Errores innatos del metabolismo. avances en el diagnostico y terapeutica / Inborn errors of metabolism. Advances in diagnosis and therapeutic

Resumen Las novedades en el campo de los errores innatos del metabolismo (EIM) son espectaculares. Se han descrito nuevos EIM, se conoce mejor sus bases fisiopatológicas y las implicaciones para el organismo. Con la llegada de las nuevas técnicas de metabolómica, lípidomica y genómica se han multiplicado los avances en el diag nóstico y permiten explorar nuevas opciones terapéu ticas. Se ha establecido una nueva clasificación de los EIM en base a los más de 1.450 EIM identificados. Está irrumpiendo una nueva especialidad, que es la medici na metabólica. El cribado neonatal se estáempezando a universalizar y nos permite hoy en día, con tándem masas, el diagnóstico de más de 20 enfermedades me tabólicas del período neonatal que tienen opciones de tratamiento. Se están creando unidades de EIM para adultos para seguir niños con EIM que sobreviven a la enfermedad y con cada vez mejor calidad de vida y se diagnostican EIM que debutan en la adolescencia o laedad adulta. Aparecen las terapias personalizadas y las guías de práctica clínica para muchos EIM. Finalmente están emergiendo cada vez nuevas opciones terapéuticas que permiten una mayor supervivencia y mejor calidad de vida. La terapia génica convencional ya se está aplicando en algunos EIM.Sin embargo, las estrategias de edición de genes con terapias de ARN pueden permitir corregir la mutación genética mini mizando los problemas asociados con la terapia génica de compensación convencional.

Abstract The advances in the field of inborn errors of metabo lism (IEM) are spectacular. New IEM have been described, their pathophysiological bases and implications for the organism are better known. With the advent of new metabolomics, lipidomics and genomics techniques, advances in diagnosis have multiplied and allow new therapeutic options to be explored. A new IEM classi fication has been established based on the more than 1.450 IEM identified. A new specialty is emerging, which is metabolic medicine. Neonatal screening is becom ing universal and allows us today, with tandem mass, to diagnose more than 20 metabolic diseases of the neonatal period, with treatment options. IEM units for adults are being created to follow-up children with IEM who survive the disease and with an increasingly better quality of life, and some IEM that start in adolescence or adulthood are diagnosed. Personalized therapies and clinical practice guidelines appear for any IEM. Finally, new therapeutic options are emerging day to day that allow a longer survival and better quality of life. Con ventional gene therapy is already being applied in some IEM. However, gene editing strategies with RNA thera pies may allow the correction of the genetic mutation, minimizing the problems associated with conventional compensation gene therapy.

Eventos paroxísticos que se confunden con epilepsia / Paroxysmal events that are confused with epilepsy

Resumen Los eventos paroxísticos no epilépticos (EPNE) se definen como episodios de aparición brusca y de breve duración que imitan a una crisis epiléptica, originados por una disfunción cerebral de origen diverso y a diferencia de la epilepsia no obedecen a una descarga neuronal excesiva. Su incidencia es mucho más elevada que la epilepsia y pueden aparecer a cualquier edad, pero son más frecuentes en los primeros años de vida. La inmadurez del sistema nervioso central en la infancia favorece que en este período las manifestaciones clínicas sean muy floridas y diferentes de otras edades. Fenómenos normales y comunes en el niño pueden también confundirse con crisis epilépticas. El primer paso para un diagnóstico correcto es establecer si este primer episodio corresponde a una crisis epiléptica o puede tratarse de un primer episodio de EPNE. Es importante seguir un protocolo de diagnóstico, valorando los antecedentes personales y familiares, sin olvidar el examen físico, analizar los posibles factores desencadenantes, los pormenores de cada episodio, si es posible un registro de los episodios, aplicar el sentido común y la experiencia y solamente proceder a los exámenes complementarios básicos como el registro EEG u otras exploraciones en caso de duda o para con firmación diagnóstica. En algunos casos se ha demostrado una base genética. Las opciones terapéuticas son escasas y la mayoría de EPNE tienen una evolución favorable.

Abstract Non-epileptic paroxysmal events (NEPE) are defined as episodes of sudden onset and short duration that mimic an epileptic seizure, caused by a brain dysfunction of diverse origin and, unlike epilepsy, are not due to excessive neuronal discharge. Its incidence is much higher than epilepsy and can appear at any age, but are more frequent in the first years of life. The immaturity of the central nervous system in childhood favors that in this period the clinical manifestations are more spectacular and different from other ages. Normal and common phenomena in children can also be confused with epileptic seizures. The first step for a correct diagnosis is to establish whether this first episode corresponds to an epileptic seizure or could be a first episode of NEPE. It is important to follow a diagnostic protocol, assessing the personal and family history, without forgetting the physical examination, analyzing the possible triggering factors, the details of each episode, if it's possible a record of the episodes, applying common sense and experience and only carrying out basic complementary tests such as EEG recording or others in case of doubt or for diagnostic confirmation. In some cases, a genetic basis has been demonstrated. Therapeutic op tions are scarce and the majority of NEPE have a favorable evolution.

Presurgical evaluation of drug-resistant paediatric focal epilepsy with PISCOM compared to SISCOM and FDG-PET.

PURPOSE: Children with drug-resistant focal epilepsy have a compromised quality of life. Epilepsy surgery can control or significantly reduce the seizures. We assessed and compared the usefulness of PISCOM, a new nuclear imaging processing technique, with SISCOM and 18F-FDG PET (FDG-PET) in pre-surgical evaluation of paediatric drug-resistant focal epilepsy. METHODS: Twenty-two children with pharmcorefractory epilepsy, mainly extratemporal, who had undergone pre-surgical assessment including SISCOM and FDG-PET and with postsurgical favorable outcome (Engel class I or II) for at least two years, were included in this proof-of-concept study. All abnormalities observed in SISCOM, FDG-PET and PISCOM were compared with each other and with the known epileptogenic zone (EZ) based on surgical treatment, histopathologic and surgical outcome results. Global interobserver agreement, Cohen's Kappa coeficient and PABAK statistic were calculated for each technique. RESULTS: PISCOM concordance with the known EZ was significantly higher than SISCOM (p<0.05), and no statistically differences were found with FDG-PET. PISCOM showed successful identification in 19 of 22 cases (86%), successful concordant with FDG-PET in 17 (77%), and SISCOM in 11 (50%). If we consider PISCOM and FDG-PET results together, both techniques successfully localized the known EZ in all cases. The measures of agreement between two experts in nuclear medicine were higher in PISCOM than in SISCOM and FDG-PET. CONCLUSION: PISCOM could provide complementary presurgical information in drug-resistant paediatric focal epilepsy, particularly in cases in which FDG-PET is doubtful or negative, replacing SISCOM and sparing the use of interictal SPECT.

Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients.

Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers. Germline gain-of-function variants in this gene have been recently implicated in microcephalic dwarfism. Common clinical features of patients with TBRS include tall stature, macrocephaly, intellectual disability (ID), and a distinctive facial appearance. Differential diagnosis of TBRS comprises Sotos, Weaver, and Malan Syndromes. The majority of these disorders present other clinical features with a high clinical overlap, making necessary a molecular confirmation of the clinical diagnosis. We here describe seven new patients with variants in DNMT3A, four of them with neuropsychiatric disorders, including schizophrenia and psychotic behavior. In addition, one of the patients has developed a brain tumor in adulthood. This patient has also cerebral atrophy, aggressive behavior, ID, and abnormal facial features. Clinical evaluation of this group of patients should include a complete neuropsychiatric assessment together with psychological support in order to detect and manage abnormal behaviors such as aggressiveness, impulsivity, and attention deficit-hyperactivity disorder. TBRS should be suspected in patients with overgrowth, ID, tall stature, and macrocephaly, who also have some neuropsychiatric disorders without any genetic defects in the commonest overgrowth disorders. Molecular confirmation in these patients is mandatory.

Epilepsia en niños con hemiparesia congénita secundaria a infartos cerebrales vasculares perinatales / Epilepsy in children with congenital hemiparesis secondary to perinatal ictus

El objetivo fue describir la frecuencia, modo de presentación y características de la epilepsia en niños con hemiparesia congénita (HC). Estudio retrospectivo, descriptivo y multicéntrico, basado en la recolección de datos de las historias clínicas de pacientes de 0 a 19 años con HC secundaria a infarto perinatal en diferentes centros de la comunidad de Cataluña. Se incluyeron 310 niños (55% varones y 45% mujeres) de un total de 13 centros de Cataluña. Edad media del debut de las crisis fue de 2 ± 1 año. Presentaron epilepsia el 29.5% (n = 76), el subtipo vascular más frecuente fue el infarto presumiblemente perinatal (51.3%), seguido del accidente isquémico arterial neonatal (18.4%), infarto hemorrágico venoso periventricular (15.8%), infarto hemorrágico neonatal (10.5%) y trombosis venosa neonatal (3.9%). La semiología de las crisis más frecuente fue la focal motora en un 82%, seguida de las focales motoras con bilateralización secundaria en el 23%, focales discognitivas en 13.5%, generalizadas 2% y espasmos 6.5%. El 67.3% se controló con monoterapia y los fármacos empleados fueron el valproato, levetiracetam o carbamacepina. Se identificó el antecedente de estatus eléctrico durante el sueño en 3 pacientes, todos asociados a lesiones extensas que incluían al tálamo. Del total con epilepsia, el 35% debutaron con convulsiones neonatales en los primeros 3 días de vida. El 30% con accidente cerebrovascular perinatal y HC presentan riesgo de padecer epilepsia durante la infancia. Aquellos con infartos isquémicos tienen el riesgo más alto, por lo que requerirán un seguimiento dirigido a detectar precozmente la epilepsia e iniciar tratamiento.

The objective was to describe the frequency, mode of presentation and characteristics of epilepsy in children with congenital hemiparesis (CH). It is a etrospective, descriptive and multicenter study, based on the collection of data from the clinical records of patients from 0 to 19 years with CH secondary to perinatal infarction in different centers of the community of Catalonia. A total of 310 children were included (55% males and 45% females), from a total of 13 centers in Catalonia. Average age of onset of the crises was 2 ± 1 year. Epilepsy was present in 29.5% (n = 76), among which the most frequent vascular subtype was arterial presumed perinatal ischemic stroke (51.3%), followed by neonatal arterial ischemic stroke (18.4%), periventricular venous infarction (15.8%), neonatal hemorrhagic stroke (10.5%) and neonatal cerebral sinovenous thrombosis (3.9%). Semiology of the most frequent seizures was motor focal in 82%, followed by focal motor with secondary bilateralization in 23%, focal discognitive in 13.5%, generalized by 2% and spasms in 6.5%. The 67.3% were controlled with monotherapy and the drugs used were valproate, levetiracetam or carbamazepine. The antecedent of electrical status during sleep was identified in 3 patients, all associated with extensive lesions that included the thalamus. Of the total number of children with epilepsy, 35% began with neonatal seizu res in the first 3 days of life. The 30% of children with perinatal stroke and CH present a risk of epilepsy during childhood. Children with ischemic strock have the highest risk, so they will require a follow-up aimed at detecting prematurely the epilepsy and start a treatment.

MRX93 syndrome (BRWD3 gene): five new patients with novel mutations.

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that either the weight, height, or head circumference are above the 97th centile or 2 to 3 SD above the mean for age and sex. Additional features, such as facial dysmorphism, developmental delay or intellectual disability (ID), congenital anomalies, neurological problems and an increased risk of neoplasia are usually associated with OGS. Genetic analysis in patients with overlapping clinical features is essential, to distinguish between two or more similar conditions, and to provide appropriate genetic counseling and recommendations for follow up. In the present paper, we report five new patients (from four unrelated families) with an X-linked mental retardation syndrome with overgrowth (XMR93 syndrome), also known as XLID-BRWD3-related syndrome. The main features of these patients include ID, macrocephaly and dysmorphic facial features. XMR93 syndrome is a recently described disorder caused by mutations in the Bromodomain and WD-repeat domain-containing protein 3 (BRWD3) gene. This article underscores the importance of genetic screening by exome sequencing for patients with OGS and ID with unclear clinical diagnosis, and expands the number of reported individuals with XMR93 syndrome, highlighting the clinical features of this unusual disease.

Trastornos paroxísticos no epilépticos en el lactante / Non-paroxysmal disorder in infant

Los trastornos paroxísticos no epilépticos (TPNE) se definen como episodios que se repiten periódicamente y que remedan una crisis epiléptica. Su aparición es generalmente brusca y de breve duración, originados por una disfunción cerebral de origen diverso y que no obedecen a una descarga neuronal excesiva (a diferencia de una crisis epiléptica). Su incidencia es diez veces más elevada que la epilepsia y pueden aparecer a cualquier edad, pero son más frecuentes en los primeros años de vida. La inmadurez del sistema nervioso en la infancia hace que en este período las manifestaciones sean muy diversas y diferentes a otras edades. El primer paso para un diagnóstico correcto es un buen interrogatorio y establecer si el episodio puede corresponder a una crisis epiléptica o a un TPNE. El diagnóstico diferencial es muy amplio, especialmente en las primeras edades. Aparte del examen neurológico completo, en caso de duda se debe ampliar el estudio con exámenes complementarios que en la mayoría de las ocasiones serán normales/ negativos. En algunos casos se ha demostrado una base genética. Las opciones terapéuticas son escasas y la mayoría de los TPNE, especialmente en el lactante, desaparecen con la edad sin dejar secuelas.

Non-epileptic paroxysmal disorders (PNED) are defined as events that mimic epileptic seizures. Its onset is usually sudden and short-lived, caused by brain dysfunction of various origins, but not due to excessive neuronal firing. Its incidence is higher than the epilepsy (10:1). They can occur at any age but are most common in children, especially in the first year of life. The immature nervous system in childhood causes in this period, paroxysmal manifestations that are very diverse and different from other ages. Normal and common paroxysmal disorders in children can mimic epileptic seizures. The first step is to establish a correct diagnosis, if the clinical paroxysmal episode is a seizure or PNED. Differential diagnosis is very broad, especially in the first ages. It's necessary a complete neurological examination in case of doubt and the study should be extended with complementary exams, investigations that in most cases will be normal/negative. In some of them, a genetic basis has been shown. Treatment options are limited and most PNED untreated have a favorable outcome.

Encephalopathies with intracranial calcification in children: clinical and genetic characterization.

BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. CONCLUSIONS: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

Orientación diagnóstica de los errores congénitos del metabolismo a partir de la neuroimagen / Diagnostic orientation of congenital errors of metabolism from neuroimaging

Resumen Las enfermedades neurometabólicas constituyen un grupo de patologías poco frecuentes y en notable expansión, de difícil diagnóstico y complicado manejo. Este artículo pretende desarrollar una orientación práctica frente a la sospecha de una enfermedad metabólica, a partir del análisis de la neuroimagen. Es muy importante para el neuropediatra sospecharlas pero siempre en función de los antecedentes , de los signos y síntomas neurológicos (retardo del desarrollo, déficit cognitivo, epilepsia refractaria, distonía, crisis metabólicas o la presencia de signos extraneurológicos inexplicados), de los hallazgos bioquímicos y de la neuroimagen. En muchas ocasiones los hallazgos son totalmente inespecíficos, sin embargo en otras situaciones la neuroimagen, en especial la resonancia magnética craneal (RM), puede ser muy orientadora o simplemente especí ca de una enfermedad metabólica. El examen pormenorizado de la RM valorando el compromiso de la sustancia blanca, de la sustancia gris, de los ganglios basales o del cerebelo podrá orientar hacia un grupo concreto de enfermedades metabólicas. Además con la RM espectroscópica (RME) y con las técnicas de difusión se pueden orientar/diagnosticar algunos errores Innatos del Metabolismo (EIM), seguir la evolución o incluso valorar la respuesta a la terapia.

Abstract Neurometabolic diseases constitute a group of rare diseases and in remarkable expansion, with difficult diagnosis and complicated management. This article aims to develop a practical orientation to the suspicion of a metabolic disease, based on the neuroimaging analysis. Neurological signs and symptoms (developmental delay, cognitive deficit, refractory epilepsy, dystonia, metabolic crises or the presence of unexplained extraneurologic signs) are very important for the neuropediatrician, but always on the basis of their antecedents, biochemical findings and of neuroimaging. In many cases neuroimaging (specially cranial magnetic resonance) (MRI) ndings are totally non-specific, however in other situations the neuroimaging can be very suspicious or simply specific to a metabolic disease. Detailed examination with MRI of white matter, gray matter, basal ganglia, or cerebellum may be directed towards a speci c group of metabolic diseases. In addition to the spectroscopic MRI and di usion techniques, some EIM can be targeted / diagnosed, follow the evolution or even evaluate the response to therapy.

Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Cost-Effectiveness Analysis of a National Newborn Screening Program for Biotinidase Deficiency.

BACKGROUND AND OBJECTIVES: There are conflicting views as to whether testing for biotinidase deficiency (BD) ought to be incorporated into universal newborn screening (NBS) programs. The aim of this study was to evaluate the cost-effectiveness of adding BD to the panel of conditions currently screened under the national NBS program in Spain. METHODS: We used information from the regional NBS program for BD that has been in place in the Spanish region of Galicia since 1987. These data, along with other sources, were used to develop a cost-effectiveness decision model that compared lifetime costs and health outcomes of a national birth cohort of newborns with and without an early detection program. The analysis took the perspective of the Spanish National Health Service. Effectiveness was measured in terms of quality-adjusted life years (QALYs). We undertook extensive sensitivity analyses around the main model assumptions, including a probabilistic sensitivity analysis. RESULTS: In the base case analysis, NBS for BD led to higher QALYs and higher health care costs, with an estimated incremental cost per QALY gained of $24,677. Lower costs per QALY gained were found when conservative assumptions were relaxed, yielding cost savings in some scenarios. The probability that BD screening was cost-effective was estimated to be >70% in the base case at a standard threshold value. CONCLUSIONS: This study indicates that NBS for BD is likely to be a cost-effective use of resources.

[Alternating hemiplegia of childhood: ATP1A3 gene analysis in 16 patients]. / Hemiplejía alternante de la infancia: estudio del gen ATP1A3 en 16 pacientes.

BACKGROUND AND OBJECTIVE: Alternating hemiplegia in childhood (AHC) is a disease characterized by recurrent episodes of hemiplegia, tonic or dystonic crisis and abnormal ocular movements. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. The objective is to describe a series of 16 patients with clinical and genetic diagnosis of AHC. PATIENTS AND METHOD: It is a descriptive, retrospective, multicenter study of 16 patients with clinical diagnosis of AHC in whom mutations in ATP1A3 were identified. RESULTS: Six heterozygous, de novo mutations were found in the ATP1A3 gene. The most frequent mutation was G2401A in 8 patients (50%) followed by G2443A in 3 patients (18.75%), G2893A in 2 patients (12.50%) and C2781G, G2893C and C2411T in one patient, respectively (6.25% each). CONCLUSIONS: In the studied population with AHC, de novo mutations were detected in 100% of patients. The most frequent mutations were D801N y la E815K, as reported in other series.

Alternating hemiplegia of childhood with a de novo mutation in ATP1A3 and changes in SLC2A1 responsive to a ketogenic diet.

BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare condition characterized by an early onset of hemiplegic episodes and other paroxysmal or permanent neurological dysfunctions. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. Regarding the differential diagnosis of AHC, glucose transporter 1 deficiency syndrome may be considered because these two disorders share some paroxystic and nonparoxystic features. PATIENT AND RESULTS: We report a typical case of AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion in the SLC2A1 gene who exhibited marked clinical improvement following ketogenic diet. CONCLUSION: Because the contribution of the SLC2A1 mutation to the clinical phenotype cannot be definitely demonstrated, the remarkable clinical response after ketogenic diet led us to the hypothesis that ketogenic diet might be effective in AHC as it provides an alternative energy source for the brain.

Identifying the cortical substrates of interictal epileptiform activity in patients with extratemporal epilepsy: An EEG-fMRI sequential analysis and FDG-PET study.

PURPOSE: The aim of this study was to apply sequential analysis of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) data to study the cortical substrates related to the generation of the interictal epileptiform activity (IEA) in patients with pharmacoresistant extratemporal epilepsy. METHODS: We analyzed fMRI data from 21 children, adolescents, and young adults patients who showed frequent bursts or runs of spikes on EEG, by using the sequential analysis method. We contrasted consecutive fixed-width blocks of 10 s to obtain the relative variations in cerebral activity along the entire fMRI runs. Significant responses (p < 0.05, family-wise error (FWE) corrected), time-related to the IEA recorded on scalp EEG, were considered potential IEA cortical sources. These results were compared with those from the fluorodeoxyglucose-positron emission tomography (FDG-PET), intracranial EEG (two patients), and surgery outcome (eight patients). KEY FINDINGS: The typical IEA was recorded in all patients. After the sequential analysis, at least one significant blood oxygen level-dependent (BOLD) response spatially consistent with the presumed epileptogenic zone was found. These IEA-related activation areas coincided when superimposed with the hypometabolism depicted by the FDG-PET. These data were also consistent with the invasive EEG findings. Epileptic seizures were recorded in eight patients. A subset of IEA-associated fMRI activations was consistent the activations at seizure-onset determined by sequential analysis. The inclusion of the IEA-related areas in the resection rendered the patients seizure-free (five of eight operated patients). SIGNIFICANCE: The EEG-fMRI data sequential analysis could noninvasively identify cortical areas involved in the IEA generation. The spatial relationship of these areas with the cortical metabolic abnormalities depicted by the FDG-PET and their intrinsic relationship regarding the ictal-onset zone could be useful in epilepsy surgery planning.

Orientación diagnóstica de las enfermedades neurometabólicas basada en la clínica, estudios metabólicos y neuroimagenológicos / [Guidelines for detection of inborn errors of metabolism based on clinical exam, analytical studies and neuroimaging techniques].

Neurometabolic disorders constitute an expanding and complex field in which it is difficult to diagnose and to acquire a specific education and training. This article tries to develop a practical orientation in the suspicion, clinical exam, biochemical studies and neuroimaging techniques for the detection of inborn errors of metabolism. It is very important for the neuropediatrician to suspect metabolic diseases depending on some of the most frequent unexplained neurological disturbances and symptoms as psychomotor delay, mental retardation, refractory epilepsy, dystonia, metabolic crisis or other extraneurological signs. It is important the diagnosis related to the new emergent therapeutic options, genetic counseling and prenatal diagnosis.

[Neurotoxicity due to methotrexate in paediatric patients. Description of the clinical symptoms and neuroimaging findings]. / Neurotoxicidad por metotrexato en pacientes pediatricos. Descripcion de los sintomas clinicos y hallazgos neurorradiologicos.

INTRODUCTION. High-dose methotrexate (MTX) has showed to increase the surveillance in children with acute lymphoblastic leukemia and other neoplasms. However, MTX may induce significant neurotoxicity. AIM. To evaluate, in our population of patients who have been treated with MTX, the incidence of neurotoxicity and to describe its main clinical and radiological characteristics. PATIENTS AND METHODS. We retrospectively review the patients who received treatment with systemic high-dose MTX and/or intrathecal MTX between 1994 and 2010. The children who presented clinical o radiological signs of neurotoxicity were reviewed. RESULTS. We identified 284 patients who received high-dose intravenous and/or intrathecal MTX. 9 patients presented neurotoxicity. The median age at diagnosis was 6 years; 6 patients were male. The diagnosis included: 6 acute lymphoblastic leukemia, 2 medulloblastoma and 1 lymphoma. 66% patients presented focal neurological dysfunction, 3 had non-specific symptoms. In 5 patients the symptomatology started the first 14 days after the MTX administration. 8 patients had complete clinical resolution, but only one presented neurological long term effects. All the patients except one showed signs of acute leukoencephalopathy in the brain MR study. These alterations resolved one year later in 3 patients; in the other patients the MR alterations persisted. The neurotoxicity management was corticosteroid, folinic acid, aminophylline and dextromethorphan. CONCLUSION. The MTX neurotoxicity it can present as acute or chronic. It has a wide clinical spectrum, ranging from sub-clinical manifestations with complete recovery to a chronic and progressive encephalopathy.

Validation of FDG-PET/MRI coregistration in nonlesional refractory childhood epilepsy.

PURPOSE: To validate the use of 18F-fluorodeoxyglucose-positron 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 (κ 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 subtle-lesional. 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.