Enfermedad de Menkes: diagnóstico clínico, bioquímico y molecular / Menkes disease: its clinical, biochemical and molecular diagnosis

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[Behavioural phenotypes in genetic mental retardation]. / Fenotipos conductuales en el retraso mental de origen genetico.

INTRODUCTION: Based on clinical and genetic knowledge about certain syndromes, in recent decades the concept of behavioural phenotypes has been developed in an attempt to deal with the complex relations between genes and behaviour. The model is not linear but rather each type of behaviour is determined by the interaction of different genes and modulated by environmental factors. DEVELOPMENT AND CONCLUSIONS: The aim of this review is to provide a global view concerning the concept of 'behavioural phenotypes' based on the description of the molecular mechanisms and clinical observations of some syndromes. There is clearly a need for geneticists, who work in a laboratory, and clinicians, who can offer qualitative and quantitative data about behaviour in certain genetic syndromes, to work in collaboration. For this reason this study describes the clinical instruments that make it possible to evaluate the core aspects of behaviour and hence undertake their scientific study in situations in which their genetic dysfunction is already known.

[Chromosomal causes that produce mental retardation: chromosome disorders that can be diagnosed in the patient]. / Causas cromosomicas que originan el retraso mental: alteraciones cromosomicas diagnosticables en el paciente.

INTRODUCTION: In all the aetiological studies carried out on idiopathic mental retardation (MR), chromosomal abnormalities are the factor that makes the most significant contribution. The alterations are more frequent when severe MR is accompanied by a dysmorphic phenotype, but can also be found in subjects with mild MR and with few signs of dysmorphism. DEVELOPMENT: This work reports on new genes and critical regions in syndromes with microdeletion, such as Wolf-Hirschhorn, Smith-Magenis and Sotos--which must be taken into account in the genetic diagnosis--and new microduplications like 15q11-q13, which is associated to a behavioural phenotype of autism. The application of new molecular techniques, such as fluorescent in situ hybridisation (FISH) with multiple telomere probes, MLPA (multiplex ligation-dependent probe amplification) and array-CGH (microarray based on compared genomic hybridisation), have shown the important role played by subtelomeric and interstitial rearrangements in the aetiology of MR. Subtelomeric alterations contribute to between 5 and 7% of cases of idiopathic MR, the higher proportion corresponding to deletions, one of the most common of which is deletion 1p36. Studies that evaluate the global genome in idiopathic MR detect from 7% to 20% of cases with anomalies, the interstitial type being more frequent than the subtelomeric kind. CONCLUSIONS: The application of new technologies to idiopathic MR opens up a promising new field for the diagnosis of new syndromes with submicroscopic alterations, so that a prognosis can be determined, treatment can be improved and the risk of relapse can be defined.

[From the clinical to the genetic diagnosis of Prader-Willi and Angelman syndromes]. / Del diagnóstico clínico al diagnóstico genético de los síndromes de Prader-Willi y Angelman.

INTRODUCTION AND DEVELOPMENT: Angelman syndrome (AS) is characterised by severe mental retardation (MR), the absence of language, ataxia and/or tremors in the extremities and a characteristic behavioural phenotype with a happy behaviour and hyperactivity. Patients often show signs of microcephaly and convulsions. Prader-Willi syndrome (PWS) is characterised by acute hypotonia and feeding problems in the neonatal period, and triggers an uncontrollable appetite in the infant that leads to obesity. Most patients have some degree of MR, behavioural disorders and hypogonadism. Both pathologies are caused by a number of genetic mechanisms that affect the 15q11-q13 region regulated by genomic imprinting, which means that only one of the two copies of the genes in this region will be functional, depending on which parent they come from. The physical or functional absence of genes that are only expressed by the mother's chromosome 15 causes PWS and gentic anomalies which affects the UBE3A gen mother's copy causes AS. CONCLUSIONS: It is important to confirm the clinical diagnosis and to establish the genetic mechanism responsible for the two syndromes, both for their consequences as regards the prognosis and for genetic counselling; it is therefore important to draw up a diagnostic algorithm.

Fenotipos conductuales en el retraso mental de origen genético / Behavioural phenotypes in genetic mental retardation

Introducción. A partir del conocimiento clínico y genéticode determinados síndromes, en las últimas décadas se ha desarrolladoel concepto de fenotipos conductuales, que pretende abordarlas complejas relaciones entre los genes y la conducta. El modelo noes lineal, sino que cada conducta está determinada por la interacciónde diversos genes, y modulada por factores ambientales. Desarrolloy conclusiones. Esta revisión pretende aportar una visión globalsobre el concepto de ‘fenotipos conductuales’, a partir de la descripciónde los mecanismos moleculares y las observaciones clínicasen algunos síndromes. Se pone en evidencia la necesidad de unacolaboración entre genetistas que desarrollan su trabajo en el laboratorioy clínicos que pueden aportar valoraciones cualitativas ycuantitativas sobre la conducta en síndromes genéticos definidos.Con este objetivo se describen los instrumentos clínicos que hacenposible valorar los aspectos nucleares de la conducta, y de estemodo abordar su estudio científico en situaciones en las cuales se hallegado a conocer la disfunción genética

Based on clinical and genetic knowledge about certain syndromes, in recent decades the concept ofbehavioural phenotypes has been developed in an attempt to deal with the complex relations between genes and behaviour.The model is not linear but rather each type of behaviour is determined by the interaction of different genes and modulated byenvironmental factors. Development and conclusions. The aim of this review is to provide a global view concerning theconcept of ‘behavioural phenotypes’ based on the description of the molecular mechanisms and clinical observations of somesyndromes. There is clearly a need for geneticists, who work in a laboratory, and clinicians, who can offer qualitative andquantitative data about behaviour in certain genetic syndromes, to work in collaboration. For this reason this study describesthe clinical instruments that make it possible to evaluate the core aspects of behaviour and hence undertake their scientificstudy in situations in which their genetic dysfunction is already known

Causas cromosómicas que originan el retraso mental: alteraciones cromosómicas diagnosticables en el paciente / Chromosomal causes that produce mental retardation: chromosome disorders that can be diagnosed in the patient

Introducción. En todos los estudios etiológicos de retrasomental (RM) idiopático, las anomalías cromosómicas son el factorque contribuye más significativamente. Las alteraciones son más frecuentescuando el RM grave se acompaña de un fenotipo dismórfico,pero pueden encontrarse también en sujetos con RM leve y conescasos signos dismórficos. Desarrollo. Se describen nuevos genes yregiones críticas de síndromes con microdeleción:Wolf-Hirschhorn,Smith-Magenis y Sotos –que deben tenerse en cuenta para el diagnósticogenético–, y nuevas microduplicaciones como la 15q11-q13,que se asocia a un fenotipo conductual de autismo. La aplicación delas nuevas técnicas moleculares como la hibridación in situ fluorescente(FISH) con multisondas multitelómero, MLPA (multiplex ligation-dependent probe amplification) y array-CGH (microarray basadoen la hibridación genómica comparada), ha puesto de manifiestola gran relevancia que tienen las reorganizaciones subteloméricase intersticiales en la etiología del RM. Las alteraciones subteloméricascontribuyen en un 5-7% de los casos con RM idiopático; lamayor proporción corresponde a las deleciones; una de las más comuneses la deleción 1p36. Los estudios que valoran el genoma globalen el RM idiopático detectan desde un 7 a un 20% de casos conanomalías, y son las intersticiales más frecuentes que las subteloméricas.Conclusiones. La aplicación de las nuevas tecnologías alRM idiopático abre un campo muy esperanzador para el diagnósticode nuevos síndromes con alteraciones submicroscópicas, a fin deestablecer un pronóstico, mejorar el tratamiento y definir el riesgode recurrencia

In all the aetiological studies carried out on idiopathic mental retardation (MR), chromosomalabnormalities are the factor that makes the most significant contribution. The alterations are more frequent when severe MR isaccompanied by a dysmorphic phenotype, but can also be found in subjects with mild MR and with few signs of dysmorphism.Development. This work reports on new genes and critical regions in syndromes with microdeletion, such as Wolf-Hirschhorn,Smith-Magenis and Sotos –which must be taken into account in the genetic diagnosis– and new microduplications like 15q11-q13,which is associated to a behavioural phenotype of autism. The application of new molecular techniques, such as fluorescent insitu hybridisation (FISH) with multiple telomere probes, MLPA (multiplex ligation-dependent probe amplification) and array-CGH (microarray based on compared genomic hybridisation), have shown the important role played by subtelomeric andinterstitial rearrangements in the aetiology of MR. Subtelomeric alterations contribute to between 5 and 7% of cases ofidiopathic MR, the higher proportion corresponding to deletions, one of the most common of which is deletion 1p36. Studiesthat evaluate the global genome in idiopathic MR detect from 7% to 20% of cases with anomalies, the interstitial type beingmore frequent than the subtelomeric kind. Conclusions. The application of new technologies to idiopathic MR opens up apromising new field for the diagnosis of new syndromes with submicroscopic alterations, so that a prognosis can be determined,treatment can be improved and the risk of relapse can be defined

Del diagnóstico clínico al diagnóstico genético de los síndromes de Prader-Willi y Angelman / From the clinical to the genetic diagnosis of prader-willi and angelman syndromes

Introduction and development. Angelman syndrome (AS) is characterised by severe mental retardation (MR), theabsence of language, ataxia and/or tremors in the extremities and a characteristic behavioural phenotype with a happybehaviour and hyperactivity. Patients often show signs of microcephaly and convulsions. Prader-Willi syndrome (PWS) ischaracterised by acute hypotonia and feeding problems in the neonatal period, and triggers an uncontrollable appetite in theinfant that leads to obesity. Most patients have some degree of MR, behavioural disorders and hypogonadism. Bothpathologies are caused by a number of genetic mechanisms that affect the 15q11-q13 region regulated by genomic imprinting,which means that only one of the two copies of the genes in this region will be functional, depending on which parent theycome from. The physical or functional absence of genes that are only expressed by the mother’s chromosome 15 causes PWSand gentic anomalies which affects the UBE3A gen mother’s copy causes AS. Conclusions. It is important to confirm theclinical diagnosis and to establish the genetic mechanism responsible for the two syndromes, both for their consequences asregards the prognosis and for genetic counselling; it is therefore important to draw up a diagnostic algorithm

Introducción y desarrollo. El síndrome de Angelman (SA)se caracteriza por retraso mental (RM) grave, ausencia del lenguaje,ataxia y/o temblores de las extremidades y un fenotipo conductualcaracterístico con conducta feliz e hiperactividad. Con frecuencialos pacientes presentan microcefalia y convulsiones. Elsíndrome de Prader-Willi (SPW) se caracteriza por una hipotoníaaguda y dificultades para la alimentación en el período neonatal, ypresenta en la infancia un apetito incontrolado que conduce a laobesidad. La mayoría de pacientes presentan algún grado de RM,problemas de comportamiento e hipogonadismo. Ambas patologíasestán causadas por varios mecanismos genéticos que afectan a laregión 15q11-q13 regulada por la impronta genómica, por lo quesólo una de las dos copias de los genes de esta región será funcionalsegún su origen parental. La ausencia física o funcional de genesque se expresan sólo del cromosoma 15 paterno causa el SPW yanomalías genéticas que afectan a la copia materna del gen UBE3Acausan el SA. Conclusión. Es importante confirmar el diagnósticoclínico y establecer el mecanismo genético responsable de ambossíndromes, por sus implicaciones pronósticas y para el consejo genético;por ello, es importante elaborar un algoritmo de diagnóstico

[Medical and behavioural aspects of Angelman syndrome]. / Aspectos médicos y conductuales del síndrome de Angelman.

INTRODUCTION: Angelman syndrome (AS) is a genetically-based disorder that is characterised by a physical and behavioural phenotype. Additionally, it presents a number of different systemic conditions that must also be taken into account. To evaluate the symptomatic spectrum of AS, we sought the aid of families linked to AS associations by sending them a questionnaire designed to investigate the clinical characteristics of AS. PATIENTS AND METHODS: The families were sent a questionnaire aimed at determining the medical and behavioural characteristics of AS. Results from 68 patients were analysed. RESULTS: The mean age at diagnosis was 4.8 years. The first symptoms that called parents' attention were feeding problems, followed by gastroesophageal reflux and hypotonia. The mean age at which patients were capable of maintaining a sitting posture was 18 months, while autonomous walking was not achieved until 43 months. Epilepsy, which was present in 91% of cases, began with febrile seizures in 55% of patients. In this study we found that a high percentage of patients with AS have a high resistance to pain (67%), a very common symptom in Prader-Willi syndrome, but little known in AS. CONCLUSIONS: This study offers a wide array of information about the clinical spectrum of AS obtained from an extensive populational sample. Some highly prevalent clinical aspects, such as the relative insensitivity to pain, have not been reported in previous publications as a symptom that is typical of AS.

Aspectos médicos y conductuales del síndrome de Angelman / Medical and behavioural aspects of angelman syndrome

Introducción. El síndrome de Angelman (SA) es un trastorno de base genética caracterizado por un fenotipo físico y conductual. Además, presenta diversas manifestaciones sistémicas que se deben tomar en consideración. Con el fin de valorar el espectro sintomático del SA, se solicitó la colaboración de familias vinculadas a asociaciones de SA mediante un cuestionario diseñado con base en las características clínicas del SA. Pacientes y métodos. Se envió a las familias un cuestionario orientado a determinar las características médicas y conductuales del SA. Se analizaron los resultados de 68 pacientes. Resultados. La edad media de diagnóstico fue de 4,8 años. Los síntomas más precoces que han llamado la atención a los padres son los problemas de alimentación, seguidos del reflujo gastroesofágico y la hipotonía. La edad media de adquisición de la sedestación es a los 18 meses, en tanto que la marcha autónoma no se adquiere hasta los 43 meses. La epilepsia, presente en el 91% de los casos, se inició con convulsiones febriles en el55%. En este estudio hemos hallado que un gran porcentaje de pacientes con SA presenta una elevada resistencia al dolor (67%),síntoma muy común en el síndrome de Prader-Willi, pero poco conocido en el SA. Conclusiones. Este estudio ofrece una amplia información sobre el espectro clínico del SA a partir de una extensa muestra poblacional. Algunos aspectos clínicos de elevada prevalencia, tales como la relativa insensibilidad al dolor, no se han recogido en publicaciones anteriores como síntoma propio del SA (AU)

Introduction. Angelman syndrome (AS) is a genetically-based disorder that is characterised by a physical and behavioural phenotype. Additionally, it presents a number of different systemic conditions that must also be taken into account. To evaluate the symptomatic spectrum of AS, we sought the aid of families linked to AS associations by sending them a questionnaire designed to investigate the clinical characteristics of AS. Patients and methods. The families were sent a questionnaire aimed at determining the medical and behavioural characteristics of AS. Results from 68 patients were analysed. Results. The mean age at diagnosis was 4.8 years. The first symptoms that called parents’ attention were feeding problems, followed by gastroesophageal reflux and hypotonia. The mean age at which patients were capable of maintaining asitting posture was 18 months, while autonomous walking was not achieved until 43 months. Epilepsy, which was present in91% of cases, began with febrile seizures in 55% of patients. In this study we found that a high percentage of patients with AS have a high resistance to pain (67%), a very common symptom in Prader-Willi syndrome, but little known in AS. Conclusions. This study offers a wide array of information about the clinical spectrum of AS obtained from an extensive populational sample. Some highly prevalent clinical aspects, such as the relative insensitivity to pain, have not been reported in previous publications as a symptom that is typical of AS (AU)

[Syndromic autism: I. General aspects]. / El autismo sindrómico: I. Aspectos generales.

INTRODUCTION AND DEVELOPMENT: The diagnosis of autism is based on the identification of certain behavioural criteria, but there is no biological test that allows us to diagnose the disorder. Yet, a considerable number of cases of autism, estimated to be somewhere between 11 and 37%, are linked to specific syndromes that can be identified according to their clinical characteristics, or by means of some biological marker. These cases are known as syndromic autism or 'double syndromes'. There is a relation between autism and certain genetic and metabolic diseases, epilepsy, infections of the nervous system, intrauterine exposure to certain substances and perinatal pathologies. CONCLUSIONS: The aim of this review is to guide the professional in the diagnosis of autistic children in order to rationalise the process by ruling out any underlying disease or syndrome related to the autistic condition. At the same time, we stress aetiological aspects of these syndromes, which make it easier to understand the biological bases of autism.

[Syndromic autism: II. Genetic syndromes associated with autism]. / El autismo sindrómico: II. Síndromes de base genética asociados a autismo.

INTRODUCTION AND DEVELOPMENT: In this study we report on the different genetic syndromes in which autism has been described as one of the possible manifestations. CONCLUSIONS: Certain genetic syndromes are providing us with extremely valuable information about the role played by genetics in autism. This is the case of the following syndromes: Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X syndrome, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, Smith-Magenis syndrome, Williams syndrome, Rett syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne's disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome and HEADD syndrome.

El autismo sindrómico: I. Aspectos generales / Syndromic autism I: general aspects

Introducción y desarrollo. El diagnóstico de autismo se basa en la identificación de determinados criterios conductuales. No existe ninguna prueba biológica que permita diagnosticar el autismo. Sin embargo, un número considerable de casos de autismo, estimado entre el 11 y 37 %, está asociado a síndromes específicos, que pueden ser identificado en base a las características clínicas, o mediante algún marcador biológico. Estos casos se conocen como autismo sindrómico o ‘síndromes dobles’. Existe una relación entre el autismo y ciertas enfermedades genéticas, metabólicas, epilepsia, infecciones del sistema nervioso, exposición intrauterina a determinadas sustancias y patología perinatal. Conclusiones. Con esta revisión se pretende orientar al profesional que diagnostica niños autistas, con el fin de racionalizar el proceso dirigido a descartar cualquier enfermedad o síndrome subyacente relacionado con el cuadro autista. Al mismo tiempo, se hace énfasis en aspectos etioló- gicos de estos síndromes, que facilitan la comprensión de las bases biológicas del autismo (AU)

Introduction and development. The diagnosis of autism is based on the identification of certain behavioural criteria, but there is no biological test that allows us to diagnose the disorder. Yet, a considerable number of cases of autism, estimated to be somewhere between 11 and 37%, are linked to specific syndromes that can be identified according to their clinical characteristics, or by means of some biological marker. These cases are known as syndromic autism or ‘double syndromes’. There is a relation between autism and certain genetic and metabolic diseases, epilepsy, infections of the nervous system, intrauterine exposure to certain substances and perinatal pathologies. Conclusions. The aim of this review is to guide the professional in the diagnosis of autistic children in order to rationalise the process by ruling out any underlying disease or syndrome related to the autistic condition. At the same time, we stress aetiological aspects of these syndromes, which make it easier to understand the biological bases of autism (AU)

El autismo sindrómico: II. Síndromes de base genética asociados a autismo / Syndromic autism: II. Genetic síndromes associated with autism

Introducción y desarrollo. Se describen los distintos síndromes de base genética, en los cuales ha sido descrito el autismo como una de sus posibles manifestaciones. Conclusiones. Determinados síndromes genéticos están aportando información muy valiosa sobre el conocimiento de la genética del autismo. Este es el caso de los siguientes síndromes: síndrome de Angelman, síndrome de Prader-Willi, duplicación 15q11-q13, síndrome X frágil, premutación del síndrome X frágil, deleción del cromosoma 2q, síndrome XYY, síndrome de Smith-Lemli-Opitz, síndrome de Apert, mutaciones del gen ARX, síndrome de De Lange, síndrome de Smith-Magenis, síndrome de Williams, síndrome de Rett, síndrome de Noonan, síndrome de Down, síndrome velocardiofacial, distrofia miotónica, enfermedad de Steinert, esclerosis tuberosa, enfermedad de Duchenne, síndrome de Timothy, deleción terminal 10p, síndrome de Cowden, mosaicismo 45 X/46 XY, síndrome de Myhre, síndrome de Sotos, síndrome de Cohen, síndrome de Goldenhar, síndrome de Joubert, síndrome de Lujan-Fryns, síndrome de Moebius, hipomelanosis de Ito, neurofibromatosis tipo 1, síndrome CHARGE y síndrome HEADD (AU)

Introduction and development. In this study we report on the different genetic syndromes in which autism has been described as one of the possible manifestations. Conclusions. Certain genetic syndromes are providing us with extremely valuable information about the role played by genetics in autism. This is the case of the following syndromes: Angelman syndrome, Prader-Willi syndrome, 15q11-q13 duplication, fragile X syndrome, fragile X premutation, deletion of chromosome 2q, XYY syndrome, Smith-Lemli-Opitz syndrome, Apert syndrome, mutations in the ARX gene, De Lange syndrome, SmithMagenis syndrome, Williams syndrome, Rett syndrome, Noonan syndrome, Down syndrome, velo-cardio-facial syndrome, myotonic dystrophy, Steinert disease, tuberous sclerosis, Duchenne’s disease, Timothy syndrome, 10p terminal deletion, Cowden syndrome, 45,X/46,XY mosaicism, Myhre syndrome, Sotos syndrome, Cohen syndrome, Goldenhar syndrome, Joubert syndrome, Lujan-Fryns syndrome, Moebius syndrome, hypomelanosis of Ito, neurofibromatosis type 1, CHARGE syndrome and HEADD síndrome (AU)

[Mental deficiency associated with a fragility of the X chromosome]. / Deficiencia mental asociada a fragilidad del cromosoma X.

Fragile X chromosome was studied in 44 male and 9 female children, affected of mental retardation. In 10 males fragile X was positive. All this patients presented mild mental deficiency with and IQ from 55 to 75. Behaviour was generally hyperkinetic except one autistic boy. Most frequent dysmorphic signs were increased head circumference and prominent large ears. Family history for mental retardation was positive almost in all cases. High percentage of children with fragile X syndrome (22.7%) encountered among male patients suggest convenience of screening, for these anomaly, of all boys affected of mild mental deficiency and all those with an autistic behaviour although lacking of dysmorphic characteristics. This will allow to know more on etiology and to offer genetic counseling to families. Although study in girls was negative, authors believe it is interesting to screen fragile X because some females with border line retardation present this chromosomic anomaly.