Validation of a Set of Instruments to Assess Patient- and Caregiver-Oriented Measurements in Spinal Muscular Atrophy: Results of the SMA-TOOL Study.

INTRODUCTION: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives. METHODS: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured. RESULTS: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items. CONCLUSIONS: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA.

SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance.

Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.

Genetic landscape of Segawa disease in Spain. Long-term treatment outcomes.

INTRODUCTION: In 2009, we described a possible founder effect of autosomal dominant Segawa disease in Córdoba (Spain) due to mutation c.265C>T (p. Q89*) in the GCH1 gene. We present a retrospective multicentre study aimed at improving our knowledge of Segawa disease in Spain and providing a detailed phenotypic-genotypic description of patients. METHODS: Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals. RESULTS: Eighty subjects belonging to 24 pedigrees had heterozygous mutations in GCH1. Seven genetic variants have been described only in our cohort of patients, 5 of which are novel mutations. Five families not previously described with p. Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0-16). The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in the phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with a levodopa/decarboxylase inhibitor for (mean ± SD) 12.4 ± 8.12 years, with 81% at doses lower than 350 mg/day (≤5 mg/kg/d in children). Eleven of 53 (20%) patients had nonresponsive symptoms that affected daily life activities. Dyskinesias (4 subjects) were the most prominent adverse effects. CONCLUSION: This study identifies 5 novel mutations and supports the hypothesis of a founder effect of p. Q89* in Andalusia. New insights are provided for the phenotypes and long-term treatment responses, which may improve early recognition and therapeutic management.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Delineating the motor phenotype of SGCE-myoclonus dystonia syndrome.

OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.

Molecular characterization of Spanish patients with MECP2 duplication syndrome.

MECP2 duplication syndrome (MDS) is an X-linked neurodevelopmental disorder characterized by a severe to profound intellectual disability, early onset hypotonia and diverse psycho-motor and behavioural features. To date, fewer than 200 cases have been published. We report the clinical and molecular characterization of a Spanish MDS cohort that included 19 boys and 2 girls. Clinical suspicions were confirmed by array comparative genomic hybridization and multiplex ligation-dependent probe amplification (MLPA). Using, a custom in-house MLPA assay, we performed a thorough study of the minimal duplicated region, from which we concluded a complete duplication of both MECP2 and IRAK1 was necessary for a correct MDS diagnosis, as patients with partial MECP2 duplications lacked some typical clinical traits present in other MDS patients. In addition, the duplication location may be related to phenotypic severity. This observation may provide a new approach for genotype-phenotype correlations, and thus more personalized genetic counselling.

PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression.

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

Microcefalia primaria hereditaria de tipo 5. No todo es virus del Zika / Hereditary primary microcephaly type 5. Not everything is Zika virus

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Urinary sulphatoxymelatonin as a biomarker of serotonin status in biogenic amine-deficient patients.

Melatonin is synthesized from serotonin and it is excreted as sulphatoxymelatonin in urine. We aim to evaluate urinary sulphatoxymelatonin as a biomarker of brain serotonin status in a cohort of patients with mutations in genes related to serotonin biosynthesis. We analized urinary sulphatoxymelatonin from 65 healthy subjects and from 28 patients with genetic defects. A total of 18 patients were studied: 14 with autosomal dominant and recessive guanosine triphosphate cyclohydrolase-I deficiency; 3 with sepiapterin reductase deficiency; and 1 with aromatic L-amino acid decarboxylase deficiency. Further 11 patients were studied after receiving serotoninergic treatment (serotonin precursors, monoamine oxidase inhibitors, selective serotonin re-uptake inhibitors): 5 with aromatic L-amino acid decarboxylase deficiency; 1 with sepiapterin reductase deficiency; 3 with dihydropteridine reductase deficiency; and 2 with 6-pyruvoyltetrahydropterin synthase deficiency. Among the patients without therapy, 6 presented low urinary sulphatoxymelatonin values, while most of the patients with guanosine triphosphate cyclohydrolase-I deficiency showed normal values. 5 of 11 patients under treatment presented low urine sulphatoxymelatonin values. Thus, decreased excretion of sulphatoxymelatonin is frequently observed in cases with severe genetic disorders affecting serotonin biosynthesis. In conclusion, sulphatoxymelatonin can be a good biomarker to estimate serotonin status in the brain, especially for treatment monitoring purposes.

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders.

INTRODUCTION: Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. METHODS AND RESULTS: The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. CONCLUSION: The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches.

Experiencia en el diagnóstico molecular de neuropatías hereditarias en un hospital pediátrico de tercer nivel / Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital

Introducción. La enfermedad de Charcot-Marie-Tooth (CMT) es la neuropatía hereditaria sensitivomotora más frecuente. Avances en el diagnóstico molecular han incrementado las posibilidades diagnósticas de estos pacientes. Pacientes y métodos. Estudio retrospectivo de 36 casos pediátricos diagnosticados de CMT en un centro terciario en el período 2003-2015. Resultados. Se identificaron 16 pacientes con CMT1A por una duplicación en PMP22; dos casos se diagnosticaron de neuropatía hereditaria con predisposición a parálisis por presión, uno de ellos con una mutación puntual en PMP22; un varón con un fenotipo leve desmielinizante se diagnosticó de CMTX1 por mutación en GJB1; un paciente con una hipotonía paralítica en el nacimiento y un patrón axonal por mutación en MFN2; un paciente de origen rumano se diagnosticó de CMT4D por una mutación en el gen NDRG1; una paciente con una atrofia muscular espinal congénita distal con neuropatía axonal leve asociada por mutación en el gen TRPV4; tres niñas de una familia consanguínea de etnia gitana se diagnosticaron de CMT axonal con descargas neuromiotónicas por una mutación en el gen HINT1; 12 pacientes no tienen diagnóstico molecular actualmente, cuatro de ellos de etnia gitana. Conclusiones. CMT1A predominó en nuestra serie (44%), como corresponde a la bibliografía. Destacamos la descripción de una paciente con una mutación en TRPV4 recientemente descrita como causa de CMT2C y tres casos de una misma familia consanguínea gitana con la misma mutación en el gen HINT1 recientemente publicada como causa de neuropatía axonal con neuromiotonía autosómica recesiva (AR-CMT2). El porcentaje de casos sin diagnóstico molecular es similar al de grandes series europeas (AU)

Introduction. Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. Patients and methods. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. Results. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven’t molecular diagnosis currently. Conclusions. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series (AU)

[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital]. / Experiencia en el diagnóstico molecular de neuropatías hereditarias en un hospital pediátrico de tercer nivel.

INTRODUCTION: Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. PATIENTS AND METHODS: Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. RESULTS: We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CONCLUSIONS: CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.

TITLE: Experiencia en el diagnostico molecular de neuropatias hereditarias en un hospital pediatrico de tercer nivel.Introduccion. La enfermedad de Charcot-Marie-Tooth (CMT) es la neuropatia hereditaria sensitivomotora mas frecuente. Avances en el diagnostico molecular han incrementado las posibilidades diagnosticas de estos pacientes. Pacientes y metodos. Estudio retrospectivo de 36 casos pediatricos diagnosticados de CMT en un centro terciario en el periodo 2003-2015. Resultados. Se identificaron 16 pacientes con CMT1A por una duplicacion en PMP22; dos casos se diagnosticaron de neuropatia hereditaria con predisposicion a paralisis por presion, uno de ellos con una mutacion puntual en PMP22; un varon con un fenotipo leve desmielinizante se diagnostico de CMTX1 por mutacion en GJB1; un paciente con una hipotonia paralitica en el nacimiento y un patron axonal por mutacion en MFN2; un paciente de origen rumano se diagnostico de CMT4D por una mutacion en el gen NDRG1; una paciente con una atrofia muscular espinal congenita distal con neuropatia axonal leve asociada por mutacion en el gen TRPV4; tres niñas de una familia consanguinea de etnia gitana se diagnosticaron de CMT axonal con descargas neuromiotonicas por una mutacion en el gen HINT1; 12 pacientes no tienen diagnostico molecular actualmente, cuatro de ellos de etnia gitana. Conclusiones. CMT1A predomino en nuestra serie (44%), como corresponde a la bibliografia. Destacamos la descripcion de una paciente con una mutacion en TRPV4 recientemente descrita como causa de CMT2C y tres casos de una misma familia consanguinea gitana con la misma mutacion en el gen HINT1 recientemente publicada como causa de neuropatia axonal con neuromiotonia autosomica recesiva (AR-CMT2). El porcentaje de casos sin diagnostico molecular es similar al de grandes series europeas.

Respuesta a everolimús en pacientes con astrocitoma de células gigantes asociado al complejo esclerosis tuberosa / Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex

Introducción. Los astrocitomas subependimarios de células gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales más comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos décadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertensión intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapéutica a la resección quirúrgica. Objetivo. Describir nuestra experiencia con everolimús para el tratamiento de pacientes con SEGA y CET. Pacientes y métodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente había sido previamente intervenido quirúrgicamente por SEGA con hidrocefalia. El diámetro máximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inició tratamiento con everolimús, 2,5 mg/día por vía oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/día en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reducción media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reducción se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimús disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugía en casos seleccionados (AU)

Introduction. Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. Aim. To describe our experience of using everolimus to treat patients with SEGA and TSC. Patients and methods. We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. Results. Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). Conclusions. Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases (AU)

[Response to everolimus in patients with giant cell astrocytoma associated to tuberous sclerosis complex]. / Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.

INTRODUCTION: Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. AIM. To describe our experience of using everolimus to treat patients with SEGA and TSC. PATIENTS AND METHODS: We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth. RESULTS: Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months). CONCLUSIONS: Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases.

TITLE: Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.Introduccion. Los astrocitomas subependimarios de celulas gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales mas comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos decadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertension intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapeutica a la reseccion quirurgica. Objetivo. Describir nuestra experiencia con everolimus para el tratamiento de pacientes con SEGA y CET. Pacientes y metodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente habia sido previamente intervenido quirurgicamente por SEGA con hidrocefalia. El diametro maximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inicio tratamiento con everolimus, 2,5 mg/dia por via oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/dia en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reduccion media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reduccion se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimus disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugia en casos seleccionados.

Síndrome de Aicardi: estudio retrospectivo de una serie de siete casos / Aicardi syndrome: retrospective study of a series of seven case reports

Introducción. El síndrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clásicamente definido por la tríada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y métodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediátrica de síndrome de Aicardi en dos hospitales universitarios durante un período de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolución fue a espasmos más allá de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, además de lesiones oftalmológicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio óptico (n = 3). Otros hallazgos fueron cardiopatía ongénita, anomalías costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El síndrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmológicas, las anomalías de la migración y organización neuronal y los quistes intracraneales. El pronóstico es grave por su elevada morbimortalidad y por la frecuente evolución a epilepsia refractaria y retraso mental grave (AU)

Introduction. The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. Patients and methods. Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. Results. We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. Conclusions. The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation (AU)

[Aicardi syndrome: retrospective study of a series of seven case reports]. / Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.

INTRODUCTION: The Aicardi syndrome is a disorder presumably X-linked dominant, classically defined by the triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile spasms, with lethality in males. PATIENTS AND METHODS: Retrospective descriptive study of patients diagnosed with Aicardi syndrome over a period of 29 years in two tertiary pediatric hospitals. RESULTS: We found seven women that developed infantile spasms before 6 months of age, epileptic spasms persisting beyond infancy in two cases, a refractory symptomatic partial epilepsy in three patients, and well-controlled partial epilepsy in one girl. Six cases presented severe-profound mental retardation and moderate-severe in a girl. Two girls died at 2 and 6 years-old. In all patients neuroimaging studies showed agenesis of the corpus callosum, intracranial cysts and malformations of cortical development. Ophthalmological lesions were chorioretinal lacunae in seven cases, anophthalmia/microphthalmia in four girls and optic nerve coloboma in three patients. Other findings were congenital heart disease, costovertebral abnormalities, cervical lymphangioma and focal hypertrichosis. CONCLUSIONS: The Aicardi syndrome should be suspected in girls with infantile spasms and agenesis of the corpus callosum. It is necessary to rule out these ophthalmologic abnormalities, malformations of cortical development and intracranial cysts. The prognosis is poor due to its high mortality and its evolution to refractory epilepsy and profound mental retardation.

TITLE: Sindrome de Aicardi: estudio retrospectivo de una serie de siete casos.Introduccion. El sindrome de Aicardi es un trastorno presumiblemente dominante ligado al cromosoma X, que afecta en exclusiva a mujeres, clasicamente definido por la triada de agenesia del cuerpo calloso, lagunas coriorretinianas y espasmos infantiles, letal en varones en la vida intrauterina. Pacientes y metodos. Estudio descriptivo retrospectivo de pacientes diagnosticadas y seguidas hasta el final de la edad pediatrica de sindrome de Aicardi en dos hospitales universitarios durante un periodo de 29 años. Resultados. Encontramos siete niñas, todas desarrollaron espasmos infantiles antes de los 6 meses de edad. La evolucion fue a espasmos mas alla de la infancia (n = 2), a epilepsia parcial farmacorresistente (n = 3) y a epilepsia parcial bien controlada (n = 1). Seis casos presentaron retraso mental grave-profundo, y uno, moderado-grave. Fallecieron dos niñas a los 2 y 6 años. En todas, los estudios de neuroimagen mostraron agenesia del cuerpo calloso, quistes intracraneales y malformaciones del desarrollo cortical cerebral, ademas de lesiones oftalmologicas: lagunas coriorretinianas (n = 7), anoftalmia/microftalmia (n = 4) y coloboma del nervio optico (n = 3). Otros hallazgos fueron cardiopatia congenita, anomalias costovertebrales, linfangioma cervical e hipertricosis focal. Conclusiones. El sindrome de Aicardi debe sospecharse en niñas con espasmos infantiles y agenesia del cuerpo calloso. Deben descartarse en estas pacientes las alteraciones oftalmologicas, las anomalias de la migracion y organizacion neuronal y los quistes intracraneales. El pronostico es grave por su elevada morbimortalidad y por la frecuente evolucion a epilepsia refractaria y retraso mental grave.

Síndrome DAMP: otra perspectiva del niño TDAH / DAMP syndrome: another approach to the ADHD child

La definición que el DSM-IV-TR hace del Trastorno por Déficit de Atención e Hiperactividad (TDAH) no hace ninguna referencia a la evidencia de muchos trabajos europeos que demuestran una mayor frecuencia de trastornos motores o alteraciones en el desarrollo de la coordinación en niños con trastornos hipercinéticos. En 1989, la Academia Americana de Psiquiatría incluye la categoría diagnóstica de Trastorno del Desarrollo de la Coordinación (TDC) para definir a niños con dificultades en el desarrollo de habilidades motoras. Existe un fenotipo clínico con entidad propia caracterizado por reunir criterios de TDAH y de TDC, en ausencia de retraso mental y parálisis cerebral, descrito por autores escandinavos en la década de los 70, conocido por el acrónimo DAMP (Déficit de Atención, control Motor y de la Percepción), que se presenta hasta en un 50% de los pacientes con ambos diagnósticos. La evolución natural del niño con DAMP es menos favorable que en el TDAH puro, con mayor riesgo de fracaso escolar e incluso de ser víctimas de acoso escolar. Los neuropediatras y pediatras, pero también los psiquiatras infantiles, deben reconocer y evaluar las dificultades motoras y de coordinación de estos pacientes y realizar recomendaciones apropiadas. Nuestro objetivo es destacar la importancia de los trastornos motores en el niño afecto de TDAH y contribuir a la difusión de esta entidad que va a precisar un abordaje diagnóstico y terapéutico diferenciado

The definition for ADHD within the DSM-IV-TR doesn't refer to the evidence of any European papers which show a higher frequency of motor impairment or alterations in the development of coordination in children with hyperkinetic disorders. In 1989, the American Academy of Psychiatry includes the diagnostic category of Developmental Disorder Coordination (DCD) to diagnose children with difficulties in the development of motor skills. There is a clinical phenotype characterized as a separated entity with criteria for ADHD and DCD, in the absence of mental retardation and cerebral palsy, described by scandinavian authors in the 70's and known by the acronym DAMP (Deficit in Attention, Motor control and Perception), which occurs in up to 50% of patients with both diagnoses. The natural history of children with DAMP is less favorable than pure ADHD, with greater risk of school failure and even of bullying. The neurologists, pediatricians and pediatric psychiatrists must recognize and evaluate motor and coordination difficulties of these patients and make appropriate recomendations. Our aim is to note the importance of motor disorders in children with ADHD and contribute to spread differential diagnosis and therapeutic approaches