[Megalencephalic leukoencephalopathy with cysts -the clinical importance in the genetic era]. / Leucoencefalopatía megalencefálica con quistes: importancia de la descripción clínica en la era genética.

INTRODUCTION: Megalencephalic leukoencephalopathy with cysts is a leukodystrophy of genetic origin that produces an alteration in the water and ion homeostasis in the brain, generating vacuolar forms and chronic oedema in the white matter with progressive neurological deterioration. It should be suspected in infants who present progressive macrocephaly during the first year of life, motor retardation and characteristic findings in magnetic resonance brain scans. CASE REPORT: We report the case of a girl who was followed up from the age of 9 months due to progressive macrocephaly and delayed psychomotor development and brain MRI findings consistent with megalencephalic leukoencephalopathy with cysts, and the appearance of epilepsy during its development. The usual genetic studies (new generation sequencing and array) were negative, but as the diagnostic criteria were met, a complementary messenger RNA and DNA study was conducted, which confirmed the presence of two pathogenic variants in MLC1. CONCLUSIONS: Megalencephalic leukoencephalopathy with cysts is a rare condition. Progressive macrocephaly in the first year of life, the absence of deterioration or slow deterioration, and the possibility of developing epilepsy, spasticity and ataxia are characteristic signs in its course. It is important for these patients to undergo an imaging test that shows findings that characterise this condition, which, together with the clinical features, makes it possible to differentiate it from other leukodystrophies and to establish a confirmatory diagnosis. Genetic studies can confirm the associated mutation that makes it possible to predict the clinicoradiological phenotype.

TITLE: Leucoencefalopatía megalencefálica con quistes: importancia de la descripción clínica en la era genética.Introducción. La leucoencefalopatía megalencefálica con quistes es una leucodistrofia de origen genético que produce una alteración de la homeostasis del agua e iones en el cerebro, generando formas vacuolares y edema crónico en la sustancia blanca con deterioro neurológico progresivo. Debe sospecharse en los lactantes que presentan macrocefalia progresiva durante el primer año de vida, retraso motor y hallazgos característicos en la resonancia magnética cerebral. Caso clínico. Niña en seguimiento desde los 9 meses por macrocefalia progresiva y retraso del desarrollo psicomotor con presencia en la resonancia magnética cerebral de hallazgos compatibles con leucoencefalopatía megalencefálica con quistes, y aparición de epilepsia en su evolución. Los estudios genéticos habituales (secuenciación de nueva generación y array) fueron negativos, pero, al cumplir los criterios diagnósticos, se procedió al estudio del ARN mensajero y el ADN complementario, que confirmó la presencia de dos variantes patogénicas en MLC1. Conclusiones. La leucoencefalopatía megalencefálica con quistes es una entidad infrecuente. Es característica la macrocefalia progresiva en el primer año de vida, la ausencia de deterioro o deterioro lento, y la posibilidad de desarrollar epilepsia, espasticidad y ataxia en su evolución. Cobra importancia en dichos pacientes la realización de una prueba de imagen que muestre hallazgos propios de la entidad, lo que, junto con la clínica, permite diferenciarla de otras leucodistrofias y establecer un diagnóstico confirmatorio. Los estudios genéticos pueden constatar la mutación asociada que posibilita predecir el fenotipo clinicorradiológico.

Síndrome de deleción de genes contiguos en Xp21: una forma inusual de presentación / Delection syndrome In Xp21: An unusual form of presentation

Introducción. Describimos el caso de un lactante en el que la asociación de distrofia muscular de Duchenne (DMD) yuna pseudohipertrigliceridemia condujeron al diagnóstico de un síndrome de deleción de genes contiguos en Xp21. Caso clínico.Niño de 7 meses de edad remitido por retraso psicomotor. En la exploración destacaba una hipotonía axial marcada. Laanalítica mostró una elevación de las enzimas musculares con niveles de creatinfosfocinasa de 12.829 UI/L, junto con cifraselevadas de triglicéridos en sangre. Los hallazgos del electromiograma fueron compatibles con afectación miopática. El estudiogenético de distrofinopatías mostró la existencia de una deleción en el gen de la distrofina. La analítica ampliada identificóconcentraciones elevadas de glicerol tanto en sangre como en orina, compatibles con un déficit de glicerolcinasa. El estudiogenético confirmó la existencia de una deleción en Xp21 de los genes responsables de la DMD, del déficit de glicerolcinasa,de la hipoplasia suprarrenal congénita (gen DAX1) y del retraso mental (gen IL1RAPL1). Conclusiones. En lactantes y niñospequeños con afectación miopática, la elevación de las cifras de creatinfosfocinasa y pseudohipertrigliceridemia debeconsiderarse el síndrome de deleción de genes contiguos en Xp21 para prevenir y tratar las complicaciones metabólicas derivadasde la hipoplasia suprarrenal (AU)

Introduction. We report a case of an infant where the association of Duchenne’s muscular dystrophy (DMD) andpseudohypertriglyceridaemia led to the diagnosis of contiguous gene deletion syndrome in Xp21. Case report. A 7-month-oldmale infant who was referred due to psychomotor retardation. The examination revealed pronounced axial hypotonia. Labfindings showed high levels of muscular enzymes with creatine phosphokinase levels of 12,829 IU/L, together with high bloodlevels of triglycerides. Electromyogram findings were consistent with myopathic compromise. The genetic study for dystrophinopathiesrevealed the existence of a deletion in the dystrophin gene. Further lab findings identified high glycerol concentrationsboth in blood and in urine that were compatible with a glycerol kinase deficiency. The genetic study confirmed the existence ofa deletion in Xp21 of the genes responsible for DMD, the glycerol kinase deficiency, the congenital adrenal hypoplasia (geneDAX1) and mental retardation (gene IL1RAPL1). Conclusions. In infants and small children with myopathic compromise,increased levels of creatine phosphokinase and pseudohypertriglyceridaemia it is essential to take into account contiguousgene deletion syndrome in Xp21 to be able to prevent and treat the metabolic complications arising from adrenal hypoplasia (AU)

[Contiguous gene deletion syndrome in Xp21: an unusual form of presentation]. / Síndrome de deleción de genes contiguos en Xp21: una forma inusual de presentación.

INTRODUCTION: We report a case of an infant where the association of Duchenne's muscular dystrophy (DMD) and pseudohypertriglyceridaemia led to the diagnosis of contiguous gene deletion syndrome in Xp21. CASE REPORT: A 7-month-old male infant who was referred due to psychomotor retardation. The examination revealed pronounced axial hypotonia. Lab findings showed high levels of muscular enzymes with creatine phosphokinase levels of 12,829 IU/L, together with high blood levels of triglycerides. Electromyogram findings were consistent with myopathic compromise. The genetic study for dystrophinopathies revealed the existence of a deletion in the dystrophin gene. Further lab findings identified high glycerol concentrations both in blood and in urine that were compatible with a glycerol kinase deficiency. The genetic study confirmed the existence of a deletion in Xp21 of the genes responsible for DMD, the glycerol kinase deficiency, the congenital adrenal hypoplasia (gene DAX1) and mental retardation (gene IL1RAPL1). CONCLUSIONS: In infants and small children with myopathic compromise, increased levels of creatine phosphokinase and pseudohypertriglyceridaemia it is essential to take into account contiguous gene deletion syndrome in Xp21 to be able to prevent and treat the metabolic complications arising from adrenal hypoplasia.

[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

[Contiguous gene deletion syndrome in Xp21: the association between glycerol kinase deficiency, congenital suprarenal hypoplasia and Duchenne's muscular dystrophy]. / Sindrome de deleción de genes contiguos en Xp21: asociación de deficiencia de glicerolcinasa, hipoplasia suprarrenal congénita y distrofia muscular de Duchenne.

INTRODUCTION: Complex glycerol kinase (GK) deficiency is a contiguous deletion of genes in Xp21 with loss of the locus for GK, for congenital adrenal hypoplasia (AHC) and/or for Duchenne's muscular dystrophy (DMD). We report the case of a 7-year-old patient with this rare disease. CASE REPORT: Our patient was a full-term male, with normal gestation and delivery, and no relevant family history. At the age of 11 days he presented a clinical picture of salt loss with lethargy, vomiting, metabolic acidosis, hypoglycaemia, hyponatraemia and hyperpotassaemia. Fluid therapy and treatment with corticoids was established. The patient's condition developed with moderate mental retardation and progressive muscular weakness. In the physical examination, the skull and face were seen to be 'hourglass' shaped. Decompensations associated to infectious processes and fasting hypoglycaemia, hydroelectrolytic disorders and ketoacidosis are all frequent. Lab findings showed a drop in cortisol levels, elevation of muscle enzymes, 'pseudohypertriglyceridaemia' and raised levels of glycerol in plasma and urine. Karyotype and neuroimaging tests were normal. A myopathic pattern was observed in the electromyogram. The genetic study confirmed the deletion in Xp21 of the genes responsible for DMD, the GK deficit and AHC. CONCLUSIONS: Early identification of this disease makes it possible to foresee the acute metabolic decompensations and to establish suitable genetic counselling. CK and triglyceride counts should be performed in all male patients that present a suprarenal hypoplasia; if levels are high, then it is necessary to confirm the raised glycerol values and to carry out a confirmatory genetic study.

Síndrome de deleción de genes contiguos en Xp21: asociación de deficiencia de glicerolcinasa, hipoplasia suprarrenal congénita y distrofia muscular de Duchenne / contiguous gene deletion syndrome in Xp21: the association between glycerol kinase deficiency, congenital suprarrenal hypoplasia and Duchenne´s muscular dystrophy

Introducción. El déficit complejo de glicerocinasa (GK) corresponde a una deleción contigua de genes en Xp21 con pérdida del locus de la GK, de la hipoplasia adrenal congénita (AHC) y/o de la distrofia muscular de Duchenne (DMD). Presentamos un paciente de 7 años con esta rara enfermedad. Caso clínico. Varón nacido a término, con gestación y parto normales, sin antecedentes familiares de interés. Presentó a los 11 días de vida un cuadro de pérdida salina con letargia, vómitos, acidosis metabólica, hipoglucemia, hiponatremia e hiperpotasemia. Se instauró un tratamiento con fluidoterapia y corticoides. Evolucionó con un retraso mental moderado y una debilidad muscular progresiva. En la exploración se objetivó un aspecto craneofacial ‘en reloj de arena’. Son frecuentes las descompensaciones asociadas a procesos infecciosos y ayuno con hipoglucemia, alteraciones hidroelectrolíticas y cetoacidosis. En la analítica destacó el descenso de cortisol, la elevación de enzimas musculares, una ‘pseudohipertrigliceridemia’ y la elevación de glicerol en plasma y orina. El cariotipo y la neuroimagen fueron normales. En el electromiograma se observó un patrón miopático. El estudio genético confirmó la deleción en Xp21 de los genes responsables de la DMD, el déficit de GK y la AHC. Conclusiones. La identificación precoz de esta enfermedad permite prever las descompensaciones metabólicas agudas y establecer un consejo genético adecuado. En todo paciente varón que presente una hipoplasia suprarrenal, se debe realizar una determinación de creatincinasa y triglicéridos, y en el caso de estar aumentados, confirmar la elevación de glicerol y realizar el estudio genético confirmatorio

Introduction. Complex glycerol kinase (GK) deficiency is a contiguous deletion of genes in Xp21 with loss of the locus for GK, for congenital adrenal hypoplasia (AHC) and/or for Duchenne’s muscular dystrophy (DMD). We report the case of a 7-year-old patient with this rare disease. Case report. Our patient was a full-term male, with normal gestation and delivery, and no relevant family history. At the age of 11 days he presented a clinical picture of salt loss with lethargy, vomiting, metabolic acidosis, hypoglycaemia, hyponatraemia and hyperpotassaemia. Fluid therapy and corticoids treatment was established. The patient’s condition developed with moderate mental retardation and progressive muscular weakness. In the physical examination, the skull and face were seen to be ‘hourglass’ shaped. Decompensations associated to infectious processes and fasting hypoglycaemia, hydroelectrolytic disorders and ketoacidosis are all frequent. Lab findings showed a drop in cortisol levels, elevation of muscle enzymes, ‘pseudohypertriglyceridaemia’ and raised levels of glycerol in plasma and urine. Karyotype and neuroimaging tests were normal. A myopathic pattern was observed in the electromyogram. The genetic study confirmed the deletion in Xp21 of the genes responsible for DMD, the GK deficit and AHC. Conclusions. Early identification of this disease makes it possible to foresee the acute metabolic decompensations and to establish suitable genetic counselling. creatin kinase and triglyceride counts should be performed in all male patients that present a suprarenal hypoplasia; if levels are high, then it is necessary to confirm the raised glycerol values and to carry out a confirmatory genetic study

[Non-specific X-linked mental retardation]. / Retraso mental inespecífico ligado al cromosoma X.

INTRODUCTION: Non-specific mental retardation is defined by the absence of somatic, neurological, biochemical or behavioural features that characterise a particular clinical variant and accounts for a large percentage of cases of X-linked mental retardation (XLMR). Genetic linkage studies showed it to have a high rate of genetic heterogeneity. DEVELOPMENT: To date, genetic linkage studies or the characterisation of chromosomal rearrangement in patients have allowed 22 different genes to be identified. Some of the most notable of these are the genes responsible for syndromic forms, such as RPS6KA3, ARX, JARID1C, XNP or MeCP2, in which the mildest mutations, with a certain amount of functional activity, cause non-specific retardation. The proteins these genes code for are directly or indirectly involved in regulating the expression of other genes. Moreover, genes such as OPHN1, PAK3, ARHGEF6, FGD1 or TM4SF2 code for proteins that interact with rho GTPases, and play a role in the transmission of signals that regulate the development of axons and dendrites. Other types of functions of the known genes include establishing and modulating synapses (DLG3, IL1RAPL, NLGN4X, GDI1), regulating transcription (ZNF41, ZNF81, PQBP1) translation (FTSJ1), and fatty acid metabolism (FACL4), etc. CONCLUSIONS: Each gene that has been identified only accounts for a minor fraction of the total amount of XLMR, and even if taken together they still do not explain half the cases of non-specific XLMR. The number of XLMR genes is expected to rise in coming years with the development of new techniques that will facilitate diagnosis and genetic counselling in the relatively near future.

Retraso mental inespecífico ligado al cromosoma X / Non-specific X-linked mental retardation

Introducción. El retraso mental inespecífico se define porla ausencia de rasgos somáticos, neurológicos, bioquímicos o conductualesque caractericen una variante clínica concreta, y suponeuna elevada fracción del retraso mental ligado al X (RMLX). Losestudios de ligamiento genéticos demostraron su elevada heterogeneidadgenética. Desarrollo. Mediante estudios de ligamiento genéticoo la caracterización de reordenamientos cromosómicos enpacientes, actualmente se han identificado 22 genes distintos. Entreellos, destacan genes responsables de formas sindrómicas, talescomo RPS6KA3, ARX, JARID1C, XNP o MeCP2, en los que lasmutaciones más leves, con cierta actividad funcional, causan retrasoinespecífico. Las proteínas codificadas por estos genes se implicandirecta o indirectamente en la regulación de la expresión deotros genes. Por otra parte, genes como OPHN1, PAK3, ARHGEF6,FGD1 o TM4SF2 codifican para proteínas que interaccionan conrho GTPasas, y participan en la transmisión de las señales queregulan el desarrollo de axones y dendritas. Otros tipos de funcionesde los genes conocidos incluyen el establecimiento y modulaciónde las sinapsis (DLG3, IL1RAPL, NLGN4X, GDI1), regulaciónde la transcripción (ZNF41, ZNF81, PQBP1), de la traducción(FTSJ1), metabolismo de los ácidos grasos (FACL4), etc. Conclusiones.Cada gen identificado sólo justifica una fracción minoritariadel total del RMLX, de modo que en conjunto no alcanzan a explicarla mitad del RMLX inespecífico. Se asume que el número degenes RMLX aumentará en los próximos años mediante el desarrollode nuevas técnicas, que facilitarán el diagnóstico y asesoramientogenético en un futuro más o menos lejano

Introduction. Non-specific mental retardation is defined by the absence of somatic, neurological, biochemical orbehavioural features that characterise a particular clinical variant and accounts for a large percentage of cases of X-linkedmental retardation (XLMR). Genetic linkage studies showed it to have a high rate of genetic heterogeneity. Development. To date,genetic linkage studies or the characterisation of chromosomal rearrangement in patients have allowed 22 different genes to beidentified. Some of the most notable of these are the genes responsible for syndromic forms, such as RPS6KA3, ARX, JARID1C,XNP or MeCP2, in which the mildest mutations, with a certain amount of functional activity, cause non-specific retardation. Theproteins these genes code for are directly or indirectly involved in regulating the expression of other genes. Moreover, genes suchas OPHN1, PAK3, ARHGEF6, FGD1 or TM4SF2 code for proteins that interact with rho GTPases, and play a role in thetransmission of signals that regulate the development of axons and dendrites. Other types of functions of the known genes includeestablishing and modulating synapses (DLG3, IL1RAPL, NLGN4X, GDI1), regulating transcription (ZNF41, ZNF81, PQBP1)translation (FTSJ1), and fatty acid metabolism (FACL4), etc. Conclusions. Each gene that has been identified only accounts fora minor fraction of the total amount of XLMR, and even if taken together they still do not explain half the cases of non-specificXLMR. The number of XLMR genes is expected to rise in coming years with the development of new techniques that will facilitatediagnosis and genetic counselling in the relatively near future