in this field are needed to assess the relation between brain asymmetries and age.

[New insights in inborn errors of metabolism are leading to new paradigms in child neurology]. / Nuevos conocimientos sobre errores congenitos del metabolismo estan dando lugar a nuevos paradigmas en neuropediatria.

In the last recent years, the -omics era has already transformed child neurology. Next generation sequencing (NGS) has identified many novel disease causing genes and phenotypes. While genetics is of great importance as a diagnostic tool, it is less helpful when it comes to a comprehensive understanding of mechanisms of brain dysfunction. Child neurologists are at high risk of being lost in genomics if they do not face the necessity of a new approach in their clinical practice. The large amount of data provided by NGS is just one more element in a complex puzzle. Different levels of complexity should be integrated in the much-needed novel child neurology paradigm. Classically, the descriptions of neurological diseases have relied on neuroanatomy and neurophysiology. However, metabolism, which strongly orchestrates the regulation of neuronal functions, has been mostly neglected in the study of brain disorders. Paradoxically, inborn errors of metabolism (IEM) have moved in the opposite direction. With more than 1100 IEM, almost 80% of which exhibit neurological symptoms, they have evolved from being initially considered as mere anecdotes to be a fundamental requisite in neuropediatric educational programs. Additionally, new complex molecule defects are leading to integrate classic metabolism and cell biology into the specific compartmentalized structure of the nervous system («cellular neurometabolism¼). This article is a brief summary of the updated IEM classification combined with major neurological presentations in a tentative towards a pathophysiology based clinical practice in child neurology. In particular we emphasize a clinical approach focused in a continuum/spectrum of symptoms.

TITLE: Nuevos conocimientos sobre errores congenitos del metabolismo estan dando lugar a nuevos paradigmas en neuropediatria.En los ultimos anos, la era -omica ya ha transformado la neuropediatria. La secuenciacion de alto rendimiento --next generation sequencing (NGS)-- ha permitido identificar numerosos genes y fenotipos nuevos que provocan enfermedades. Aunque la genetica tiene indudablemente una gran importancia como herramienta diagnostica, no es de tanta utilidad cuando se trata de obtener una comprension mas amplia de los mecanismos involucrados en la disfuncion cerebral. Los neuropediatras corren el riesgo de perderse en la genomica si no asumen la necesidad de un nuevo enfoque en su practica clinica. La gran cantidad de datos que arroja la NGS es simplemente un elemento mas en un complejo rompecabezas. Se deberian integrar distintos niveles de complejidad en el nuevo paradigma de la neuropediatria que tanto se echa en falta. Tradicionalmente, las descripciones de las enfermedades neurologicas se han basado en la neuroanatomia y la neurofisiologia. Sin embargo, el metabolismo, que tiene un papel crucial en la regulacion de las funciones neuronales, se ha obviado en la mayoria de estudios sobre los trastornos cerebrales. Paradojicamente, los errores congenitos del metabolismo (ECM) han tomado la direccion contraria. Con un total de mas de 1.100 ECM, casi el 80% de los cuales manifiestan sintomas neurologicos, han pasado de considerarse inicialmente como anecdoticos a constituir un elemento fundamental en cualquier programa de educacion neuropediatrica. Ademas, los nuevos defectos hallados en las moleculas complejas estan promoviendo la integracion del metabolismo y la biologia celular clasicos en la estructura compartimentada especifica del sistema nervioso («neurometabolismo celular¼). Este articulo constituye un breve resumen de la clasificacion de los ECM actualizada en combinacion con las principales presentaciones neurologicas en un intento de lograr una practica clinica neuropediatrica basada en la fisiopatologia. De manera particular, hacemos hincapie en un enfoque clinico centrado en un amplo continuo/espectro de sintomas.

Abnormalities in flatfishes of the south-west Atlantic Ocean.

Five adult paralichthyid specimens with various kinds of abnormalities are reported from the south-west Atlantic Ocean. These abnormal flatfish specimens represent the first records of wholly ambicoloured Paralichthys orbignyanus specimens having a deep notch between the eye and dorsal fin and a partially albinistic specimen having skeletal deformities and only the second record of an almost totally ambicoloured specimen. We also report the first observation of reversal in Paralichthys patagonicus and an almost totally ambicoloured, reversed Xystreurys rasile.

Spatial and temporal variability of carbonaceous aerosols: Assessing the impact of biomass burning in the urban environment.

Biomass burning (BB) is a significant source of atmospheric particles in many parts of the world. Whereas many studies have demonstrated the importance of BB emissions in central and northern Europe, especially in rural areas, its impact in urban air quality of southern European countries has been sparsely investigated. In this study, highly time resolved multi-wavelength absorption coefficients together with levoglucosan (BB tracer) mass concentrations were combined to apportion carbonaceous aerosol sources. The Aethalometer model takes advantage of the different spectral behavior of BB and fossil fuel (FF) combustion aerosols. The model was found to be more sensitive to the assumed value of the aerosol Ångström exponent (AAE) for FF (AAEff) than to the AAE for BB (AAEbb). As result of various sensitivity tests the model was optimized with AAEff=1.1 and AAEbb=2. The Aethalometer model and levoglucosan tracer estimates were in good agreement. The Aethalometer model was further applied to data from three sites in Granada urban area to evaluate the spatial variation of CMff and CMbb (carbonaceous matter from FF or BB origin, respectively) concentrations within the city. The results showed that CMbb was lower in the city centre while it has an unexpected profound impact on the CM levels measured in the suburbs (about 40%). Analysis of BB tracers with respect to wind speed suggested that BB was dominated by sources outside the city, to the west in a rural area. Distinguishing whether it corresponds to agricultural waste burning or with biomass burning for domestic heating was not possible. This study also shows that although traffic restrictions measures contribute to reduce carbonaceous concentrations, the extent of the reduction is very local. Other sources such as BB, which can contribute to CM as much as traffic emissions, should be targeted to reduce air pollution.

Déficit de 3-hidroxiacil-CoA-deshidrogenasa de cadena larga: a propósito de un caso / Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A case report

CASO CLÍNICO: Paciente de 5 años de edad remitido para valoración oftalmológica con el diagnóstico de déficit de 3-hidroxiacil-CoA deshidrogenasa de cadena larga. Presentaba como antecedente la aparición de crisis metabólicas agudas precipitadas por infecciones banales y rabdomiólisis. El examen oftalmoscópico reveló una atrofia coriorretiniana peripapilar y una maculopatía granular difusa. La agudeza visual era de 6/6 en ambos ojos y las pruebas electrofisiológicas normales. DISCUSIÓN: Se realiza una revisión de la bibliografía y los conocimientos recientes de esta enfermedad mediante la descripción de un caso clínico documentando los hallazgos obtenidos mediante autofluorescencia y tomografía de coherencia óptica para mejorar el conocimiento existente sobre ella

CLINICAL CASE: A five-year-old patient, with a diagnosis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, was referred for an ophthalmological examination. He had a history of acute metabolic crises precipitated by intercurrent infections,as well as rhabdomyolysis. The fundoscopic examination revealed a peripapillary chorioretinal atrophy and a diffuse granular appearance of the macular retinal pigment epithelium. Best corrected visual acuity was 6/6 in both eyes, and he had a normal electroretinography test. DISCUSSION: We perform a review of the literature and recent findings in relation to this disease through the description of a clinical case in order to improve the knowledge of this uncommon disorder

Dataset reporting BCKDK interference in a BCAA-catabolism restricted environment.

This data article contains complementary figures to the research article "Mitochondrial response to the BCKDK-deficiency: some clues to understand the positive dietary response in this form of autism" [1]. Herein we present data relative to the effect of knocking down BCKDK gene on the real time oxygen consumption rate of fibroblasts obtained from a Maple Syrup Urine Disease (MSUD) patient. Interference of BCKDK expression on such cells showing a reduced branched-chain α-ketoacid dehydrogenase (BCKDHc) activity; let us generate a scenario to study the direct effect of BCKDK absence in an environment of high branched-chain amino acids (BCAAs) concentrations. Data relative to the effectiveness of the knockdown together with the potentiality of the BCKDK-knockdown to increase the deficient branched-chain α-ketoacid dehydrogenase activity detected in MSUD patients are also shown.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: A case report. / Déficit de 3-hidroxiacil-CoA-deshidrogenasa de cadena larga: a propósito de un caso.

CLINICAL CASE: A five-year-old patient, with a diagnosis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, was referred for an ophthalmological examination. He had a history of acute metabolic crises precipitated by intercurrent infections,as well as rhabdomyolysis. The fundoscopic examination revealed a peripapillary chorioretinal atrophy and a diffuse granular appearance of the macular retinal pigment epithelium. Best corrected visual acuity was 6/6 in both eyes, and he had a normal electroretinography test. DISCUSSION: We perform a review of the literature and recent findings in relation to this disease through the description of a clinical case in order to improve the knowledge of this uncommon disorder.

Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism.

Mutations on the mitochondrial-expressed Branched Chain α-Keto acid Dehydrogenase Kinase (BCKDK) gene have been recently associated with a novel dietary-treatable form of autism. But, being a mitochondrial metabolism disease, little is known about the impact on mitochondrial performance. Here, we analyze the mitochondrial response to the BCKDK-deficiency in patient's primary fibroblasts by measuring bioenergetics, ultra-structural and dynamic parameters. A two-fold increase in superoxide anion production, together with a reduction in ATP-linked respiration and intracellular ATP levels (down to 60%) detected in mutants fibroblasts point to a general bioenergetics depletion that could affect the mitochondrial dynamics and cell fate. Ultrastructure analysis of BCKDK-deficient fibroblasts shows an increased number of elongated mitochondria, apparently associated with changes in the mediator of inner mitochondria membrane fusion, GTPase OPA1 forms, and in the outer mitochondrial membrane, mitofusin 2/MFN2. Our data support a possible hyperfusion response of BCKDK-deficient mitochondria to stress. Cellular fate also seems to be affected as these fibroblasts show an altered proportion of the cells on G0/G1 and G2/M phases. Knockdown of BCKDK gene in control fibroblasts recapitulates most of these features. Same BCKDK-knockdown in a MSUD patient fibroblasts unmasks the direct involvement of the accelerated BCAAs catabolism in the mitochondrial dysfunction. All these data give us a clue to understand the positive dietary response to an overload of branched-chain amino acids. We hypothesize that a combination of the current therapeutic option with a protocol that considers the oxidative damage and energy expenditure, addressing the patients' individuality, might be useful for the physicians.

Diseases of the Synaptic Vesicle: A Potential New Group of Neurometabolic Disorders Affecting Neurotransmission.

The general concept of inborn error of metabolism is currently evolving into the interface between classical biochemistry and cellular biology. Basic neuroscience is providing increasing knowledge about the mechanisms of neurotransmission and novel related disorders are being described. There is a necessity of updating the classic concept of "inborn error of neurotransmitters (NT)" that considers mainly defects of synthesis and catabolism and transport of low weight NT molecules. Monogenic defects of the synaptic vesicle (SV), and especially those affecting the SV cycle are a potential new group of NT disorders since they end up in abnormal NT turnover and release. The most common clinical manifestations include epilepsy, intellectual disability, autism and movement disorders, and are in the continuum symptoms of synaptopathies. Interestingly, brain malformations and neurodegenerative conditions are also present within SV diseases. Metabolomics, proteomics, and other -omic techniques probably will provide biomarkers and contribute to therapeutic targets in the future.

A statistical algorithm showing coenzyme Q10 and citrate synthase as biomarkers for mitochondrial respiratory chain enzyme activities.

Laboratory data interpretation for the assessment of complex biological systems remains a great challenge, as occurs in mitochondrial function research studies. The classical biochemical data interpretation of patients versus reference values may be insufficient, and in fact the current classifications of mitochondrial patients are still done on basis of probability criteria. We have developed and applied a mathematic agglomerative algorithm to search for correlations among the different biochemical variables of the mitochondrial respiratory chain in order to identify populations displaying correlation coefficients >0.95. We demonstrated that coenzyme Q10 may be a better biomarker of mitochondrial respiratory chain enzyme activities than the citrate synthase activity. Furthermore, the application of this algorithm may be useful to re-classify mitochondrial patients or to explore associations among other biochemical variables from different biological systems.

Identification of Poor-outcome Biliopancreatic Carcinoma Patients With Two-marker Signature Based on ATF6α and p-p38 "STARD Compliant".

Biliopancreatic cancer is one of the most aggressive solid neoplasms, and incidence is rising worldwide. It is known that ATF6α is one of the transmembrane proteins that acts crucially in endoplasmic reticulum stress response, and knockdown induces apoptosis of pancreatic cells. Apart from this, p-p38 has been previously correlated with better outcome in pancreatic cancer. Interestingly, ATF6α knockdown pancreatic cells showed increased p-p38. The aim of this study was to evaluate the expression of these 2 proteins, p-p38 and ATF6α, and their correlation with the outcome of biliopancreatic adenocarcinoma patients. Samples from patients with biliopancreatic adenocarcinoma that underwent pancreaticoduodenectomy from 2007 to 2013 were used to construct a tissue microarray to evaluate p-p38 and ATF6α proteins by immunohistochemistry. We observed that both markers showed a tendency to impact in the time to recurrence; then a combination of these 2 proteins was analyzed. Combination of ATF6α(high) and p-p38(low) was strongly associated with a higher risk of recurrence (hazard ratio 2.918, P = 0.013). This 2-protein model remained significant after multivariate adjustment.We proposed a 2-protein signature based on ATF6α(high) and p-p38(low) as a potential biomarker of risk of recurrence in resected biliopancreatic adenocarcinoma patients.

Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis.

Maple syrup urine disease (MSUD) is a rare metabolic disorder for which the newborn screening (NBS) is possible but it has not been yet implemented for most Spanish regions. In the present study, we assess the clinical features and outcome of 14 MSUD Spanish patients with similar treatment protocol diagnosed either by NBS or by clinical symptoms. Eight patients were detected by NBS, four classic and four moderate MSUD. The average age at detection was 4.6 days, the mean plasmatic concentration of leucine at diagnosis was 1807 µM; the average number of days with leucine >1000 µM was 0.7 (0-4) and the mean number of total hospitalizations was 1.6 (0-5). Mean follow-up time was 70 months. They had good evolution: all remain asymptomatic, but 2 patients have attention deficit and hyperactivity disorder. Six patients with late diagnosis of classic MSUD were followed during 41 months. All presented with acute encephalopathy during the first month of life, mean leucine levels of 2355 µM, mean number of days with leucine >1000 µM of 6.6 (1-13) and mean number of total hospitalizations of 5.3 (4-7). Only two patients have a psychomotor development index in the lower limit (80 and 83). For all patients a good genotype-phenotype correlation was found and four novel mutations were identified: p.A311H, p.T84S, p.T397L, pL398P. Our study support that NBS improves prognosis of MSUD patients. But early diagnosis and an aggressive treatment together with a close monitoring of leucine levels improve neurological evolution in MSUD patients, even for those not detected by NBS.

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. METHODS: We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next-generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion algorithm with an optimised score cut-off. RESULTS: We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a 'pure JS' phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS subtypes. CONCLUSIONS: This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes and enable gene-specific treatments in the future.

Comunicación neuronal y metabolismo sináptico en epilepsia infantil / Neuronal communication and synaptic metabolism in childhood epilepsy

Introducción. Los conocimientos que la neurociencia básica y el neurometabolismo están aportando en epilepsia pediátrica, y en concreto en mecanismos de comunicación sináptica, crecen rápidamente. Existe, no obstante, una desconexión entre estos avances y una visión que los integre de manera global y en la práctica clínica y terapéutica. Objetivos. Ofrecer una visión integradora de los diferentes mecanismos moleculares y metabólicos que se conocen y postulan en epilepsia pediátrica, y sugerir conceptos como el de ‘metabolismo sináptico’ y ‘fenotipos sinápticos’ como herramientas útiles para desarrollar este enfoque. Desarrollo. Se revisan los estudios más destacados que intentan explicar las características esenciales de la comunicación sináptica en el cerebro en desarrollo, a través de diferentes moléculas, básicamente proteínas sinápticas, canales iónicos (cotransportadores de cloro, sodio y potasio), la compartimentalización pre y postsináptica, y los principales actores metabólicos (neurotransmisores, metabolismo energético, factores de crecimiento y lípidos). A partir de esta combinación de mecanismos biológicos se sugieren ejemplos de ‘fenotipos sinápticos’ en dos casos concretos de epilepsia genética (SCN1A) y metabólica (epilepsia con respuesta a la piridoxina). Conclusiones. Una perspectiva holística, entendiendo la diversidad de elementos relacionados y que suceden en determinados momentos del neurodesarrollo, puede ayudar a delinear fenotipos, vías de metabolismo sináptico y conectividad cerebral, que faciliten no sólo la comprensión de la fisiopatología, sino nuevas aproximaciones terapéuticas en epilepsia pediátrica (AU)

Introduction. Basic neuroscience and neurometabolism are providing a rapidly increasing amount of knowledge on paediatric epilepsy and, more specifically, on the mechanisms involved in synaptic communication. There is, however, a mismatch between these advances and a vision that integrates them in a global way, in clinical and therapeutic practice. Aims. To offer an integrative view of the different molecular and metabolic mechanisms that are known and postulated in paediatric epilepsy, and to suggest concepts such as ‘synaptic metabolism’ and ‘synaptic phenotypes’ as useful tools for developing this approach. Development. We also review the most notable studies that attempt to explain the essential characteristics of synaptic communication in the developing brain by means of different molecules, essentially synaptic proteins, ion channels (chlorine, sodium and potassium co-transporters), and pre- and post-synaptic compartmentalisation, as well as the main players in metabolism (neurotransmitters, energy metabolism, growth factors and lipids). This combination of biological mechanisms has led to examples of ‘synaptic phenotypes’ being suggested in two specific cases of genetic (SCN1A) and metabolic epilepsy (epilepsy with response to pyridoxine). Conclusions. A holistic perspective, which takes into account the diversity of elements that are related and which take place at certain times in neurodevelopment, can help to define phenotypes, channels for synaptic metabolism and brain connectivity, which facilitate not only the understanding of the pathophysiology, but also new therapeutic approaches in paediatric epilepsy (AU)

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre- and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.

Parkinsonism and inborn errors of metabolism.

Parkinsonism is a frequent neurological syndrome in adulthood but is very rare in childhood. Early forms of Parkinsonism have many distinctive features as compared to Parkinsonism in adults. In fact, rather than Parkinsonism, the general concept "hypokinetic-rigid syndrome" (HRS) is more accurate in children. In general, the terms "dystonia-parkinsonism", "parkinsonism-plus", or "parkinsonism-like" are preferred to designate these forms of paediatric HRS. Inborn errors of metabolism (IEM) constitute an important group amongst the genetic causes of Parkinsonism at any age. The main IEM causing Parkinsonism are metal-storage diseases, neurotransmitter defects, lysosomal storage disorders and energy metabolism defects. IEM should not be neglected as many of them represent treatable causes of Parkinsonism. Here we review IEMs causing this neurological syndrome and propose diagnostic approaches depending on the age of onset and the associated clinical and neuroimaging features.

[Chordoma]. / Les chordomes.

PURPOSES: To review in the literature, all the epidemiological, clinical, radiological, histological and therapeutic data regarding chordomas as well as various notochordal entities: ecchordosis physaliphora, intradural and intraparenchymatous chordomas, benign notochordal cell tumors, parachordomas and extra-axial chordomas. To identify different types of chordomas, including familial forms, associations with tuberous sclerosis, Ollier's disease and Maffucci's syndrome, forms with metastasis and seeding. To assess the recent data regarding molecular biology and progress in targeted therapy. To compare the different types of radiotherapy, especially protontherapy and their therapeutic effects. To review the largest series of chordomas in their different localizations (skull base, sacrum and mobile spine) from the literature. MATERIALS: The series of 136 chordomas treated and followed up over 20 years (1972-2012) in the department of neurosurgery at Lariboisière hospital is reviewed. It includes: 58 chordomas of the skull base, 47 of the craniocervical junction, 23 of the cervical spine and 8 from the lombosacral region. Similarly, 31 chordomas in children (less than 18 years of age), observed in the departments of neurosurgery of les Enfants-Malades and Lariboisière hospitals, are presented. They were observed between 1976 and 2010 and were located intracranially (n=22 including 13 with cervical extension), 4 at the craniocervical junction level and 5 in the cervical spine. METHODS: In the entire Lariboisière series and in the different groups of localization, different parameters were analyzed: the delay of diagnosis, of follow-up, of occurrence of metastasis, recurrence and death, the number of primary patients and patients referred to us after progression or recurrence and the number of deaths, recurrences and metastases. The influence of the quality of resection (total, subtotal and partial) on the prognosis is also presented. Kaplan-Meier actuarial curves of overall survival and disease free survival were performed in the entire series, including the different groups of localization based on the following 4 parameters: age, primary and secondary patients, quality of resection and protontherapy. In the pediatric series, a similar analysis was carried-out but was limited by the small number of patients in the subgroups. RESULTS: In the Lariboisière series, the mean delay of diagnosis is 10 months and the mean follow-up is 80 months in each group. The delay before recurrence, metastasis and death is always better for the skull base chordomas and worse for those of the craniocervical junction, which have similar results to those of the cervical spine. Similar figures were observed as regards the number of deaths, metastases and recurrences. Quality of resection is the major factor of prognosis with 20.5 % of deaths and 28 % of recurrences after total resection as compared to 52.5 % and 47.5 % after subtotal resection. This is still more obvious in the group of skull base chordomas. Adding protontherapy to a total resection can still improve the results but there is no change after subtotal resection. The actuarial curve of overall survival shows a clear cut in the slope with some chordomas having a fast evolution towards recurrence and death in less than 4 years and others having a long survival of sometimes more than 20 years. Also, age has no influence on the prognosis. In primary patients, disease free survival is better than in secondary patients but not in overall survival. Protontherapy only improves the overall survival in the entire series and in the skull base group. Total resection improves both the overall and disease free survival in each group. Finally, the adjunct of protontherapy after total resection is clearly demonstrated. In the pediatric series, the median follow-up is 5.7 years. Overall survival and disease free survival are respectively 63 % and 54.3 %. Factors of prognosis are the histological type (atypical forms), localization (worse for the cervical spine and better for the clivus) and again it will depend on the quality of resection. CONCLUSIONS: Many different pathologies derived from the notochord can be observed: some are remnants, some may be precursors of chordomas and some have similar features but are probably not genuine chordomas. To-day, immuno-histological studies should permit to differentiate them from real chordomas. Improving knowledge of molecular biology raises hopes for complementary treatments but to date the quality of surgical resection is still the main factor of prognosis. Complementary protontherapy seems useful, especially in skull base chordomas, which have better overall results than those of the craniocervical junction and of the cervical spine. However, we are still lacking an intrinsic marker of evolution to differentiate the slow growing chordomas with an indolent evolution from aggressive types leading rapidly to recurrence and death on which more aggressive treatments should be applied.

[Follicular dendritic cell sarcoma in head and neck region]. / Sarcome à cellules folliculaires dendritiques de la région ORL.

Follicular dendritic cell sarcomas are a recently described entity, with biphenotypic characteristics of lymphomas and sarcomas. The treatment is hardly consensual in the literature. We report two head and neck cases, of favorable outcome after surgery and radiotherapy. Histopathology and differential diagnoses are discussed as well as the therapeutic strategies used.

DCF (docetaxel, cisplatin and 5-fluorouracil) chemotherapy is a promising treatment for recurrent advanced squamous cell anal carcinoma.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is a rare disease, mostly diagnosed at early stage. After concurrent chemoradiation (CRT) with mitomycin C and 5-fluorouracil (5FU), local or metastatic recurrences occur in >20% of the patients. After treatment failure, cisplatin (CDDP)-based chemotherapy is the standard option, but complete response (CR) is a rare event and the prognosis remains poor. PATIENTS AND METHODS: Eight consecutive patients with advanced recurrent SCCA after CRT were treated with DCF regimen (docetaxel 75 mg/m(2) day 1, CDDP 75 mg/m(2) day 1 and 5FU at 750 mg/m(2)/day for 5 days every 3 weeks). Tumour samples were analysed for human papillomavirus (HPV) genotyping, as well as p16 and p53 expression. RESULTS: After a median follow-up of 41 months, the overall survival rate at 12 months was 62.5% (95% CI 22.9-86.1 months). Four patients achieved a complete remission and remain relapse-free at the time of analysis with a progression-free survival of 19, 33, 43 and 88 months. Three of these patients underwent surgery for all involved metastatic sites. For all of them, pathological CR was confirmed. DCF regimen appeared feasible in these patients previously exposed to pelvic CRT, and no grade IV toxicity occurred. All patients in complete remission had HPV-16-positive SCCA, while HPV could only be detected among 50% of the non-responding patients. Of interest, immunohistochemical study revealed a p16(+)/p53(-) phenotype in these patients, while none of non-responders expressed p16. CONCLUSION: The high level of complete and long-lasting remission among SCCA patients treated with DCF regimen supports the assessment of this strategy in prospective cohorts.

Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency.

Pyruvate carboxylase deficiency is a rare metabolic disorder, with three different phenotypes. We aim to report the case of a newborn presenting the severe neonatal form of this deficiency (the B or "French" phenotype, hypokinesia and rigidity being the main features) and the results of the study of classic neurotransmitters involved in movement control. Hyperdopaminergic transmission (both in the cerebrospinal fluid and in the substantia nigra) and hypoGABAergic transmission (in the substantia nigra) were found. Both gamma-aminobutyric acid and dopamine markers were found coexisting in individual neurons of the substantia nigra. This is the first time this phenomenon has been reported in the literature. We discuss the possible role of GABAergic deficiency, its interaction with other neurotransmitters and its implication in neurotransmitter homeostasis. A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity.