[Autosomal recessive diseases with mental retardation]. / Enfermedades autosómicas recesivas con retraso mental.

INTRODUCTION: Autosomal recessive diseases with mental retardation are disorders that affect autosomes, and their genetic expression occurs in individuals who are homozygotic for a mutation, while heterozygotic subjects are unaffected carriers. If both parents are carriers, the theoretical possibility of their children also being carriers is 50%, the risk of the children being affected by the disease is 25%, and there is a 25% chance of their being healthy. They are an important source of mental deficiencies and inborn errors of metabolism (IEM) are some of their characteristic syndromes. DEVELOPMENT: The genetic disorders known as IEM can be classified according to the metabolism they affect, that is, purines, pyrimidines, amino acids, and so on. One of the lysosomal disorders is Tay-Sachs disease, which is rare among the general population but is very frequent in populations with a high rate of consanguinity, such as the Ashkenazi Jews. One of the most notable disorders affecting the metabolism of amino acids is the case of phenylketonuria due to mutations in the phenylalanine hydroxylase gene (PAH). It accounts for 0.5-1% of mental diseases and appears with a frequency rate of between 1/11,500 and 1/14,000 in newborn infants. Its early diagnosis through neonatal screening programmes makes it possible to start administering a phenylalanine-free diet and thus prevent mental retardation. CONCLUSIONS: Knowledge of this kind of autosomal diseases with neurological involvement, together with their correct and early diagnosis, makes it possible to establish suitable treatment regimens in some cases and to carry out genetic counselling in all of them.

[Experimental models used in research into genetic disorders that involve intellectual disability]. / Modelos experimentales utilizados en la investigación de trastornos genéticos que cursan con discapacidad intelectual.

INTRODUCTION: A basic principle of molecular and clinical medicine states that the function of the organs and the cells they are made up of is determined by the overall set of specific proteins. Therefore, the function of each organ depends on the molecules present in each cell, and hence it comes as no surprise to find that when tissue function is altered, different changes have taken place in the proteins. In the nervous system there are numerous examples of changes in proteins that correlate with functional alterations, either during normal or pathological development. DEVELOPMENT: In order to understand these relations, and to establish models in which to study the aetiopathogenesis of the disease, it is necessary to direct steady synthesis or to suppress synthesis in the brain of the protein that is potentially involved in the development of the disease. In consequence, it is possible to determine whether the presence or the absence of the protein is the direct or indirect cause of the effects; this is one of the main goals that must be achieved in order to enable researchers to define potential therapeutic targets in hereditary diseases. In order to manipulate the specific protein causing a pathology, we use experimental animal models as essential research tools, since they enable us to determine which mechanisms are altered and how the function of a particular protein affects the mechanisms being studied. CONCLUSIONS: Suppressing a gene or its over-expression in models using genetically modified mice will provide us with a means of modifying the genome and, eventually, the protein in the different tissues as well as in the nervous system in an attempt to imitate the genetic pathology that involves mental retardation. By controlling or suppressing the expression of a protein in the brain it becomes possible to remodel the functional profile of the tissue and study the consequences of molecular genetic manipulation, together with the biochemical, cytological and physiological processes, under normal basal conditions and under specific stimuli or conditions such as stress.

Enfermedades autosómicas recesivas con retraso mental / Autosomal recessive diseases with mental retardation

Introducción. Las enfermedades autosómicas recesivascon retraso mental son alteraciones que afectan a los autosomas ysu expresión genética se da en individuos que son homocigotos parauna mutación, y los heterocigotos son portadores no afectos.Con ambos padres portadores, la posibilidad teórica de que sushijos sean portadores es del 50%, un riesgo de 25% de hijos afectadospor la enfermedad, y otro 25% sanos. Son origen importantede deficiencias mentales, y algunos síndromes característicos sonlos errores congénitos del metabolismo (ECM). Desarrollo. Los trastornosgenéticos de los ECM se pueden clasificar de acuerdo con elmetabolismo alterado: purinas, pirimidinas, aminoácidos, etc. Dentrode los trastornos lisosomales se encuentra la enfermedad de Tay-Sachs, que es rara en la población general, pero con una alta frecuenciaen poblaciones de gran consanguinidad, como los judíosasquenazí. Entre las alteraciones que afectan al metabolismo delos aminoácidos, es especialmente relevante el caso de la fenilcetonuriapor mutaciones en el gen de fenilalanina hidroxilasa (PAH).Supone un 0,5-1% de las enfermedades mentales, y aparece conuna frecuencia de l/11.500-1/14.000 en recién nacidos. Su diagnósticoprecoz con los programas de cribado neonatal permite instaurarla administración de una dieta alimenticia carente de fenilalaninay evitar el retraso mental. Conclusiones. El conocimiento ycorrecto y precoz diagnóstico de este tipo de enfermedades autosómicascon afectación neurológica permite establecer unas pautasadecuadas de tratamiento en unos casos y de asesoramiento genéticoen todos

Introduction. Autosomal recessive diseases with mental retardation are disorders that affect autosomes, and theirgenetic expression occurs in individuals who are homozygotic for a mutation, while heterozygotic subjects are unaffectedcarriers. If both parents are carriers, the theoretical possibility of their children also being carriers is 50%, the risk of thechildren being affected by the disease is 25%, and there is a 25% chance of their being healthy. They are an important sourceof mental deficiencies and inborn errors of metabolism (IEM) are some of their characteristic syndromes. Development. Thegenetic disorders known as IEM can be classified according to the metabolism they affect, that is, purines, pyrimidines, aminoacids, and so on. One of the lysosomal disorders is Tay-Sachs disease, which is rare among the general population but is veryfrequent in populations with a high rate of consanguinity, such as the Ashkenazi Jews. One of the most notable disordersaffecting the metabolism of amino acids is the case of phenylketonuria due to mutations in the phenylalanine hydroxylase gene(PAH). It accounts for 0.5-1% of mental diseases and appears with a frequency rate of between 1/11,500 and 1/14,000 innewborn infants. Its early diagnosis through neonatal screening programmes makes it possible to start administering aphenylalanine-free diet and thus prevent mental retardation. Conclusions. Knowledge of this kind of autosomal diseases withneurological involvement, together with their correct and early diagnosis, makes it possible to establish suitable treatmentregimens in some cases and to carry out genetic counselling in all of them

Modelos experimentales utilizados en la investigación de trastornos genéticos que cursan con discapacidad intelectual / Experimental models used in research into genetic disorders that involve intellectual disability

Introducción. Es un principio básico en medicina moleculary clínica que el conjunto de proteínas específicas determinan lafunción de la célula y los órganos que componen. Por tanto, la funciónde cada órgano depende de las moléculas presentes en cada célula;no es sorprendente que cuando se altera la función tisular hanocurrido distintos cambios en las proteínas. En el sistema nerviosohay numerosos ejemplos de cambios en proteínas que se correlacionancon alteraciones funcionales, ya sea durante el desarrollo normalo patológico. Desarrollo. Para entender estas relaciones, y paraestablecer modelos en los que estudiar la etiopatogenia de la enfermedad,es necesario dirigir la síntesis estable o anular la síntesis enel cerebro de la proteína candidata involucrada en el desarrollo dela enfermedad. Como resultado, se puede determinar si la presenciade la proteína o su ausencia causa los efectos directamente o indirectamente;es una de las metas principales para poder definir potencialesdianas terapéuticas de las enfermedades hereditarias. Paraafectar la proteína específica causante de una patología, usamosmodelos animales de experimentación como herramientas esencialesen la investigación; con ellos se pueden establecer qué mecanismosse alteran y cómo afecta la función de la proteína concreta a losmecanismos estudiados. Conclusiones. La anulación de un gen o susobreexpresión, a través de modelos de ratón modificados genéticamente,proporcionarán un medio para modificar el genoma y, alfinal, la proteína de los distintos tejidos y también del sistema nervioso,en un intento de imitar la patología genética que cursa conretraso mental. Controlando o anulando la expresión de una proteínaen el cerebro es posible remodelar el perfil funcional del tejido yestudiar las consecuencias de la manipulación genética molecular,y los procesos bioquímicos, citológicos y fisiológicos, bajo condicionesbasales y bajo estímulos o condiciones específicas como elestrés

Introduction. A basic principle of molecular and clinical medicine states that the function of the organs and the cellsthey are made up of is determined by the overall set of specific proteins. Therefore, the function of each organ depends on themolecules present in each cell, and hence it comes as no surprise to find that when tissue function is altered, different changeshave taken place in the proteins. In the nervous system there are numerous examples of changes in proteins that correlate withfunctional alterations, either during normal or pathological development. Development. In order to understand these relations,and to establish models in which to study the aetiopathogenesis of the disease, it is necessary to direct steady synthesis or tosuppress synthesis in the brain of the protein that is potentially involved in the development of the disease. In consequence, it ispossible to determine whether the presence or the absence of the protein is the direct or indirect cause of the effects; this is oneof the main goals that must be achieved in order to enable researchers to define potential therapeutic targets in hereditarydiseases. In order to manipulate the specific protein causing a pathology, we use experimental animal models as essentialresearch tools, since they enable us to determine which mechanisms are altered and how the function of a particular proteinaffects the mechanisms being studied. Conclusions. Suppressing a gene or its over-expression in models using geneticallymodified mice will provide us with a means of modifying the genome and, eventually, the protein in the different tissues as well asin the nervous system in an attempt to imitate the genetic pathology that involves mental retardation. By controlling or suppressingthe expression of a protein in the brain it becomes possible to remodel the functional profile of the tissue and study theconsequences of molecular genetic manipulation, together with the biochemical, cytological and physiological processes, undernormal basal conditions and under specific stimuli or conditions such as stress

[Neonatal screening for cystic fibrosis]. / Cribado neonatal de fibrosis quística.

OBJECTIVE: To analyze the efficiency of the method of neonatal screening for cystic fibrosis (CF) used in Castille and Leon (Spain), which is carried out with blood from Guthrie spots. MATERIAL AND METHODS: A total of 36,086 newborns were studied from January 1999 to June 2001. Immunoreactive trypsinogen (IRT) was quantified in all samples and genetic study covering 87.5 % of mutations in the CFTR gene was carried out when IRT levels were > 60 ng/mL. The sweat test was performed in all children in whom at least one mutation was detected. RESULTS: IRT values of > 60 ng/mL were found in 285 children (0.79 %). Of these, eight children (2.8 %) were diagnosed with CF and a further 11 children (3.9 %) with a negative sweat test were found to have one mutation and were thus classified as healthy carriers. To date, no false negatives have been detected. CONCLUSIONS: The two-stage screening method fulfills the required criteria. Its sensitivity is 98.5 % and the basic model can be used in other regions although genetic screening should be optimized by pilot programs to identify the local spectrum of CFTR mutations.

Cribado neonatal de fibrosis quística / Neonatal screening for cystic fibrosis

Objetivo: Analizar la eficacia del método utilizado para el cribado neonatal de fibrosis quística en Castilla y León, realizado con muestras de sangre impregnadas en papel absorbente. Material y métodos: Se estudiaron 36.086 recién nacidos desde enero de 1999 a junio de 2001 mediante cuantificación de tripsinógeno inmunorreactivo (TIR). Cuando los valores fueron superiores a 60 ng/ml se buscaron mutaciones en el gen CFTR con una cobertura del 87,5% de los alelos mutantes en nuestra población. Se solicitó estudio mediante test del sudor en todos los niños en los que se encontró una mutación. Resultados: Se detectaron valores de TIR > 60 ng/ml en 285 niños (0,79%), se diagnosticó fibrosis quística en 8/285 (2,8%) y en otros 11/285 (3,9%) se encontró una mutación, con test de sudor negativo, por lo que se consideraron portadores sanos. Hasta la actualidad no se tiene noticia de la aparición de ningún falso negativo. Conclusiones: El método de cribado en dos fases utilizado cumple los criterios exigibles con una sensibilidad del 98,5%. El modelo general del estudio puede utilizarse en otras comunidades, aunque el rastreo de mutaciones deberá ser optimizado realizando programas piloto que identifiquen el espectro local de mutaciones de fibrosis quística. (AU)

Eficacia de un test clínico como preselección de niños con sospecha de síndrome X frágil / Effectiveness of a clinical checklist in the preselection of children with suspicion of fragile x syndrome

Antecedentes: El síndrome X frágil (SXF) es la causa hereditaria más frecuente de retraso mental. Puede diagnosticarse con técnicas de genética molecular, pero su variada expresión dificulta la sospecha clínica. Objetivo: Se valora la utilidad de un test de seis criterios clínicos como método de preselección a los niños candidatos para estudio genético del síndrome. Pacientes y métodos: Se estudiaron 70 pacientes varones entre 2 y 10años, con retraso mental de causa desconocida, aplicándoseles un test con seis criterios clínicos (retraso mental, historia familiar de retraso mental, facies alargada, orejas grandes, conducta autística y déficit de atención) que se valoraron de 0 a 2 puntos. En todos se realizó estudio molecular del gen SXF usando reacción en cadena de la polimerasa y Southern-blot. Resultados: El estudio molecular confirmó la mutación completa (>200 repeticiones CGG) en 14/70 (20%) niños. La suma de 6puntos en el test fue el límite más discriminativo y fue alcanzado por los 14 enfermos con mutación (100%), pero sólo por 2 de 56 casos (3,5%) sin mutación. El mejor modelo diagnóstico fue la asociación del retraso mental, deficiencia de atención e hiperactividad, historia familiar de retraso mental y orejas grandes seguido de la facies alargada y la conducta autista. Conclusión: Un test clínico de 6 parámetros facilita la preselección de niños con sospecha de SXF para ser confirmados luego con técnicas de genética molecular (AU)

[Effectiveness of a clinical test in the preselection of children with suspected fragile X syndrome]. / Eficacia de un test clínico como preselección de niños con sospecha de síndrome X frágil.

BACKGROUND: Fragile X syndrome (FXS) is the most frequent hereditary cause of mental retardation. It can be diagnosed by molecular genetic techniques, but clinical suspicion is made less likely by it variable expression. OBJECTIVE: To assess the effectiveness of a six-item checklist in the preselection of children who are candidates for FXS genetic study. MATERIAL AND METHODS: We studied 70 male patients aged between 2 and 10 years with mental retardation of unknown cause. In all patients a checklist with six clinical criteria (mental retardation, history of familial mental retardation, long face, large ears, autistic-like behaviour, and attention deficit disorder with hyperactivity) measured from 0-2 points was applied and molecular genetic studies using polymerase chain reaction and Southern-blot were performed. RESULTS: In 14 of the 70 children (20%) molecular study confirmed full mutation (200 CGG repeats). A score of six points in the test had the greatest discriminatory power and was reached by 14 patients (100%) with mutation, but only by 2of 56patients (3.5%) without mutation. The most accurate diagnostic model was the association of mental retardation, attention deficit disorder with hyperactivity, large ears and a history of familial mental retardation followed by long face and autistic-like behaviour. CONCLUSIONS: The six-item checklist improved the preselection of children with suspicion of FXS, which was later confirmed by molecular genetic techniques.