Juvenile neuronal ceroid lipofuscinosis: clinical course and genetic studies in Spanish patients.

BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL, NCL3, Batten disease) is usually caused by a 1.02-kb deletion in the CLN3 gene. Mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). We report the clinical course and molecular studies in 24 patients with JNCL collected from 1975 to 2010 with the aim of assessing the natural history of the disorder and phenotype/genotype correlations. PATIENTS AND METHODS: Patients were classified into the groups of vJNCL with mutations in the CLN1 gene and/or granular osmiophilic deposit (GROD) inclusion bodies (n = 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene and/or fingerprint (FP) profiles (n = 13). Psychomotor impairment included regression of acquired skills, cognitive decline, and clinical manifestations of the disease. We used Kaplan-Meier analyses to estimate the age of onset of psychomotor impairment. RESULTS: Patients with vJNCL showed learning delay at an earlier age (median 4 years, 95% confidence interval [CI] 3.1-4.8) than those in the cJNCL group (median 8 years, 95% CI 6.2-9.7) (P = 0.001) and regression of acquired skills at a younger age. Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. There may be a Gypsy ancestry for V181L missense mutation in the CLN1 gene. CONCLUSIONS: The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Further studies of genotype/phenotype correlation will be helpful for understanding the pathogenesis of this disease.

[Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. / Lipofuscinosis neuronal ceroidea: algoritmo diagnóstico y descripción clínica de las variantes infantil tardía finlandesa (CLN5) y turca (CLN7).

INTRODUCTION: The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in child-hood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). CASE REPORTS: We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started with behaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia, loss of walking ability within 2-3 years and vegetative state at 11 years of age. CONCLUSIONS: The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies.

Infantile neuronal ceroid lipofuscinosis: follow-up on a Spanish series.

Infantile neuronal ceroid lipofuscinosis (INCL; NCL1, Haltia-Santavuori disease) is caused by mutations in the CLN1/PPT gene which are associated with an early onset INCL phenotype. The most detailed descriptions of INCL have come from Finland and a few series have been reported from southern European countries. Clinical course and follow-up of six Spanish patients with INCL are reported with the aim of assessing the chronological evolution and severity of this disease. The age at disease onset ranged from 8 to 15 months. Delayed motor skills were the initial symptom when the disease began before 12 months of age, and ataxia was the first sign when the disease began later. Cognitive decline, which is described between 12 and 18 months of age, occurred from 16 to 20 months of age. In our series early stage is characterized by motor impairment, cognitive decline and autistic features. Visual failure may appear simultaneously with the neurological symptoms, leading quickly to blindness. As reported, psychomotor regression appeared between 2 and 3 years of age. Myoclonic jerks occurred after 24 months of age and epilepsy was the last symptom of the disease. We report two novel mutations in a patient without epilepsy to date and describe the features of two siblings homozygous for the V181M (c.541G>A) mutation, associated with the most severe INCL phenotype. The clinical evolution might be helpful to identify patients affected by this rare disease. Early diagnosis is essential in order to provide genetic counselling to affected families. Our series may contribute to the study of the genotype-phenotype INCL correlation in the Mediterranean countries.

[Five years' experience in a paediatric epilepsy unit]. / Experiencia de cinco años en una unidad de epilepsia pediátrica.

INTRODUCTION AND AIMS: The epilepsy monitoring unit is a space inside a hospital, which objective is to reproduce epileptic seizures in order to better study of an epileptic patient. We have analysed data from all the patients admitted to our pediatric epilepsy unit in the last 5 years. PATIENTS AND METHODS: 191 patients have been admitted in our unit, and we have obtained seizures in 186 admissions (monitoring efficacy, 85.9%). In this report we summarize characteristics of these children, type of seizures and treatment. RESULTS: The most frequent cause of epilepsy in our series is cortical development malformation. Patients are often late in their admission, with a median time of 3 to 4 years from epileptic onset to admission in the epilepsy unit. After the study, 22 patients underwent functional epilepsy surgery, all of them with excellent results, 9 patients underwent vagal nerve stimulator implantation and in 66 patients their previous pharmacological treatment was modified. CONCLUSIONS: The efficacy of our monitoring unit is similar to previously published, 85.9%. After the admission, we have changed diagnose in 57% of the patients and pharmacological treatment in 29%. We recommend the study in a monitoring epilepsy unit of every patient with refractory epilepsy, meaning an epilepsy that does not respond to 2-3 different appropriate treatments.

Lipofuscinosis neuronal ceroidea: algoritmo diagnóstico y descripción clínica de las variantes infantil tardía finlandesa (CLN5) y turca (CLN7) / Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the variants late infantile Finnish (CLN5) and Turkish (CLN7) Introduction. The neuronal ceroid lipofuscinosis

Introducción. Las lipofuscinosis neuronales ceroideas (LNC) se clasifican, según la edad de inicio de la sintomatología, en cuatro formas clínicas principales en la infancia: infantil, infantil tardía, juvenil y congénita (CLN1, CLN2, CLN3 y CLN10).Las formas variantes infantiles tardías (CLN5, CLN6, CLN7 y CLN8) se caracterizan por una gran variabilidad fenotípica y la mayoría de los pacientes proceden de Finlandia y Turquía (variante finlandesa, CLN5, y turca, CLN7). Casos clínicos. Se describen tres pacientes con la variante finlandesa y un cuarto paciente con la variante turca, procedentes de diferentes familias. Se propone un algoritmo que facilite el diagnóstico de este grupo de enfermedades poco prevalentes. Las pacientes con la variante finlandesa iniciaron un trastorno de conducta entre los 2,6 y 4,6 años seguido de dificultades de aprendizaje y déficit visual a los 6 años de edad. Las crisis epilépticas generalizadas y mioclonoatónicas aparecieron a los 7 años con sacudidas mioclónicas posteriormente. Las pacientes desarrollaron ataxia y ceguera a los 9años, y manifestaron una importante discapacidad a los 11 años de edad. El paciente con la variante turca presentó epilepsia refractaria desde los 2 años de edad seguido de un rápido deterioro con ataxia, pérdida de la deambulación en los dos a tres años siguientes y estado vegetativo a los 11 años.Conclusiones. El espectro de las formas variantes de LNC presenta una distribución geográfica cada vez más amplia. Nuestro estudio aporta tres nuevas mutaciones en el gen CLN5 y propone un protocolo de diagnóstico que facilite los estudios de correlación genotipo-fenotipo (AU)

Introduction. The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in childhood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). Case reports. We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started withbehaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia,loss of walking ability within 2-3 years and vegetative state at 11 years of age.Conclusions. The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies (AU)

Experiencia de cinco años en una unidad de epilepsia pediátrica / Five years’ experience in a paediatric epilepsy unit

Introducción y objetivos. La unidad de monitorización continua videoelectroencefalográfica (video-EEG) es una zona dentro del ámbito hospitalario cuyo objetivo es intentar reproducir el mayor número de crisis en un paciente para su estudio. Hemos realizado un análisis de los datos de los pacientes ingresados en los últimos cinco años en nuestra unidad de epilepsia pediátrica. Pacientes y métodos. En total han ingresado 191 pacientes, obteniéndose crisis en 186 (eficacia de la monitorización del 85,9%). En este estudio se resumen las características de estos niños, del tipo de crisis que presentaron y de su tratamiento. Resultados. La causa más frecuente de epilepsia en nuestros niños han sido las malformaciones del desarrollo cortical. Los pacientes tardaron un promedio de 3-4 años desde el inicio de la epilepsia hasta el ingreso en la unidad. Tras el ingreso, 22 pacientes fueron sometidos a cirugía funcional de la epilepsia, con resultados excelentes, a nueve niños se les implantó un estimulador del nervio vago y a 66 se les modificó el tratamiento médico previo, con mejoría significativa de su clínica y su calidad de vida. Conclusiones. La eficacia de la monitorización en nuestra unidad es similar a estudios previos publicados, del 85,9%. Tras el ingreso, hemos modificado el diagnóstico en un 57% y el tratamiento médico en un 29%. Aún tardamos mucho tiempo en ingresar a un paciente en la unidad de monitorización. Recomendamos el estudio en una unidad de monitorización continua video-EEG a todo paciente con epilepsia farmacorresistente, considerada como aquélla que no responde tras dos o tres tratamientos antiepilépticos adecuados (AU)

Introduction and aims. The epilepsy monitoring unit is a space inside a hospital, which objective is to reproduce epileptic seizures in order to better study of an epileptic patient. We have analysed data from all the patients admitted to our pediatric epilepsy unit in the last 5 years. Patients and methods. 191 patients have been admitted in our unit, and we have obtained seizures in 186 admissions (monitoring efficacy, 85.9%). In this report we summarize characteristics of these children, type of seizures and treatment. Results. The most frequent cause of epilepsy in our series is cortical development malformation. Patients are often late in their admission, with a median time of 3 to 4 years from epileptic onset to admission in the epilepsy unit. After the study,22 patients underwent functional epilepsy surgery, all of them with excellent results, 9 patients underwent vagal nerve stimulator implantation and in 66 patients their previous pharmacological treatment was modified. Conclusions. The efficacy of our monitoring unit is similar to previously published, 85.9%. After the admission, we have changed diagnose in 57% of the patients and pharmacological treatment in 29%. We recommend the study in a monitoring epilepsy unit of every patient with refractory epilepsy, meaning an epilepsy that does not respond to 2-3 different appropriate treatment (AU)

Asociación entre la diabetes mellitus de tipo 1 y la enfermedad celíaca: 6 años de cribado serológico sistemático / Association between type 1 diabetes and celiac disease: six years of systematic serological screening

Introducción. La enfermedad celíaca (EC) y la diabetes mellitus tipo 1 son alteraciones crónicas que comparten susceptibilidad genética, presencia de anticuerpos órgano específicos e influencia de factores ambientales. Según un estudio transversal realizado el año 2001 en nuestro centro, el 8,3% de los pacientes diabéticos tiene anticuerpos específicos de la EC y el 4,9% presenta una lesión intestinal Marsh III. Con estos antecedentes, se instaura el cribado serológico sistemático para la EC en los pacientes que debutan diabetes mellitus de tipo 1 (DM1).El objetivo de este estudio es valorar el resultado de esta estrategia y caracterizar a los pacientes celíacos detectados. Material y métodos. Se estudian los 202 pacientes diabéticos que debutan durante el período 2002–2007 controlados en la Unidad de Diabetes de nuestro hospital. Se determina la concentración sérica de anticuerpos antitransglutaminasa en el debut diabético con controles anuales. Resultados y discusión. l 6,4% (13/202) de los pacientes diabéticos debutantes tiene EC, siendo más frecuente entre los que la debutan precozmente (p=0,016) y mostrando un orden de aparición aleatorizado de ambas enfermedades. En estos pacientes, la EC es mayoritariamente asintomática. La mitad de ellos muestra una respuesta serológica parcial a la dieta sin gluten, lo que sugiere una falta de motivación para el tratamiento dietético.Según nuestra experiencia, el control metabólico de los pacientes diabéticos con EC puede ser complicado y una elevada proporción de casos (p=0,013) requiere el uso de bombas de infusión continua de insulina (AU)

Introduction. Celiac disease and type 1 diabetes mellitus are chronic diseases that share a genetic susceptibility, presence of organ specific autoantibodies and influence of environmental factors. According to a cross-sectional study performed in our hospital in 2001, 8.3% of diabetic patients have positive serological markers for celiac disease and 4.9% have a Marsh grade III intestinal lesion. With this background, we began systematic serological screening for CD on onset of type 1 diabetes. Our aim was to evaluate the results of this strategy, as well as characterizing the patients diagnosed with celiac disease. Material and methods. We studied 202 cases with type 1 diabetes onset detected from 2002 to 2007 and controlled in our Diabetes Unit. Serum Anti-transglutaminase antibodies were analyzed at onset and yearly. Results and discussion. We found that 6.4% (13/202) of diabetic patients had celiac disease, which was more frequent among patients with early diabetes onset (P=0.016). In our series, the order of appearance of both disorders is fortuitous. These celiac patients are mainly asymptomatic, and half of them show a partial serological response to a gluten free diet, probably due a lack of motivation in following the dietary treatment.In our experience, the metabolic control of diabetic patients with celiac disease can be difficult, and a high proportion of cases (P=0.013), require the use of insulin infusion pump (AU)