[ARX mutations and mental retardation of unknown etiology: three new cases in Spain]. / Mutaciones en el gen ARX y retraso mental no filiado: tres nuevos casos en España.

INTRODUCTION: Mental retardation has an approximated prevalence of 2% in the general population and its most frequent cause is X-fragile syndrome. This genetic disorder predominantly affects males and it is mainly caused by the expansion of CGG in FMR1 gene. Recently has been demonstrated that mutations in a new called ARX gene (aristaless-related homeobox) can also cause a similar form of X linked mental retardation, as well as other neurological disorders (autism, Partington or West syndrome). The most frequent mutation that has been reported is the c.428_451 dup24, which comprises almost 60% of all described. It causes an expansion of a polyalanine tract of ARX protein. CASE REPORTS: We report three cases of mental retardation in two different families where the mutation in ARX gene c.428_451 dup24 was found while X-fragile syndrome screening was made. Personal and familiar history, phenotype and evolution are described. CONCLUSION: The molecular analysis of this mutation should be considered as a routine for the genetic diagnosis of mental retardation in males of nondrafted cause.

Mutaciones en el gen ARX y retraso mental no filiado: tres nuevos casos en España / Arx mutations and mental retardation of unknow etiology: Three new cases in Spain

Introducción. El retraso mental tiene una prevalencia aproximada del 2% en la población general, y la causa hereditaria más frecuente es el síndrome X frágil. Esta entidad afecta predominantemente a varones y está fundamentalmente causada por la expansión del triplete CGG en el gen FMR1. Recientemente, se ha demostrado que mutaciones en un nuevo gen llamado ARX (aristaless related homeobox) pueden ocasionar también una forma similar de retraso mental ligado al X, entreun amplio espectro de trastornos neurológicos relacionados (autismo, síndrome de Partington o síndrome de West, entre otros). La mutación más frecuentemente descrita, aproximadamente un 60% del total, es la duplicación de 24 pares de bases en el exón 2 (c.428_451 dup24), que produce una expansión de un tramo de polialanina en la proteína ARX. Casos clínicos.Se comunican tres casos de retraso mental no filiado, pertenecientes a dos familias distintas, en los que se halló la mutación en el gen ARX c.428_451 dup24 al realizar un estudio genético adicional al cribado de síndrome X frágil. Se describen los antecedentes personales y familiares, características fenotípicas y evolución de cada uno de ellos. Conclusión. El análisis molecular de dicha mutación debería considerarse de rutina para el diagnóstico genético de retraso mental en varones de causa no filiada

Introduction. Mental retardation has an approximated prevalence of 2% in the general population and its mostfrequent cause is X-fragile syndrome. This genetic disorder predominantly affects males and it is mainly caused by the expansion of CGG in FMR1 gene. Recently has been demonstrated that mutations in a new called ARX gene (aristalessrelated homeobox) can also cause a similar form of X linked mental retardation, as well as other neurological disorders (autism, Partington or West syndrome). The most frequent mutation that has been reported is the c.428_451 dup24, which comprises almost 60% of all described. It causes an expansion of a polyalanine tract of ARX protein. Case reports. We reportthree cases of mental retardation in two different families where the mutation in ARX gene c.428_451 dup24 was found while X-fragile syndrome screening was made. Personal and familiar history, phenotype and evolution are described. Conclusion. The molecular analysis of this mutation should be considered as a routine for the genetic diagnosis of mental retardation inmales of nondrafted cause

[Mosaic trisomy 9: report of a new case with a long-term survival]. / Mosaicismo de trisomía 9: caso de larga supervivencia.

INTRODUCTION: Trisomy 9 is an uncommon chromosome abnormality that may be seen in a mosaic or non-mosaic state. OBJECTIVE: To better define the phenotype and prognosis of this disorder we report a new case of mosaic trisomy 9 with a long-term survival. CLINICAL REPORT: We present the case of a female patient, born from the first pregnancy of a healthy couple. Fetal ultrasounds disclosed intrauterine growth retardation and oligohydramnios. Cesarean section was performed in the 34th week. Birth weight was 1,478 g. Neonatal examination showed: dolichocephaly; hypotelorism, microphthalmia, short palpebral fissures; broad-based nose with bulbous tip; micrognathia; low-set malformed ears; abnormal hands and feet; no other malformations. The initial karyotype determination was normal (46,XX). At 17 months of age, a second karyotype was requested because the patient developed severe psychomotor retardation. Chromosome analysis showed mosaic trisomy 9 (46,XX/47,XX, + 9). Six months later, a single upper central incisor was noted. To our knowledge, this feature has not been reported previously in the trisomy 9. The patient is now 4 years old. She shows severe psychomotor retardation, but no other complications. COMMENTS: It is important to be aware of the possibility that mosaicism may exist in a patient with normal blood karyotype and abnormal phenotype. We conclude that a great number of cells is needed in order to obtain a correct karyotype diagnosis. Correct diagnosis is essential to define the prognosis and provide accurate genetic counselling.

Mosaicismo de trisomía 9: caso de larga supervivencia / Mosaic trisomy 9: report of a new case with a long-term survival

Introducción: La trisomía 9 es una aneuploidía infrecuente y, por tanto, difícil de sospechar. Objetivo: Comunicar un nuevo caso de mosaicismo de trisomía 9, de larga supervivencia, para contribuir al mejor conocimiento de sus características clínicas y pronóstico. Caso clínico: Primera hija de padres sanos. Retraso de crecimiento intrauterino asimétrico y oligohidramnios. Nace a las 34 semanas con 1.478 g de peso, depresión respiratoria y fenotipo anómalo: dolicocefalia; hipotelorismo, microftalmia, hendiduras palpebrales pequeñas; nariz de base ancha y punta en bulbo; micrognatia; orejas de implantación baja, y anomalías en las manos y los pies. Ausencia de malformaciones en los órganos internos. Cariotipo: normal (46,XX). A los 17 meses, ante el retraso psicomotor evidente y las alteraciones descritas se realiza un segundo cariotipo convencional insistiendo en el análisis de un mayor número de células. Se halla un mosaicismo de trisomía 9 (46,XX/47,XX, 1 9). Como dato fenotípico curioso, a los 24 meses aparece un incisivo único superior medial, no descrito antes en otros casos de trisomía 9. Actualmente, tiene 4 años, un retraso mental profundo y ninguna otra complicación. Comentarios: Destaca la mayor dificultad diagnóstica de los mosaicismos; por lo que se debe insistir en el análisis de un número suficiente de células al estudiar el cariotipo. Además, es importante su diagnóstico en sujetos con anomalías fenotípicas, para dar información correcta a los padres en orden a su pronóstico y a la futura descendencia (AU)

Introduction: Trisomy 9 is an uncommon chromosome abnormality that may be seen in a mosaic or non-mosaic state. Objective: To better define the phenotype and prognosis of this disorder we report a new case of mosaic trisomy 9 with a long-term survival. Clinical report: We present the case of a female patient, born from the first pregnancy of a healthy couple. Fetal ultrasounds disclosed intrauterine growth retardation and oligohydramnios. Cesarean section was performed in the 34th week. Birth weight was 1,478 g. Neonatal examination showed: dolichocephaly; hypotelorism, microphthalmia, short palpebral fissures; broad-based nose with bulbous tip; micrognathia; low-set malformed ears; abnormal hands and feet; no other malformations. The initial karyotype determination was normal (46,XX). At 17 months of age, a second karyotype was requested because the patient developed severe psychomotor retardation. Chromosome analysis showed mosaic trisomy 9 (46,XX/47,XX, 1 9). Six months later, a single upper central incisor was noted. To our knowledge, this feature has not been reported previously in the trisomy 9. The patient is now 4 years old. She shows severe psychomotor retardation, but no other complications. Comments: It is important to be aware of the possibility that mosaicism may exist in a patient with normal blood karyotype and abnormal phenotype. We conclude that a great number of cells is needed in order to obtain a correct karyotype diagnosis. Correct diagnosis is essential to define the prognosis and provide accurate genetic counseling (AU)

[Effects of valproate on sexual development]. / Efectos del ácido valproico sobre el desarrollo sexual.

INTRODUCTION: Valproate use in young girls has been associated with the adverse endocrinological effects of weight gain and hyperandrogenism. Furthermore, polycystic ovaries and hyperinsulinism have been described in adult women. In men and young boys, however, the possible adverse endocrinological effects of valproate have scarcely been analyzed. OBJECTIVES: The aim of this study was to evaluate the effects of valproate treatment on pubertal development, especially the possible hyperandrogenic effects, in girls and boys with epilepsy. MATERIAL AND METHODS: Twenty-three girls and 15 boys (aged 8-16 years old) who were undergoing valproate treatment for epilepsy were compared with 15 control girls and 10 control boys of the same age range. Anthropometric indexes, sexual maturation, and hirsutism scores were evaluated. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, androstenedione, dehydroepiandrosterone, estradiol, and insulin were measured. Ultrasound examination of ovaries and estimation of bone age through X-ray of the left hand were also performed. RESULTS: Valproate did not affect pubertal development in the study group. No hirsutism or polycystic ovaries were found. Increases in weight, relative weight, and body mass index were observed in the group undergoing valproate treatment, but no statistically significant differences compared with the control group were found. Plasma testosterone was higher in valproate-treated girls (0.71 0.51 ng/ml) than in control girls (0.35 0.15) (p 0.001). This finding was independent of valproate dose and treatment duration. Hyperandrogenism was not found in valproate-treated boys. CONCLUSIONS: Valproate may induce hyperandrogenism in epileptic girls but not in boys. This is an early adverse effect and is independent of the dose used. No changes in normal pubertal development or physical repercussions were found in epileptic patients.

Efectos del ácido valproico sobre el desarrollo sexual / Effects ofvalproate on sexual development

Introducción La utilización del ácido valproico se ha relacionado en niñas y adolescentes con efectos adversos endocrinológicos: ganancia de peso e hiperandrogenismo. Además, en mujeres adultas se han descrito ovarios poliquísticos e hiperinsulinismo. En varones apenas se han estudiado los posibles efectos adversos endocrinológicos. Objetivos: El objetivo de este estudio fue evaluar los efectos del ácido valproico en el desarrollo puberal en chicas y en chicos epilépticos, en especial relación con su posible efecto hiperandrogénico. Material y métodos: Se incluyeron 23 chicas y 15 chicos (entre 8 y 16 años) epilépticos, tratados con ácido valproico, se compararon con 15 niñas control y 10 niños control del mismo rango de edad. Se valoraron índices antropométricos y las escalas de desarrollo sexual e hiperandrogenismo. Se midieron las concentraciones séricas de hormona foliculostimulante (FSH) y luteinizante (LH), testosterona, androstendiona, deshidroepiandrosterona, estradiol e insulina. Se valoraron los ovarios mediante ecografía y la edad ósea mediante radiografía de la mano izquierda. Resultados: El ácido valproico no afectó el desarrollo puberal en el grupo estudio. No se apreció hirsutismo ni ovarios poliquísticos. Se observó un aumento de peso, peso relativo e índice de masa corporal, pero sin que existieran diferencias estadísticamente significativas respecto al grupo control. La testosterona plasmática en las niñas tratadas (0,71 0,51 ng/ml) fue mayor que en el grupo control (0,35 0,15) (p 0,001) y este hallazgo fue independiente del tiempo de tratamiento o de la dosis empleada. En los chicos tratados no se encontró hiperandrogenismo. Conclusiones: El ácido valproico induce hiperandrogenismo analítico en niñas epilépticas, pero no en niños. Este es un efecto adverso precoz e independiente de la dosis. No hay cambios en el desarrollo puberal normal ni repercusión clínica en los/as pacientes epilépticos/as (AU)

[Epidemiology of mental deficiency. The Safor study (II): age at detection, person making the diagnosis, medical studies]. / Epidemiología de la deficiencia mental. El estudio de la Safor (II): edad de detección, agente que lo detecta y estudio médico.

As part of an epidemiological study on Mental Deficiency which was carried out in an area of the region of Valencia, a study has been made of the age when Mental Deficiency can be detected, who made this discovery, and which children have been the object of a medical study. 12% of the cases were detected at birth, 16% before the age of 3, 7% at 3, and 64% after the age of 4. In 16% of the cases the deficiency was detected by the family, in 20% of the cases a doctor and a psychologist in 62% of the cases. A medical study to discovered the causes of the Mental Deficiency was only carried out in 44% of the cases.

[Epidemiology of mental deficiency. The study of Safor (I): prevalence and etiology]. / Epidemiología de la deficiencia mental. El estudio de la Safor (I): prevalencia y etiología.

An epidemiological study of Mental Deficiency was carried out in an area of the region of Valencia. A prevalence of children between 0-14 years old were found to have an IQ of below 70; 14,10 every 1,000 over a period from september 1987 to june 1988. This prevalence increases gradually according to age, reaching a high point at 10 and another at 14. These fluctuations are due to extreme and less serious cases. 29% of the cases can be attributed to prenatal causes. 9% are perinatal, and 49% are a postnatal origin. In 57% of the cases no cause has been found, and can be considered of unknown etiology.