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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.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.PISCOM concordance with the known EZ was significantly higher than SISCOM (p0.05), 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.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.

Mitochondrial translation defects are a continuously growing group of disorders showing a large variety of clinical symptoms including a wide range of neurological abnormalities. To date, mutations in PTCD3, encoding a component of the mitochondrial ribosome, have only been reported in a single individual with clinical evidence of Leigh syndrome. Here, we describe three additional PTCD3 individuals from two unrelated families, broadening the genetic and phenotypic spectrum of this disorder, and provide definitive evidence that PTCD3 deficiency is associated with Leigh syndrome. The patients presented in the first months of life with psychomotor delay, respiratory insufficiency and feeding difficulties. The neurologic phenotype included dystonia, optic atrophy, nystagmus and tonic-clonic seizures. Brain MRI showed optic nerve atrophy and thalamic changes, consistent with Leigh syndrome. WES and RNA-seq identified compound heterozygous variants in PTCD3 in both families: c.[1453-1GC];[1918CG] and c.[710del];[902CT]. The functional consequences of the identified variants were determined by a comprehensive characterization of the mitochondrial function. PTCD3 protein levels were significantly reduced in patient fibroblasts and, consistent with a mitochondrial translation defect, a severe reduction in the steady state levels of complexes I and IV subunits was detected. Accordingly, the activity of these complexes was also low, and high-resolution respirometry showed a significant decrease in the mitochondrial respiratory capacity. Functional complementation studies demonstrated the pathogenic effect of the identified variants since the expression of wild-type PTCD3 in immortalized fibroblasts restored the steady-state levels of complexes I and IV subunits as well as the mitochondrial respiratory capacity. Additionally, minigene assays demonstrated that three of the identified variants were pathogenic by altering PTCD3 mRNA processing. The fourth variant was a frameshift leading to a truncated protein. In summary, we provide evidence of PTCD3 involvement in human disease confirming that PTCD3 deficiency is definitively associated with Leigh syndrome.

Phenylketonuric (PKU) patients are a population at risk for sleep disorders due to deficits in neurotransmitter synthesis. We aimed to study the prevalence of sleep disorders in early-treated PKU children and adolescents and assessed correlations with dopamine and serotonin status. We compared 32 PKU patients (16 females, 16 males; mean age 12 years), with a healthy control group of 32 subjects (16 females, 16 males; mean age 11.9 years). 19 PKU patients were under dietary treatment and 13 on tetrahydrobiopterin therapy. Concurrent phenylalanine (Phe), index of dietary control and variability in Phe in the last year, tyrosine, tryptophan, prolactin, and ferritin in plasma, platelet serotonin concentration, and melatonin, homovanillic and 5-hydroxyindoleacetic acid excretion in urine were analyzed. Sleep was assessed using Bruni's Sleep Disturbance Scale for Children. Sleep disorders were similar in both groups, 15.6% in control group and 12.5% in PKU group. In PKU patients, no correlations were found with peripheral biomarkers of neurotransmitter synthesis nor different Phe parameters, 43.3% had low melatonin excretion and 43.8% low platelet serotonin concentrations. Despite melatonin and serotonin deficits in early-treated PKU patients, the prevalence of sleep disorders is similar to that of the general population.

Analyze pre-surgical evaluation modalities, surgical failures, long-term results of surgery and neurocognitive outcome in children with Low-grade Epilepsy Associated brain Tumors (LEAT).Retrospective observational study of 37 children who underwent epilepsy surgery, with a minimum follow-up of 12 months. At time of surgery, pharmaco-sensitivity (Group 1; n = 8) and drug-resistance (Group 2; n = 29), were considered.Age range of seizure onset was 5 months-14 years (mean 5.73years) and age at surgery was 2.2-18.7years (mean 10.7years). Gangliogliomas (35.1%) or DNTs (29.7%), combined or not to a focal cortical dysplasia (FCD), were the most frequent. Extended lesionectomy 16 children (43.2%) were the most frequently used surgical approach in both groups. At one year of follow-up, 36 children (97.2%) were classified as Engel I. Within the age-range studied, duration of epilepsy and time to surgery appeared to have no impact on clinical and neurocognitive outcome in both groups. It is noteworthy, however, that antiseizure medications (ASMs) were withdrawn in 100% of the pharmacosensitive group vs 34.5% of the drug-resistant group (p = 0.002). In children with a pharmaco-sensitive epilepsy, neurocognitive evaluation showed significant improvement in the verbal comprehension index (p = 0.029).Epilepsy-surgery is a safe therapeutic option for LEATs including for children with seizures controlled by ASMs. Presence of associated lesions is not rare. Comprehensive pre-surgical evaluation increases the chances for control of the seizures, the early discontinuation of medications and favours neurocognitive development.

The Catalonian Newborn Screening Program (CNSP) began in 1969, in Barcelona. It was promoted by Dr. Juan Sabater Tobella and supported by Barcelona Provincial Council and Juan March Foundation. That is how the Institute of Clinical Biochemistry was born, whose aims were diagnosis, research and teaching, along with the spirit of contributing to the prevention of mental retardation. The CNSP began with the detection of phenylketonuria (PKU), and, in 1982, the Program was expanded with the inclusion of congenital hypothyroidism detection. Towards 1990, the Program covered almost 100% of all newborns (NB) in Catalonia. In 1999, the CNSP was expanded with the incorporation of cystic fibrosis. It took fourteen years, until 2013, to make the largest expansion so far, with the incorporation of 19 metabolic diseases to the screening panel. The detection of sickle cell disease began in 2015 and in 2017 the detection of severe combined immunodeficiency was included. Currently, the CNSP includes 24 diseases in its main panel. Since 1969, 2,787,807 NBs have been screened, of whom 1,724 have been diagnosed with any of these diseases, and 252 of other disorders by differential diagnosis with those included in the main panel. The global prevalence is 1: 1,617 NBs affected by any of the diseases included in the CNSP and 1: 1,140 NBs if incidental findings diagnosed through the CNSP are included.El Programa de Cribado Neonatal de Cataluña (PCNC) se inició en el año 1969, en Barcelona, impulsado por el Dr. Juan Sabater Tobella y apoyado por la Diputación de Barcelona y la Fundación Juan March. Así nació el Instituto de Bioquímica Clínica para acometer funciones asistenciales, de investigación y docencia, con el espíritu de contribuir a la prevención del retraso mental. El PCNC se inició con la detección de la fenilcetonuria (PKU) y en el año 1982 se amplió con la detección del hipotiroidismo congénito. Hacia el año 1990 la cobertura territorial llegó casi al 100% de todos los recién nacidos en Cataluña. En 1999 se amplió el PCNC con la incorporación de la fibrosis quística y tras catorce años, en 2013, se realizó la ampliación más numerosa hasta ahora, con la incorporación de la detección de 19 enfermedades metabólicas hereditarias. En el año 2015 comenzó la detección de la enfermedad de células falciformes y en el 2017 la detección de la inmunodeficiencia combinada grave. Actualmente, el PCNC incluye la detección de 24 enfermedades. Desde su inicio en el año 1969, se han cribado 2.787.807 recién nacidos, de los cuales 1.724 han sido diagnosticados de alguna de las 24 enfermedades que componen nuestro panel principal y 252 por diagnóstico diferencial de las primeras. En total la prevalencia global es de 1:1.617 RN afectos de alguna de las enfermedades incluidas en el PCNC y de 1:1.140 RN si se incluyen los hallazgos incidentales encontrados.

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.

Phenylketonuria, also known as PKU, is the most frequent congenital inborn error of metabolism. The severe form or classic PKU untreated causes intellectual disability, although with the early detection programs in the neonatal period, diagnosis and treatment prevent the appearance of the symptoms. Despite early diagnosis and treatment we have observed some neurotoxicity in treated PKU patients. We analyzed the factors involved apart from the toxicity due to the high cerebral concentrations of phenylalanine (Phe), the defects of synthesis of neurotransmitters, the alteration of cerebral myelination, the effect of the elevation of Phe in the processes of transport and distribution of neutral amino acids with an abnormal synthesis of brain proteins, plasma and cerebral tyrosine deficiency, the neurotoxicity of Phe metabolites, the defect of cholesterol biosynthesis or the increase of oxidative stress. White matter alterations in early treated PKU patients have an important role in neurological manifestations. The treatment of PKU is for life and is based on the reduction of foods containing Phe combined with the administration of a special formula or tetrahydrobiopterin (BH4) treatment. New therapeutic options will be analyzed.La fenilcetonuria, también conocida como PKU, es el error congénito más frecuente del metabolismo de los aminoácidos. La forma grave o PKU clásica no tratada, causa una discapacidad intelectual, aunque los programas de detección en el período neonatal, el diagnóstico y el tratamiento evitan la aparición de los síntomas. A pesar de un diagnóstico y tratamiento temprano hemos observado cierta neurotoxicidad en los pacientes con PKU tratados. Analizamos los demás factores implicados, aparte de la toxicidad por las elevadas concentraciones cerebrales de fenilalanina (Phe), se revisan los defectos de síntesis de neurotransmisores, las alteración de la mielinización cerebral, el efecto de la elevación de Phe en los procesos de transporte y distribución de los aminoácidos neutros con una síntesis anómala de proteínas cerebrales, la deficiencia plasmática y cerebral de tirosina, la neurotoxicidad de los metabolitos de Phe, el defecto de la biosíntesis del colesterol o el aumento del estrés oxidativo. Las alteraciones de la sustancia blanca en los pacientes con PKU tienen un papel importante en las manifestaciones neurológicas. El tratamiento de la PKU es para toda la vida y se basa en la reducción del aporte de alimentos que contienen Phe combinado con la administración de una fórmula especial, o en el tratamiento con tetrahidrobiopterina (BH4). Se analizan nuevas opciones terapéuticas.

Introduction: Phenylketonuria (PKU) is a rare metabolic disease that causes slight-to-severe neurological symptoms. Slow performance has been observed in PKU but the influence of high-order (i.e., not purely motor) deficits and of temporary variations of the phenylalanine (Phe) level on this slowness has not been fully corroborated as yet. Response speed and the effect of motor practice during the performance of a visuomotor coordination task were measured, in a group of patients with early-treated phenylketonuria (ET PKU). Method: We compared the performance of a group of early-treated PKU patients with ages ranging from 11 to 25 years and a control group of healthy volunteers on a computerized visuomotor task. Participants performed rapid movements towards one of five response buttons, as indicated by a visual stimulus that could appear in five different positions on a computer screen. The results of our visuomotor task were correlated with neurobiological data (Phe levels) and with neuropsychological measures of motor (finger tapping) and executive functions (Stroop task). Results: The ET PKU group showed slower responses than the control group. Furthermore, an absence of a practice effect (i.e., faster response times at the end of the study) was found in the PKU group but not in the control group. Our results also revealed that this absence of practice effect correlated with higher Phe levels on the testing day with respect to the average Phe level of the previous 12 months and, although weakly, with performance on the Stroop task. Conclusions: This pattern of results indicates slower visuomotor performance and a less beneficial effect of practice in ET PKU. The correlations found among our visuomotor measures, the same-day Phe level, and the Stroop test may reflect the negative effects of dopamine reduction in brain areas involved in motor control, selective attention, and learning

Cerebral neurotransmitter (NT) deficiency has been suggested as a contributing factor in the pathophysiology of brain dysfunction in phenylketonuria (PKU), even in early-treated phenylketonuric patients. The study aimed to review dopamine and serotonin status in PKU, and the effect of the impaired neurotransmission. Several mechanisms are involved in the pathophysiology of PKU, primarily characterized by impaired dopamine and serotonin synthesis. These deficits are related to executive dysfunctions and social-emotional problems, respectively, in early treated patients. Blood phenylalanine is the main biomarker for treatment compliance follow-up, but further investigations and validation of peripheral biomarkers may be performed to monitor NT status. The development of new therapies is needed not only for decreasing blood and brain phenylalanine levels but also to improve NT syntheses.

Aim To perform metabolic testing on 406 patients (age range 3–22y [mean 6.71, SD 4.15], 343 males and 63 females) with nonsyndromic autism spectrum disorders (ASD) to assess the diagnostic yield. In addition, we reviewed our hospital's clinical database of 8500 patients who had undergone metabolic testing to be identified for inborn errors of metabolism (IEM), and described the characteristics of those with IEM and nonsyndromic ASD. Method Neuropsychological evaluation included the Social Communication Questionnaire and Child Behavior Checklist. For metabolic testing/screening, urine samples were analyzed for the diagnosis of cerebral creatine deficiency syndromes, purine and pyrimidine disorders, amino acid metabolism defects, mucopolysaccharidoses, and organic acidurias. Results The 406 recruited participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria of ASD. No biochemical evidence of a metabolic disorder was detected in any of the 406 patients studied. Concerning the retrospective evaluation from the 8500 who had metabolic testing, 464 individuals had a diagnosis of an IEM (394 without the diagnosis of ASD and 70 with ASD diagnosis). Only one individual with IEM had a diagnosis of nonsyndromic ASD at the time of the metabolic study; the metabolic testing had revealed diagnosis of urea-cycle disorder. Interpretation Metabolic testing should be considered in the work-up of individuals with syndromic ASD, but metabolic testing is not cost-effective for individuals with nonsyndromic ASD.

© The Author(s) 2019., Identifying diseases displaying chronic low plasma Coenzyme Q10 (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005–2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients., This work was supported by grant from the Instituto de Salud Carlos III (ISCIII-FIS PI17/00109, PI17/00021, PI17/01286, PI15/00166 and PI15/01082), the FEDER Funding Program from the European Union, CIBERER-ISCIII and Departamento de Ciencia, Tecnología y Universidad del Gobierno de Aragón (Grupos de Referencia B33_17R).

Background Despite dietary intervention, individuals with early treated phenylketonuria (ETPKU) could present neurocognitive deficits and white matter (WM) abnormalities. The aim of the present study was to evaluate the microstructural integrity of WM pathways across the whole brain in a cohort of paediatric ETPKU patients compared with healthy controls (HCs), by collecting DTI-MRI (diffusion tensor magnetic resonance imaging) data and diffusion values (mean diffusivity (MD), radial diffusivity (RD) and fractional anisotropy (FA)). Methods DTI-MRI data and diffusion values (MD, RD, FA) from WM tracts across the whole brain were analized using Tract Based Spatial Statistics (TBSS), in 15 paediatrics TPKU patients (median age: 12 years) and compared with 11 HCs. Areas showing abnormal values in the patient group were correlated (Pearson) with age, lifetime Phe values, last year median and mean Phe, concurrent Phe values in plasma, urine neurotransmitters status biomarkers, and with a processing speed task. Results ETPKU showed bilaterally decreased MD values compared with HCs in the body and splenium of the corpus callosum, superior longitudinal fasciculus, corona radiata and in the posterior limb of the internal capsule. RD values followed a similar pattern, although decreased RD values in PKU patients were also found in the anterior limb of the internal capsule and in the cerebral peduncle. Decreased MD and RD values within the aforementioned regions had significant negative correlations with age, last year median and mean Phe and concurrent Phe values. No correlations were found with monoamines in urine or processing speed task. Conclusions ETPKU patients showed MD and RD values significantly decreased across the whole brain when compared with HCs, and this damage was associated with high Phe values and the age of patients. Despite this microstructural damage, no affectation in processing speed was observed in patients with good metabolic control. DTI-MRI sequences could be used as a technique to quantify WM damage that is difficult to be detect in T1 or T2-weighted images, but also to quantify damage of WM through the follow up of patients with poor metabolic control in prospective studies.

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.

Identifying diseases displaying chronic low plasma Coenzyme Q10 (CoQ) values may be important to prevent possible cardiovascular dysfunction. The aim of this study was to retrospectively evaluate plasma CoQ concentrations in a large cohort of pediatric and young adult patients. We evaluated plasma CoQ values in 597 individuals (age range 1 month to 43 years, average 11 years), studied during the period 2005–2016. Patients were classified into 6 different groups: control group of healthy participants, phenylketonuric patients (PKU), patients with mucopolysaccharidoses (MPS), patients with other inborn errors of metabolism (IEM), patients with neurogenetic diseases, and individuals with neurological diseases with no genetic diagnosis. Plasma total CoQ was measured by reverse-phase high-performance liquid chromatography with electrochemical detection and ultraviolet detection at 275 nm. ANOVA with Bonferroni correction showed that plasma CoQ values were significantly lower in the PKU and MPS groups than in controls and neurological patients. The IEM group showed intermediate values that were not significantly different from those of the controls. In PKU patients, the Chi-Square test showed a significant association between having low plasma CoQ values and being classic PKU patients. The percentage of neurogenetic and other neurological patients with low CoQ values was low (below 8%). In conclusión, plasma CoQ monitoring in selected groups of patients with different IEM (especially in PKU and MPS patients, but also in IEM under protein-restricted diets) seems advisable to prevent the possibility of a chronic blood CoQ suboptimal status in such groups of patients.

About 25% of seizures in the neonatal period have causes other than asphyxia, ischaemia or intracranial bleeding. Among these are primary genetic epileptic encephalopathies with sometimes poor prognosis and high mortality. In addition, some forms of neonatal infant seizures are due to inborn errors of metabolism that do not respond to common AEDs, but are amenable to specific treatment. In this situation, early recognition can allow seizure control and will prevent neurological deterioration and long-term sequelae. We review the group of inborn errors of metabolism that lead to newborn/infant seizures and epilepsy, of which the treatment with cofactors is very different to that used in typical epilepsy management.

Inborn errors of metabolism (IEM) are rare conditions that represent more than 1000 diseases, with a global prevalence of approximately 1:2000 individuals. Approximately, 40%-60% of IEM may present with epilepsy as one of the main neurologic signs. Epilepsy in IEM may appear at any age (fetal, newborn, infant, adolescent, or even adult). Different pathophysiological mechanisms may be responsible for the clinical phenotype, such as disturbances in energy metabolism (mitochondrial and fatty oxidation disorders, GLUT-1, and cerebral creatine deficiency), accumulation of complex molecules (lysosomal storage disorders), toxic mechanisms (organic acidurias and urea cycle disorders), or impairment of neurotransmission. Early diagnosis and, in some cases, an effective treatment may result in an excellent evolution of the IEM, in particularly seizure control. This review attempts to delineate a summary of IEM that may present with seizures or epilepsy and emphasizes the management in treatable conditions.

Creatine deficiency syndromes are a group of disorders of creatine (Cr) synthesis and transport characterized by intellectual disability, language delay, epilepsy, autism spectrum disorder, and movement disorders secondary to decrease of Cr concentration in the brain. Synthesis defects are treatable, therefore an early diagnosis and treatment is essential. The aim of this article is to review the Cr metabolism and function in the central nervous system. We describe the optimal diagnostic protocol in Cr deficiency syndromes based on biochemical methods, neuroradiological (1H-MRS), and molecular analysis. Finally, a treatment approach of the different Cr deficiency syndromes is described.

Resumen Fundamento y objetivo La hemiplejia alternante de la infancia (HAI) es una enfermedad caracterizada por episodios recurrentes de hemiplejia, crisis tonicas o distonicas y movimientos oculares anormales de inicio precoz. Recientemente se han identificado mutaciones en el gen ATP1A3 como mecanismo causante de esta enfermedad. El objetivo es describir una serie de pacientes con diagnostico clinico y genetico de HAI. Pacientes y metodo Se trata de un estudio descriptivo, retrospectivo y multicentrico, de 16 pacientes con diagnostico clinico de HAI, en quienes se documentaron mutaciones en el gen ATP1A3. Resultados En la serie estudiada se encontraron 6 mutaciones distintas en el gen ATP1A3, todas en heterocigosis y de novo. La mutacion mas comun fue G2401A, presente en 8 pacientes (50%), seguida por la mutacion G2443A en 3 pacientes (18,75%), G2893A en 2 pacientes (12,50%), y C2781G, G2893C y C2411T en sendos pacientes (6,25% cada una). Conclusiones En la poblacion estudiada con HAI se detectaron mutaciones de novo en el 100% de los pacientes estudiados. Las 2 mutaciones mas frecuentes fueron la G2401A y la G2443A.

To assess the clinical features and severity of tics and environmental factors influencing tic expression in a cohort of children with tic disorders.We performed a cross-sectional study in a cohort of children and adolescents (N = 92) with tic disorders referred to the outpatient clinic of a tertiary-level paediatric centre in Barcelona. The severity of tics was evaluated using the Yale Global Tic Severity Scale (YGTSS). A questionnaire including a list of environmental factors and common daily activities that might influence tic occurrence was completed for patients greater than 5 years old.Children were classified as having Tourette syndrome (TS) (52 patients), chronic motor or phonic tics (22 patients) and tics of less than 12 months' duration (18 patients). Tics worsened with stressful situations, activities related to school, playing video games and watching TV. A significant proportion of children reported a reduction in tics while they were concentrating on artistic or creative activities or when playing sports and participating in outdoor activities. The YGTSS scores were higher for TS patients (P.001) and correlated positively with the time of evolution of tics (r = .273, P = .026). Poor school performance was associated with TS (p = .043) and higher scores on the YGTSS (P = .018), as well as attention deficit/hyperactivity disorder (P = .007).Several activities of daily living were identified as modifying tic severity in children and may be important clues for tic management. In a subgroup of children with TS, tics were associated with significant morbidity and poor academic performance. Our results emphasise the importance of developing specific school programmes and tailored recommendations in patients with TS.

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.

This paper presents findings from studies of EF in individuals with early-treated PKU within the context of recent advances in neuropsychological theory and research. It focuses on means of assessment, contexts of assessment, and the best way to define and investigate EF. Several conclusions can be drawn based on the findings presented here. The first conclusion is that there is clear evidence for phenylalanine-related EF-deficits in early-treated PKU, particularly with respect to prepotent response inhibition and the manipulation or monitoring component of working memory. An important note, however, is that measurement of EF in PKU has become too fragmented, as different researchers and clinicians use different definitions of EF, and subsequently, different instruments to measure EF. This appears to be one of the most important causes of mixed results. A second conclusion is that there appears to be a need to incorporate at least one specific, relatively new taxonomy of EF in PKU-research, i.e. the taxonomy that distinguishes hot and cool EFs, where hot EF is associated with regulation of affect/emotions and motivation, or regulatory functions when the context contains such elements, while cool EF concerns decontextualized regulatory abilities. PKU in adults is increasingly associated with different mental health problems, despite supposedly good treatment standards and adherence throughout childhood and adolescence. Since hot EF is strongly associated with such mental health problems, it is recommended that the hot–cool taxonomy will feature more prominently in future PKU-studies.

The transition process from paediatric to adult care is a subject of great interest in recent years, especially in chronic diseases with childhood onset, such as inborn errors of metabolism (IEM). Advances in diagnosis and treatment of these diseases have improved their prognosis, with a high number of patients with IEM who currently reach adult age and need to be attended to by non-paediatric professionals. The objective of this work is to establish action guidelines so that the specialists involved can guarantee a successful transition of these patients' healthcare.After carrying out a bibliographic review of the subject, the authors, beginning with their own experience, produced an initial document which was subjected to successive debates until the final document was obtained. The consensus recommendation was decided by the majority in case of criterion discrepancy.A series of recommendations are presented for the best clinical management of the transitions of care of patients with IEM from the paediatric to adult care setting in order to achieve the best results in this process given the special characteristics of this patient subgroup and the main difficulties entailed in the transition process.The role of the internal medicine doctor in this transition process and correct interrelation with the paediatric and social setting is stressed. Furthermore, actions and attitudes are suggested to improve the quality of said transition.

Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1 were recently identified in patients with fatal encephalopathy displaying a biochemical phenotype consistent with defects in lipoic acid-dependent enzymatic activities and respiratory chain complexes. This discovery highlighted the molecular function of NFU1 as an iron-sulfur(Fe-S) cluster protein necessary for lipoic acid biosynthesis and respiratory chain complexes activities. To understand the pathophysiological mechanisms underlying this disease we have characterized the protein expression profiles of patients carrying NFU1 mutations. Fibroblasts from patients with the p.Gly208Cys mutation showed complete absence of protein-bound lipoic acid and decreased SDHA and SDHB subunits of complex II. In contrast, subunits of other respiratory chain complexes were normal. Protein lipoylation was also decreased in muscle and liver but not in other tissues available (brain, kidney, lung) from NFU1 patients. Although levels of the respiratory chain subunits were unaltered in tissues, BN-PAGE showed an assembly defect for complex II in muscle, consistent with the low enzymatic activity of this complex. This study provides new insights into the molecular bases of NFU1 disease as well as into the regulation of NFU1 protein in human tissues. We demonstrate a ubiquitous expression of NFU1 protein and further suggest that defects in lipoic acid biosynthesis and complex II are the main molecular signature of this disease, particularly in patients carrying the p.Gly208Cys mutation.

Mitochondrial DNA depletion syndrome (MDS) is a clinically heterogeneous group of mitochondrial disorders characterised by a quantitative reduction of the mitochondrial DNA copy number. Three main clinical forms of MDS: myopathic, encephalomyopathic and hepatocerebral have been defined, although patients may present with other MDS associated clinical symptoms and signs that cover a wide spectrum of onset age and disease. We studied 52 paediatric individuals suspected to have MDS. These patients have been divided into three different groups, and the appropriate MDS genes have been screened according to their clinical and biochemical phenotypes. Mutational study of DGUOK , MPV17 , SUCLA2 , SUCLG1 and POLG allowed us to identify 3 novel mutations (c.1048G>A and c.1049G>T in SUCLA2 and c.531 + 4A>T in SUCLG1 ) and 7 already known mutations in 10 patients (8 families). Seventeen patients presented with mtDNA depletion in liver or muscle, but the cause of mtDNA depletion still remains unknown in 8 of them. When possible, we quantified mtDNA/nDNA and CS activity in the same tissue sample, providing an additional tool for the study of MDS. The ratio (mtDNA/nDNA)/CS has shed some light in the discrepant results between the mtDNA copy number and the enzymatic respiratory chain activities of some cases.

Background: Adenylosuccinate lyase (ADSL) deficiency is an autosomal recessive disorder of the purine synthesis which results in accumulation of succinylpurines (succinyladenosine (S-Ado) and succinylamino-imidazole carboxamide riboside (SAICAr)) in body fluids. Patients present developmental delay, often accompanied by epilepsy and autistic spectrum disorders. Objectives: To describe atypical neurological features in the evolution of three novel unrelated cases of ADSL deficiency. Patients: A 9-year-old boy with severe cognitive impairment and autistic behaviour received d-ribose therapy for one year. Drug withdrawal was associated with acute neurological deterioration, severe brain atrophy and demyelination on MRI. The second patient is a 5.5-year-old girl with mild developmental delay who presented a benign course with moderate cognitive impairment as the only feature in her evolution. The final patient is a 14-year-old boy with severe cognitive impairment who developed drug-resistant epilepsy and bathing reflex seizures, progressive spasticity in the lower limbs and thoracic deformity. Methods: SAICAr and S-Ado in urine were analysed by HPLC with diode array detection. Diagnosis was confirmed by molecular analysis of the ADSL gene. Results: An elevation of S-Ado and SAICAr excretion in urine was detected in all three patients. The patients were homozygous for the missence change p.I369L and for the novel change p.M389V. Conclusion: Drug-resistant epilepsy and specific therapeutic interventions may modify the neurological outcome in ADSL deficiency. d-ribose must be considered with caution as, in our experience, it returns no clinical benefit and drug withdrawal can precipitate status epilepticus and acute neurological deterioration. © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved., Caixa Girona; Koplowitz Fundation; CIBERER

Introduction: “Kernicterus” is a term currently used to describe bilirubin induced brain injury in the neuro-pathological studies. This is a confusing term and nowadays we prefer bilirubin encephalopathy or bilirubin induced neurological dysfunction. The clinical signs vary and it is clearly decreasing in prevalence in developed countries. Materials and methods: We review a series of 7 patients with bilirubin encephalopathy and variable neurological manifestations, who were seen in the Neuropaediatric Department in the last 10 years. Only one patient died in the neonatal period with hyperbilirubinaemia, sepsis and multi-organ failure. Results: Diverse aetiological factors were related to hyperbilirubinaemia. All patients had clinical symptoms due to hyperbilirubinaemia. Neuroimaging during the neonatal period showed involvement of the nucleus pallidus, with hyperintensity in T1 in the brain MR scan as the most consistent finding. All the patients who survived developed neurological signs and we try to correlate them with biochemical, clinical, neuroimaging and neurophysiological parameters. Conclusions: An increase in the number of patients with bilirubin encephalopathy has been observed over the last few years, and we attempt to find out the causes. The increased survival of the low birth weight newborns, the increase in the immigration population and the use of diagnostic neuroimaging contribute to this increase. It is a great challenge for the neonatologist and for neuropaediatricians to prevent its occurrence and to minimise the effects of bilirubin encephalopathy. Resumen: El término: “kernicterus” se aplicó inicialmente a la tinción amarilla de los ganglios basales en estudios necrópsicos, pero es un término impreciso y se habla más de encefalopatía por bilirrubina o de disfunción neurológica inducida por la bilirrubina. Clínicamente la toxicidad por hiperbilirrubinemia puede ser muy variable y en países desarrollados tiende a desaparecer. Material y métodos: Revisamos una serie de 7 pacientes con encefalopatía por bilirrubina y diferentes grados de compromiso neurológico, atendidos en los últimos 10 años en el Servicio. Solo falleció un paciente en período neonatal con hiperbilirrubinemia, sepsis y fallo multiorgánico. Resultados: Las causas etiológicas de la hiperbilirrubinemia fueron muy variadas. Los 7 pacientes presentaron ictericia, clínica neonatal, la neuroimagen ya permitió demostrar las lesiones en núcleo pálido con hiperintensidad de T1. Todos los pacientes presentaron manifestaciones clínicas en período neonatal, y secuelas neurológicas más o menos graves en los 6 supervivientes que se intentan correlacionar con los demás parámetros bioquímicos, clínicos, de neuroimagen y neurofisiológicos. Conclusiones: Hemosconstatadounincrementodelasobservacionesdedisfunciónneurológica inducida por la bilirrubina y nos planteamos conocer las causas de esta situación. La mayor supervivencia de los grandes prematuros, el aumento de la población inmigrante y la posibilidad del diagnóstico por neuroimagen contribuyen a este incremento. Continua siendo un reto para el neonatólogo y el neuropediatra evitar su presentación y minimizar los efectos de la toxicidad por bilirrubina en período neonatal. Keywords: Newborn, Bilirrubin, Kernicterus, Neurological dysfunction, Nucleus pallidus, Neuroimaging, Palabras clave: Neonato, Bilirrubina, Kernicterus, Disfunción neurológica, Núcleo pálido, Neuroimagen

Resumen: El término “kernicterus” se aplicó inicialmente a la tinción amarilla de los ganglios basales en estudios necrópsicos, pero es un término impreciso y se habla más de encefalopatía por bilirrubina o de disfunción neurológica inducida por la bilirrubina. Clínicamente la toxicidad por hiperbilirrubinemia puede ser muy variable y en países desarrollados tiende a desaparecer. Material y métodos: Revisamos una serie de 7 pacientes con encefalopatía por bilirrubina y diferentes grados de compromiso neurológico, atendidos en los últimos 10 años en el Servicio. Solo falleció un paciente en período neonatal con hiperbilirrubinemia, sepsis y fallo multiorgánico. Resultados: Las causas etiológicas de la hiperbilirrubinemia fueron muy variadas. Los 7 pacientes presentaron ictericia, clínica neonatal, la neuroimagen ya permitió demostrar las lesiones en núcleo pálido con hiperintensidad de T1. Todos los pacientes presentaron manifestaciones clínicas en período neonatal, y secuelas neurológicas más o menos graves en los 6 supervivientes que se intentan correlacionar con los demás parámetros bioquímicos, clínicos, de neuroimagen y neurofisiológicos. Conclusiones: Hemos constatado un incremento de las observaciones de disfunción neurológica inducida por la bilirrubina y nos planteamos conocer las causas de esta situación. La mayor supervivencia de los grandes prematuros, el aumento de la población inmigrante y la posibilidad del diagnóstico por neuroimagen contribuyen a este incremento. Continua siendo un reto para el neonatólogo y el neuropediatra evitar su presentación y minimizar los efectos de la toxicidad por bilirrubina en período neonatal. Abstract: Introduction: “Kernicterus” is a term currently used to describe bilirrubin induced brain injury in the neuro-pathological studies. This is a confusing term and nowadays we prefer bilirrubin encephalopathy or bilirrubin induced neurological dysfunction. The clinical signs vary and it is clearly decreasing in prevalence in developed countries. Material and methods: We review a series of 7 patients with bilirrubin encephalopathy and variable neurological manifestations, who were seen in the Neuropaediatric Department in the last 10 years. Only one patient died in the neonatal period with hyperbilirubinaemia, sepsis and multi-organ failure. Results: Diverse aetiological factors were related to hyperbilirubinaemia. All patients had clinical symptoms due to hyperbilirubinaemia. Neuroimaging during the neonatal period showed involvement of the nucleus pallidus, with hyperintensity in T1 in the brain MR scan as the most consistent finding. All the patients who survived developed neurological signs and we try to correlate them with biochemical, clinical, neuroimaging and neurophysiological parameters. Conclusions: An increase in the number of patients with bilirrubin encephalopathy has been observed over the last few years, and we attempt to find out the causes. The increased survival of the low birth weight newborns, the increase in the immigration population and the use of diagnostic neuroimaging contribute to this increase. It is a great challenge for the neonatologist and for neuropaediatricians to prevent its occurrence and to minimise the effects of bilirrubin encephalopathy. Palabras clave: Neonato, Bilirrubina, Kernicterus, Disfunción neurológica, Núcleo pálido, Neuroimagen, Keywords: Newborn, Bilirrubin, Kernicterus, Neurological dysfunction, Nucleus pallidus, Neuroimaging

Resumen Fundamento y objetivo Conocer el control de la fenilcetonuria (PKU) en las unidades de seguimiento espanolas y realizar un registro de pacientes. Pacientes y metodo Pacientes con PKU diagnosticados y/o seguidos en Espana, con fenilalanina previa al tratamiento > 360 μmol/L. Cuestionarios: datos anonimizados incluidos, aquellos aportados por las unidades durante el ano 2010. Resultados Se han recogido datos de las 18 unidades de seguimiento espanolas. El 83% muestran una composicion multidisciplinaria y todas controlan pacientes de todas las edades, con criterios de tratamiento, en general, uniformes. Se han registrado datos de 688 pacientes con PKU, con una mediana de edad de 14 anos (extremos 1 mes-53 anos); un 41,5% eran mayores de 18 anos. Un 71,8% se diagnosticaron precozmente. Un 15,8% tienen una PKU leve, el 26% una forma moderada y el 51,5% la forma clasica. Un 78,6% de los pacientes son tratados con dieta restringida en proteinas, el 9,3% con tetrahidrobiopterina (BH4) y dieta libre y un 7,8% con BH4 y dieta. El control dietetico es bueno en el 58,6% de pacientes, regular en el 26% y malo en un 15,4%. La mediana del coeficiente intelectual del total de pacientes con PKU es de 97 (extremos 25-145). El porcentaje de pacientes de diagnostico tardio con complicaciones neurologicas y conductuales es significativamente mayor al de los diagnosticados precozmente. El 13,3% de adultos han cursado estudios universitarios y el 37,5% tiene pareja estable. Conclusiones Este estudio permite evaluar el funcionamiento de las unidades de seguimiento de la PKU en Espana, asi como registrar y analizar, por primera vez, los datos de los pacientes con PKU controlados en ellas. Se demuestra la necesidad de unidades de enfermedades metabolicas de adultos y el valor del diagnostico precoz en el pronostico de los pacientes con PKU.

Alternating hemiplegia of childhood (AHC) is a rare disorder with diagnosis based on clinical criteria, as no laboratory, neuroradiological or genetic markers are currently available. The pathogenic mechanisms are still an enigma. Some hypotheses have been proposed such as hemiplegic migraine variant, epileptic mechanism, channelopathy and mitochondrial disorder, but none of these has been confirmed. Our aim was to analyze the results of metabolic studies performed on a series of 157 European patients who fulfilled diagnostic criteria for AHC. We tried to find a common metabolic abnormality, related with AHC. We did not find significant abnormalities in basic metabolic screening, at different ages. Neurotransmitters in cerebrospinal fluid (n = 26) were normal in all of the patients. Mitochondrial respiratory chain enzyme activities were analyzed in 19 muscle biopsies; in 4 cases, different MRC enzyme deficiencies were demonstrated, ranging from mild-unspecific deficiencies to more profound and probably primary defects. Although we did not find specific metabolic markers in our series, some metabolic disorders such as pyruvate dehydrogenase deficiency, MELAS, cerebral glucose transporter defect and neurotransmitter deficiency can exhibit symptoms similar to those of AHC and need to be ruled out before a diagnosis of AHC can be established. Further studies including high-throughput diagnostic technologies seem necessary to elucidate the etiology of this severe and enigmatic disorder.

Summary 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.

We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G>T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545+5G>A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins.

Resumen Fundamento y objetivo Comparar los datos clinicos, bioquimicos y geneticos de dos series de pacientes con deficiencia de biotinidasa. Pacientes y metodos Quince casos detectados en el cribado neonatal y seis en el cribado selectivo para sordera o para enfermedades metabolicas hereditarias. Resultados Ningun caso detectado en el cribado neonatal presentaba sintomas y solo uno con deficiencia parcial desarrollo convulsiones que cedieron con biotina. La mutacion p.D444H y la doble mutacion [p.D444H; p.A171T] fueron las mas frecuentes en este grupo. Sin embargo, los seis pacientes diagnosticados en el cribado selectivo presentaban sintomas neurologicos y las mutaciones detectadas fueron p.L32fs, p.G34fs, p.T401I, p.D444H, p.T532 M y p.L466fs. Todos los pacientes con sintomas o con deficiencia profunda de biotinidasa se trataron con dosis farmacologicas de biotina (10-30 mg/dia). Conclusion La deficiencia de biotinidasa debe incluirse en los programas de cribado neonatal con el fin de tratar precozmente incluso las formas parciales. Las diferentes mutaciones identificadas en las dos series de pacientes indican que el analisis genetico mediante secuenciacion directa del gen BTD seria util para el diagnostico rapido de las formas parciales o profundas de la enfermedad.

Aim The purpose of this review was to provide an update on cognitive function in individuals with mild hyperphenylalaninemia (mHPA), the most clinically and biochemically benign form of phenylketonuria. Method A review was conducted of the existing literature on mHPA. Individuals with mHPA, whose plasma phenylalanine concentration had always remained lower than 360μmol/L without dietary restriction, were considered. Results The review of the literature indicated that there is no consensus concerning the definition of mHPA. There are few studies regarding the cognitive functions of individuals with mHPA, results are contradictory, and samples are difficult to compare from one study to another. Most studies focus only on descriptions of IQ when assessing cognitive functions. The existing literature indicates that, in general, children with mHPA do not show significant cognitive impairments, but usually achieve scores between those of individuals with phenylketonuria and those of comparison groups with regard to the cognitive functions assessed. Interpretation When assessing cognitive functions in individuals with hyperphenylalaninemia, it is not enough to measure only IQ, as deficits in executive functions can be present even when an individual’s IQ is within a normal range. Further studies are needed of individuals with mHPA, using consistent selection criteria, in order to make it possible to exclude the presence of cognitive impairment and to establish a consensus regarding the level of phenylalanine that necessitates dietary treatment.

To investigate the relationship between neurological complications, neuroradiological findings, and behavioral problems, age at diagnosis and dietary control along the follow-up of the PKU patients in our metabolic unit.Retrospective study of the PKU patients diagnosed and controlled in our unit from 1985 to 2010.Registry of patients in a database with 50 items filled in by review of the clinical histories. Statistical study of the data (SPSS, 19.0 version).121 patients were included (median age: 16.0, range 1 month-46 years). 76% of them were diagnosed through neonatal screening. 12.4% had mild-PKU, 19% moderate-PKU and 68.6% classic-PKU. 88.4% of patients were treated with a protein-restricted diet, and 11.6% with BH4. 97.7% of the early diagnosed patients had normal IQ, while 46.3% of late diagnosed patients had mental retardation, 28.5% were borderline and 25% had normal IQ. In early diagnosed patients, there was a significantly negative correlation between IQ [mean (SD) 100 (11.1)] and the index of dietary control during the first six years of life [median (range) 310 (105-992)] and that of the immediately past year [348 (106-1127)] (p0.0001). The proportion of patients with late diagnosis and neurological and behavioral problems was significantly higher than that of the early diagnosed ones (p0.001). The proportion of early diagnosed patients with neurological and behavioral problems who had good, intermediate or poor dietary control during the first 6 years of life and the immediately past year was significantly different (p0.001).The results show the impact of early diagnosis and good dietary treatment on the IQ and on the percentage of neurological complications and behavioral problems in PKU patients.

BackgroundAlternating 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 resultsWe 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.ConclusionBecause 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.

Patients having inborn errors of intermediary metabolism (IEMs) may have element deficiencies related to dietary treatment. Our objective was to study several elements [cobalt (Co), copper (Cu), zinc (Zn), selenium (Se), manganese (Mn), molybdenum (Mo) and magnesium (Mg)] in patients with IEMs with and without dietary treatment and to compare these results with those established in a healthy paediatric population. We studied 72 patients with IEMs (age range 2 months–44 years; median 10.5 years), with and without protein-restricted dietary treatment. Control values were established in 92 subjects (age range 1 day–42 years; median 6.5 years). Dietary treatment consisted of a natural protein-restricted diet supplemented with a special formula, depending on the specific metabolic defect. Samples were analysed with an Agilent 7500ce-ICP mass spectrometer. Significant differences were observed when we compared patients under dietary treatment and control values for Se and Co (P < 0.0001). No differences were observed for the other elements when the different groups were compared, except for Co (IEM patients without dietary treatment vs control group; P = 0.003). For Se and cobalamin, the daily intake of our patients (Se 48 ± 16 µg/day; cobalamin 3.5 µg/day) was slightly higher than the recommended daily averages (RDAs) (40 µg/day and 1.8 µg/day, respectively). We concluded that IEM patients under dietary treatment showed significantly lower selenium values in spite of correct supplementation, reinforcing the idea that these patients should be regularly monitored, at least for this element. Further investigations seem advisable about Se and Co availability in special diets.

Resumen Fundamento y objetivo Los sindromes de deficiencia cerebral de creatina (Cr) constituyen un grupo de enfermedades neurometabolicas caracterizadas por deficiencia o ausencia de Cr en el cerebro. Cursan con retraso del desarrollo/mental y trastornos del lenguaje, y puede asociarse a epilepsia o a trastornos del movimiento. Se conocen 3 defectos: 2 de la sintesis —deficiencia de guanidinoacetato metiltransferasa (GAMT) y argininaglicina amidinotransferasa (AGAT)— y uno del transporte (CRTR). En este trabajo presentamos los 3 primeros pacientes espanoles con deficiencia de GAMT y comparamos su fenotipo clinico y respuesta al tratamiento con otros casos publicados. Pacientes y metodo Los pacientes presentan retraso mental, epilepsia y conducta autista. La paciente 1 asocia corea grave. El diagnostico se realizo mediante estudios bioquimicos para cuantificar metabolitos especificos y actividad enzimatica y geneticos del gen GAMT. Resultados En orina y plasma se detecto aumento de guanidinoacetato. La resonancia magnetica con espectroscopia revelo reduccion marcada de Cr cerebral. Los estudios enzimaticos mostraron disminucion de la actividad GAMT en fibroblastos y el estudio molecular revelo mutaciones en el gen GAMT. Tras el diagnostico, se inicio tratamiento con suplemento de Cr, y se asocio en los pacientes 2 y 3 una dieta restringida en arginina y suplemento de ornitina, con mejoria parcial. Conclusiones Los pacientes con deficiencia de GAMT presentan un fenotipo inespecifico pero relativamente constante. Deben buscarse los sindromes de deficiencia cerebral de Cr en pacientes con retraso mental/psicomotor de etiologia desconocida, especialmente si se acompanan de trastornos del movimiento y epilepsia. Es importante el diagnostico precoz en casos tratables como la deficiencia de GAMT.

Objectives To search for biochemical and molecular markers for the diagnosis of patients and carriers with 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency. Design and methods Organic acids in urine, MHBD activity in fibroblasts, immunoblotting and molecular studies were performed in seven patients. Seven carriers were also studied. Results Under low protein diet or poor feeding all the patients showed only a slightly altered organic acid profile. Measurement of 2-methyl-3-hydroxybutyric acid and tiglylglycine after an isoleucine loading test, failed to demonstrate the carrier status of one patient. However, measurement of 2-ethylhydracrylic acid (EHA) was positive in all the carriers tested. MHBD activity was clearly deficient in males and in one female patient. We identified four missense mutations, two of them were novel. Conclusions Quantification of EHA may be of help for the diagnosis of the heterozygous condition. The carrier females showed the classical biochemical variability of X-linked diseases due to random X-chromosome inactivation.

A new neuro-ophthalmological syndrome has been described recently, consisting of paroxysmal tonic upward deviation of the eyes with ataxia. Episodes occur daily and are always relieved by sleep. Onset is usually under one year of age and the symptoms gradually disappear during childhood. The authors describe three new patients in whom an autosomal dominant mode of inheritance was a constant finding, as well as clumsiness and delayed acquisition of independent gait. Treatment with levodopa was of clear benefit.

SUMMARY Three patients with subacute necrotising encephalolmyelopathy are reported, all of whose CT brain-scans showed areas of low attenuation in the basal ganglia, especially in the lenticular nucleus. The authors suggest that this brain-scan appearance may help in the diagnosis of this disorder during life. ZUSAMMENFASSUNG CT Befunde hei suhakuter nekrotisierender Encephalomyelopathie Es wird uber drei Patienten mit subakuter nekrotisierender Encephalomyelopathie berichtet, bei denen das Hirn CT hypodense Areale in den Basalganglien, insbesondere im Nucleus lenticularis, aufwies. Die Autoren sind der Meinung, dap dieser Befund beim Hirn CT die Diagnose dieser Erkrankung zu Lebzeiten erleichtern kann. RESUMEN Aspecto del scanner en la encefolomielopatia necrotizanre Tres pacientes con encefalomielopatia necrotizante subaguda mostraban en su scanner cerebral areas de baja densidad en los ganglios basales, especialmente en el nucleo lenticular. Los auteres sugieren que esta imagen en el scanner puede ayudar al diagnostico de esta enfermedad en vida.

The study of neurometabolic diseases is still in a prolonged preliminary stage. The catalogue of these diseases continues to grow; some known clinical syndromes have been subdivided into a number of variants once the genes that cause them have been identified, and at the same time new metabolic disorders have been discovered that aggravate or contribute to forms of epilepsy not previously classified as cerebral metabolic disorders.This review presents the basic principles underlying the recognition and treatment of epilepsy caused by neurometabolic diseases. These disorders are divided (purely for the sake of convenience) into epilepsy presenting in newborn infants, children, and adolescents and adults, recognizing that there is a significant degree of overlap between these chronological stages. Current analytical methods and therapeutic approaches are summarized both from a general point of view and within the context of each clinical syndrome, acknowledging that each patient presents specific peculiarities and that, in general, antiepileptic drugs provide few benefits compared with more specific types of therapy (eg, special diets or vitamins) when indicated. We also include therapeutic recommendations and a general approach to fulminant epilepsies of neurometabolic origin, emphasizing the importance of identifying all of the proband's relatives who may be potential carriers of a genetic disorder during the diagnostic and genetic counselling process. Particular emphasis is placed on disorders for which there is curative treatment and on the importance of follow-up by expert professionals.It is expected that in a few years' time it will be possible to know the metabolomic profile of these diseases (possibly by non-invasive methods), thus facilitating accurate diagnosis and making it possible to establish the response to treatment and to identify all individuals who are carriers or remain minimally symptomatic in terms of their risk of manifesting or transmitting epilepsy.