[Epilepsy and inborn errors of metabolism]. / Epilepsia y errores congénitos del metabolismo.

INTRODUCTION: Epilepsy is a common manifestation in inborn errors of metabolism, with varying degrees of severity and response to treatment. OBJECTIVE: To determine its incidence and characteristics in metabolic diseases. MATERIAL AND METHODS: A retrospective review of neuropaediatric and metabolic databases was performed. Data on the type of epilepsy, age of onset and refractoriness were collected. RESULTS: Two cases out of three (66%) with molybdenum cofactor deficiency and neonatal epileptic encephalopathy; three with vitamin-sensitive epilepsies: pyridoxamine sulphate oxidase deficiency, antichitin and biotinidase deficiency, early onset and good seizure control with biotin; one with homocystinuria, with late onset and polytherapy; one with Menkes disease difficult to control; two with GLUT-1 deficiencies with absent and generalized discharges in the electroencephalogram; five (33%) peroxisomes in monotherapy, except for a suspected peroxisome biogenesis deficiency; 13 (34%) lysosomal deficiencies; a glycosylation disorder, with infantile and refractory spasms; seven (8.5%) organic aminoacidopathies and acidurias, one with infantile spasms (propionic acidemia), three with nonketotic hyperglycinemia with neonatal epileptic encephalopathy, one with monotherapy (leukinosis) and two (3.3%) with unscreened hyperphenylalaninemia; and five (20%) mitochondrial, most of which had oxidative phosphorylation deficiencies. CONCLUSIONS: The diagnosis of metabolic epilepsy requires a high level of suspicion in unscreened diseases. The semiology of the seizures and the electrocardiogram data are not characteristic, but some clinical data may provide guidance, such as early onset and refractoriness, neuroimaging and some biochemical markers. Although genetic studies are increasingly cost-effective in epilepsy, we must continue to search for earlier biomarkers and test targeted therapeutic trials.

TITLE: Epilepsia y errores congénitos del metabolismo.Introducción. La epilepsia es una manifestación común en los errores congénitos del metabolismo, con gravedad y respuesta al tratamiento variables. Objetivo. Determinar su incidencia y características en enfermedades metabólicas. Material y métodos. Se trata de una revisión retrospectiva de bases de datos de neuropediatría y metabolismo. Los datos recogidos son tipo de crisis, edad de inicio y refractariedad. Resultados. Dos casos de tres (66%) con defecto del cofactor del molibdeno y encefalopatía epiléptica neonatal; tres epilepsias sensibles a las vitaminas: déficit de piridoxamina sulfato oxidasa, déficit de antiquitina y de biotinidasa, de comienzo precoz y buen control de crisis con biotina; una homocistinuria, con inicio tardío y politerapia; una enfermedad de Menkes de difícil control; dos déficits de GLUT-1 con ausencias y descargas generalizadas en el electroencefalograma; cinco (33%) peroxisomales en monoterapia, salvo una sospecha de déficit de biogenia de peroxisomas; 13 (34%) lisosomales; un trastorno de la glucosilación, con espasmos infantiles y refractario; siete (8,5%) aminoacidopatías/acidurias orgánicas, uno con espasmos infantiles (acidemia propiónica), tres con hiperglicinemias no cetósicas con encefalopatía epiléptica neonatal, uno con monoterapia (leucinosis) y dos (3,3%) con hiperfenilalaninemias no cribadas; y cinco (20%) mitocondriales, la mayoría con déficit de la fosforilación oxidativa. Conclusiones. El diagnóstico de epilepsia metabólica precisa un alto índice de sospecha en enfermedades no cribadas. La semiología de las crisis y los datos en el electroencefalograma no son característicos, pero algunos datos clínicos, como el inicio precoz y la refractariedad, de neuroimagen y ciertos marcadores bioquímicos pueden orientar. Aunque los estudios genéticos son cada vez más rentables en la epilepsia, debemos seguir buscando biomarcadores más precoces y probar ensayos terapéuticos dirigidos.

A novel mutation in the ZNF462 gene c.3306dup; p.(Gln1103Thrfs*10) is associated to Weiss-Kruszka syndrome. A case report.

BACKGROUND: Weiss-Kruszka syndrome (WSKA) is a rare disorder caused by mutations in the ZNF462 gene or deletion of 9p31.2 chromosome region, involving ZNF462. The prevalence of WSKA is unknown as only 24 affected individuals have been described. This syndrome should be suspected in individuals presenting mild global developmental delay and common craniofacial abnormalities. CASE PRESENTATION: We presented a case of an infant, 3 years and 4-month life who presented pondostatural and psychomotor retardation, generalized hypotonia with hypermobility, bilateral palpebral ptosis, epicanthal folds, and poorly expressive facies as the main clinical features. These characteristics lead to the realization of genetics studies that resulted in the identification of a novel mutation c.3306dup; p.(Gln1103Thrfs*10) in ZNF462. CONCLUSIONS: WSKA should be suspected in individuals presenting mild global developmental delay, ptosis, downslanting palpebral fissures, exaggerated Cupid's Bow, arched eyebrows, epicanthal folds and short upturned nose with a bulbous tip. Hypertrophy of the ventricular septum and severe OSA were described in our patient and should be considered in future reviews of the disease. This case is added to the reduced number of publications previously reported regarding WSKA and contributes to understanding the genetic characteristics, clinical features, and diagnosis of this syndrome.Abbreviations: WSKA: Weiss-Kruszka syndrome; CP: craniofacial perimeter; WES: whole-exome sequencing; RSV: respiratory syncytial virus; OSA: obstructive sleep apnoea; ACMG: American College of Medical Genetics and Genomics.

[Early infantile epileptic encephalopathy due to ITPA mutation]. / Encefalopatía epiléptica infantil precoz por mutación en ITPA.

TITLE: Encefalopatía epiléptica infantil precoz por mutación en ITPA.

[Atypical presentation of early childhood epileptic encephalopathy associated with the gene KCNT1]. / Presentación atípica de encefalopatía epiléptica infantil precoz asociada al gen KCNT1.

TITLE: Presentación atípica de encefalopatía epiléptica infantil precoz asociada al gen KCNT1.

[Infant with intracranial calcifications and retinopathy]. / Lactante con calcificaciones intracraneales y retinopatia.

INTRODUCTION: Intracranial calcifications can have a number of different causes, and the distribution and characteristics they present in neuroimaging can orient the specialist towards one or another. It is important to rule out the most frequent entities that are accompanied by intracranial calcifications, but other more remote genetic causes, such as Coats plus syndrome, should not be overlooked. CASE REPORT: Ex-premature female Infant with a gestational age of 34 weeks, diagnosed with retinopathy at 9 months after presenting strabismus. At 2 years of age, an MRI scan was performed for right hemiparesis, in which an image suggestive of a neoplasm was initially observed. Upon completion of the study with a cranial computed tomography scan, extensive calcifications were observed predominantly in the basal ganglia along with cystic lesions. After ruling out the most frequent causations of intracranial calcifications, the association between the retinopathy and the neurological features was established, and Coats plus syndrome was confirmed by a genetic study that revealed the presence of two hitherto unreported variants in heterozygosis in the CTC1 gene. CONCLUSION: Coats plus syndrome is an extraordinarily rare autosomal recessive disease, caused by mutations in the CTC1 gene, which involves the appearance of retinal telangiectasias, brain cysts, calcifications in deep nuclei and leukoencephalopathy, as well as other bone and gastrointestinal conditions. Treatment is symptomatic and the disease has a poor prognosis.

TITLE: Lactante con calcificaciones intracraneales y retinopatia.Introduccion. Las calcificaciones intracraneales pueden tener multiples etiologias, y la distribucion y las caracteristicas que presenten en la neuroimagen pueden orientar hacia unas u otras. Es importante descartar las entidades mas frecuentes que cursan con calcificaciones intracraneales, pero no deben olvidarse otras causas geneticas mucho mas remotas, como el sindrome de Coats plus. Caso clinico. Lactante exprematura de 34 semanas de edad gestacional, diagnosticada de retinopatia a los 9 meses al presentar estrabismo. A los 2 años de edad se realizo una resonancia magnetica por hemiparesia derecha, en la que se observo una imagen sugestiva inicialmente de neoplasia. Al completar el estudio con una tomografia computarizada craneal, se observaron extensas calcificaciones de predominio en los ganglios basales y lesiones quisticas. Tras descartarse las etiologias mas frecuentes de calcificaciones intracraneales, se llego a la asociacion de la retinopatia y la clinica neurologica y se confirmo el sindrome de Coats plus mediante estudio genetico, que revelo la presencia de dos variantes en heterocigosis no documentadas hasta la fecha en el gen CTC1. Conclusion. El sindrome de Coats plus es una enfermedad autosomica recesiva extraordinariamente infrecuente, provocada por mutaciones en el gen CTC1, que supone la aparicion de telangiectasias retinianas, quistes cerebrales, calcificaciones en los nucleos profundos y leucoencefalopatia, ademas de otras afecciones oseas y gastrointestinales. El tratamiento es sintomatico y la enfermedad tiene un mal pronostico.

Our experience with the aetiological diagnosis of global developmental delay and intellectual disability: 2006-2010.

INTRODUCTION: Global developmental delay (GDD) and intellectual disability (ID) are common reasons for consultation in paediatric neurology. Results from aetiological evaluations of children with GDD/ID vary greatly, and consequently, there is no universal consensus regarding which studies should be performed. MATERIAL AND METHOD: We review our experience with determining aetiological diagnoses for children with GDD/ID who were monitored by the paediatric neurology unit over the 5-year period between 2006 and 2010. RESULTS: During the study period, 995 children with GDD/ID were monitored. An aetiological diagnosis was established for 309 patients (31%), but not in 686 (69%), despite completing numerous tests. A genetic cause was identified in 142 cases (46% of the total aetiologies established), broken down as 118 cases of genetic encephalopathy and 24 of metabolic hereditary diseases. Our data seem to indicate that diagnosis is easier when GDD/ID is associated with cerebral palsy, epilepsy, infantile spasms/West syndrome, or visual deficit, but more difficult in cases of autism spectrum disorders. Genetic studies provide an increasing number of aetiological diagnoses, and they are also becoming the first step in diagnostic studies. Array CGH (microarray-based comparative genomic hybridisation) is the genetic test with the highest diagnostic yield in children with unexplained GDD/ID. DISCUSSION: The cost-effectiveness of complementary studies seems to be low if there are no clinically suspected entities. However, even in the absence of treatment, aetiological diagnosis is always important in order to provide genetic counselling and possible prenatal diagnosis, resolve family (and doctors') queries, and halt further diagnostic studies.

[Prader-Willi and Angelman syndromes: 21 years of experience]. / Síndromes de Prader-Willi y de Angelman. Expriencia de 21 años.

INTRODUCTION: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) were the first syndromes in humans that were known to originate from the phenomenon of the genomic imprinting. We review our experience of 21 years with PWS and AS that were confirmed with the genetically. RESULTS: Of the 13,875 patients recorded during the study period, 11 were diagnosed with PWS (18%), 7 males (63.6%) and 4 females (36.4%), with a mean age of 9.06 years (+/- 6.92, range: 0.68-21.6). The time of the follow up of this group was 3.83 years (+/- 4.03, range: 0.49-15.3), and the age at diagnosis was 4.4 years (+/- 6.84, range: 0.03-19.38). Almost three quarters (72.7% of the PWS patients had a uniparental dysomy and 27.3% a paternal deletion. Six patients (8%) were diagnosed with AS, 4 females (66.6%) and 2 males (33.4%), with a mean age of 14.65 years (+/- 11.89, range: 1.3-30.7). The time of follow up was 6.76 years (+/- 5.89,range: 0.16-15), and the age at diagnosis was 8.84 years (+/- 9.11, range: 1.10-23). A maternal deletion was present in 83.3% of the AS patients and 16.7% had a maternal dysomy. DISCUSSION: As genetic advances are made these pathologies are confirmed before. Unlike the data in the literature, in our series most patients diagnosed with PWS (72'3%) had uniparental disomy. Recent studies correlation genotype with phenotype, in PWS is more serious if it occurs a deletion and in SA is milder in the case of uniparental disomy. CONCLUSIONS: Genetic studies must be performed in view of the established clinical symptoms: neonatal hypotonia of unknown cause in PWS and psychomotor deficits with autism features, particularly associated with epilepsy, must be evaluated in AS to prevent diagnostic uncertainties, unnecessary complementary examinations and to provide early genetic counselling.

Prenatal encephalopathies of unknown origin. Our 19-years experience. To what extent must genetic and biochemical studies be carried out?

INTRODUCTION: We examine those prenatal encephalopathies with clinical or neuroimaging data of encephalopathy before the birth. They affect a significant number of children seen by paediatric neurologists. They can be of disruptive origin (due to vascular problems, drugs, toxins or congenital infections), and genetically determined. We include cases of autism spectrum disorder and mental retardation with no history of perinatal of postnatal damages. MATERIAL AND METHODS: We analysed our 19 year neuro-paediatric data base in search of prenatal encephalopathies and their diagnostic origin. We also analyse the studies made in the cases with a diagnosis of unknown origin. RESULTS: The 19 year period of study in the data base included 11,910 children, and 1596 (13.5%) were considered as prenatal encephalopathies; 1307 children (81.4%) had a diagnosis of unknown origin, despite many investigations being done in a large number of them. DISCUSSION: Most of the children included in this study suffer a rare disease, and whether they are identified or not, they increasingly require an early diagnosis. Peroxisomal, mitochondrial, lysosomal diseases, carbohydrate glycosylation deficiency syndrome and other inborn error of metabolism, congenital infections and genetic encephalopathies, can be clinically indistinguishable in early life and require specific studies to identify them. Early diagnosis requires strategies using step-wise systematic studies, giving priority to those diseases that could be treated, and in many cases using an individualised approach. We believe that the potential benefits of early diagnosis, including savings on further studies, genetic counselling and prenatal diagnosis, overcome the financial costs.

[Continuous monitoring of a guideline: Bell's palsy]. / Monitorización continua de un protocolo: parálisis facial a frigore.

INTRODUCTION: The preparation and review of child neurology guidelines can reduce the variability of our medical practice, thus improving health care. We present the continuous monitoring of our Bell's palsy guideline. MATERIAL AND METHODS: Emergency and medical reports of the children seen in Child Neurology surgery from July 2006 to August 2009 (group 2) are reviewed for the purpose of finding out the present level of compliance with guideline quality criteria and compare it with the previously reviewed period (group 1, from March 2003 to June 2006). Scientific evidence on this topic is also updated. RESULTS: Comparing the compliance rate in group 1 with group 2 shows a rise in group 2 from 85.1% to 100% in facial expression description, from 11.1% to 31.6% on whether or not there is evidence of Herpes Zoster vesicles, from 77.7% to 84.2% whether or not there is evidence fundoscopic examination, and from 77.7% to 86.8% as regards cranial nerve function remaining normal. The rate of fact sheet issue, recorded for the first time in group 2, is 21.1%. DISCUSSION: Medical auditing allows us to evaluate our medical practice and set up ways for improvement according to the deficiencies found. We insist on striving to improve the written record of the most relevant data and never overlook the importance of issuing the fact sheets to parents and paediatricians, to ensure continuity of medical care.

[Epilepsy onset between one month and three months of life: our 11 years experience]. / Epilepsia de inicio entre el mes y los tres meses de vida: nuestra experiencia de 11 años.

INTRODUCTION: The prognosis of epilepsy is basically determined by its aetiology. Early onset of seizures is generally associated with poor progress. MATERIAL AND METHODS: We review our experience in epilepsy with children born after 1 January 1997 and who had their first seizure between 1 and 3 months of age before January 2008. RESULTS: Eighteen cases diagnosed with epilepsy and a first seizure between 1 and 3 months of age were included. One case was within the Dravet syndrome spectrum with the c829 T>G c277G heterozygous mutation of the SCN1A gene. Four were cryptogenic epilepsies and thirteen were asymptomatic: 2 were inborn errors of metabolism (biotinidase deficiency with a response to biotin and Leigh's syndrome); 2 were of infectious origin and the remaining nine prenatal encephalopathy. Nine (50%) currently have a severe psychomotor delay and 2 died. The cryptogenic cases had a relatively poor progress. CONCLUSIONS: Our experience corroborates the poor prognosis associated with early onset, between 1 and 3 months, of epileptic seizures. Given the wide aetiological range and the poor prognosis in the absence of specific treatment, an appropriate diagnostic-therapeutic strategy is required to avoid diagnostic uncertainties and can identify potentially treatable cases, such as some inborn errors of metabolism. In this age group, the protocol for convulsions of unknown cause must be the same as that for neonatal convulsions, including treatment with a vitamin cocktail, after collecting biological samples.

[Benign intracranial hypertension: experience over 18 years]. / Hipertensión intracraneal benigna. Experiencia en 18 años.

INTRODUCTION: There are transient intracranial hypertension cases, recognizable by bulging fontanelle in infants and by papilloedema in children. We present our experience in benign intracranial hypertension (BIH) cases, excluding traumatic brain injuries, encephalitis and meningitis. RESULTS: Among the entire neuropaediatric database, with 10,720 children in 18 years, 31 cases had the diagnosis of BIH. Sixteen aged between 2.3 and 8.9 months (75% males), all of them with transient bulging fontanelle, and 15 aged between 4.4 and 13.7 years (73.3% females), all of them with papilloedema which was subsequently resolved. A total of 75% of infants had recently finished corticosteroid treatment for bronchitis. In the older children, there was 1 case associated with excessive vitamin A intake and 1 mastoiditis. Transfontanelle ultrasonography or CT was performed on all infants and CT or MRI in every child. Lumbar puncture was also performed on 7 infants and on 13 children. Infants developed favourably in a few days, and children did so between 1 week and 5 months, some with treatment. DISCUSSION: BIH usually has a favourable outcome, although it may take longer in children than in infants, but it can have serious visual repercussions, even blindness, so ophthalmological control is necessary. It is normally diagnosed by exclusion of other intracranial hypertension causes. MRI and lumbar puncture must be done on all children or infants who do not progress favourably. Acetazolamide and furosemide, corticosteroids, repeated lumbar punctures and optic nerve sheath fenestration should be considered in those who do not progress well.

[Congenital infection by cytomegalovirus. A review of our 18 years' experience of diagnoses]. / Infección congénita por citomegalovirus. Revisión de nuestra experiencia diagnóstica de 18 años.

INTRODUCTION: Infection by cytomegalovirus (CMV) is the most frequent congenital viral infection. Although it offers a wide range of manifestations, it nevertheless continues to be underdiagnosed if there are no symptoms in the newborn infant, which is what most commonly happens. A definitive retrospective diagnosis can only be reached after the first three weeks by detecting CMV DNA in blood on the filter paper used in the neonatal screening test. PATIENTS AND METHODS: The article reviews our experience with congenital CMV from a diagnostic perspective and with the study of CMV DNA in the heel prick test. RESULTS: Of the 10,855 patients included in the neuropaediatric service database, there were 11 cases of congenital CMV. The diagnosis was only probable in four cases and it was definitive in seven of them, the diagnosis being obtained in the neonatal period in four of these patients and retrospectively in three others, by means of the heel prick test. The heel prick test was performed in 10 cases altogether, and was positive in five of them. CONCLUSIONS: There can be no doubt that many cases of congenital CMV infection are still not diagnosed. Retrospective study of congenital infection by CMV by detecting DNA in blood from the filter paper used in the neonatal screening test should be considered in the presence of severe symptoms and different clinical pictures such as: delayed intrauterine growth, microcephaly, neurosensory hypoacusis, chorioretinitis, mental retardation, behavioural disorders (especially autistic spectrum disorders), intracranial calcifications, encephaloclastic disorders, leukoencephalopathy, cortical dysplasia and malformations of the temporal lobe or the hippocampus. Given its availability, ready access and low cost, the benefits to be gain from continuing to use the heel prick test should be reconsidered.