Mutación de novo en heterocigosis en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria / De novo heterozygous mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria

Introducción: La etiología del retraso mental autosómico dominante 1, también conocido como pseudo-Angelman, trastorno del neurodesarrollo asociado a MBD5 o haploinsuficiencia MBD5, radica en una microdeleción del cromosoma 2q23.1 o en una alteración específica del gen MBD5, que constituye la mínima región afectada en la citada microdeleción. Objetivo: Comunicar el caso de una niña con una mutación heterocigota y de novo en el gen MBD5 asociada a heterotopía en banda bilateral y polimicrogiria. Caso clínico: Niña de 8 años, seguida evolutivamente desde los 18 meses por presentar la asociación de discapacidad intelectual y retraso motor graves, ausencia de desarrollo del lenguaje, hipotonía segmentaria, frente ancha y cifoescoliosis. En la resonancia magnética cerebral se observó la presencia de una heterotopía en banda bilateral y polimicrogiria parietooccipital de predominio izquierdo. En el exoma se detectó la variante de novo c.397+1G > C en heterocigosis en el gen MBD5. Conclusión: Constituye la primera observación con una mutación heterocigota en el gen MBD5 asociada a un trastorno en la migración neuronal

Introduction: The aetiology of autosomal dominant mental retardation type 1, also known as pseudo-Angelman, MBD5-associated neurodevelopmental disorder or MBD5 haploinsufficiency, lies in a microdeletion of chromosome 2q23.1 or in a specific alteration of the MBD5 gene, which constitutes the minimum region affected in the aforementioned microdeletion. Aim: To report the case of a girl with a heterozygous de novo mutation in the MBD5 gene associated with bilateral band heterotopia and polymicrogyria. Case Report: We report the case of an 8-year-old girl who was submitted to a developmental follow-up from the age of 18 months after presenting the association of severe intellectual disability and motor delay, lack of language development, segmental hypotonia, a wide forehead and kyphoscoliosis. Magnetic resonance imaging of the brain revealed the presence of a bilateral band heterotopia and parietooccipital polymicrogiria predominant on the left side. In the exome the de novo heterozygous variant c.397+1G > C was detected in the MBD5 gene. Conclusion: This is the first observation of a heterozygous mutation in the MBD5 gene associated with a neuronal migration disorder

Tratamiento de la deficiencia en colina cinasa beta con citicolin / Treatment of choline kinase beta deficiency with citicoline

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Severe neurological abnormalities in a young boy with impaired thyroid hormone sensitivity due to a novel mutation in the MCT8 gene.

Monocarboxylate transporter 8 (MCT8) is an active and specific thyroid hormone transporter into neurons. MCT8 mutations cause an X-linked condition known as Allan-Herndon-Dudley syndrome and are characterized by impaired psychomotor development and typical abnormal thyroid function. We describe a 10-year-old boy with severe cognitive disability, axial hypotonia, spastic quadriplegia and sporadic dyskinetic episodes. He initially presented with thyroid dysfunction (high FT3, low rT3, low FT4 and normal TSH) and generalized retardation of the cerebral and cerebellar myelination in brain magnetic resonance imaging. The clinical and laboratory findings led to sequencing of the SLC16A2/MCT8 gene, which identified a novel missense mutation in exon 5. The study of peripheral markers of thyroid function suggests a paradoxical state of thyrotoxicosis in some peripheral tissues. Our patient had a typical clinical presentation at birth but because of the rarity of his disease his diagnosis was not made until the age of 7. The delay can also be explained by the omission of the free T3 assay in the first thyroid evaluation performed. This case therefore highlights the possible benefit of including the T3 assay in the study of patients with severe psychomotor disability of unknown etiology, thus eliminating extra costs for unnecessary complementary diagnostic tests.

Copy number variation analysis of patients with intellectual disability from North-West Spain.

Intellectual disability (ID) is a complex and phenotypically heterogeneous neurodevelopmental disorder characterized by significant deficits in cognitive and adaptive skills, debuting during the developmental period. In the last decade, microarray-based copy number variation (CNV) analysis has been proved as a strategy particularly useful in the discovery of loci and candidate genes associated with these phenotypes and is widely used in the clinics with a diagnostic purpose. In this study, we evaluated the usefulness of two genome-wide high density SNP microarrays -Cytogenetics Whole-Genome 2.7M SNP array (n=126 patients; Group 1) and CytoScan High-Density SNP array (n=447 patients; Group 2)- in the detection of clinically relevant CNVs in a cohort of ID patients from Galicia (NW Spain). In 159 (27.7%) patients, we detected 186 rare exonic chromosomal imbalances, that were grouped into the following classes: Clinically relevant (67/186; 36.0%), of unknown clinical significance (93/186; 50.0%) and benign (26/186; 14.0%). The 67 pathogenic CNVs were identified in 64 patients, which means an overall diagnostic yield of 11.2%. Overall, we confirmed that ID is a genetically heterogeneous condition and emphasized the importance of using genome-wide high density SNP microarrays in the detection of its genetic causes. Additionally, we provided clinical and molecular data of patients with pathogenic or likely pathogenic CNVs and discussed the potential implication in neurodevelopmental disorders of genes located within these variants.

Manifestaciones articulares en enfermos de Lyme / Articular manifestations in patients with Lyme disease

Objetivos. Determinar el porcentaje de pacientes con clínica articular entre los enfermos de Lyme en el NO de España y conocer su evolución y respuesta al tratamiento. Pacientes. Se realizó un estudio retrospectivo (2006-2013) revisando las historias clínicas de los enfermos de Lyme con clínica articular. Se analizaron las manifestaciones clínicas, los datos de laboratorio, el tratamiento y la evolución de los enfermos. Resultados. Diecisiete de 108 pacientes confirmados como enfermos de Lyme (15,7%) presentaban clínica articular. De estos 17, el 64,7% presentó artritis, el 29,4% artralgias y el 5,9% bursitis. La rodilla fue la articulación más afectada. La clínica articular se asoció frecuentemente a manifestaciones neurológicas, dermatológicas o cardíacas. La mayoría de los pacientes estaban en fase iii. El 11,8% evolucionó a artritis crónica recidivante, aunque recibieron tratamiento adecuado. Conclusiones. En zonas con elevado riesgo de picadura por garrapatas, la presencia de clínica articular debe hacernos sospechar la posibilidad de una enfermedad de Lyme con objeto de establecer de forma precoz un tratamiento adecuado que evite secuelas (AU)

Objectives. To determine the percentage of Lyme patients with articular manifestations in NW Spain and to know their evolution and response to treatment. Patients. A retrospective study (2006-2013) was performed using medical histories of confirmed cases of Lyme disease showing articular manifestations. Clinical and laboratory characteristics, together with the treatment and evolution of the patients, were analysed. Results. Seventeen out of 108 LD confirmed patients (15.7%) showed articular manifestations. Regarding those 17 patients, 64.7%, 29.4% and 5.9% presented arthritis, arthralgia and bursitis, respectively. The knee was the most affected joint. Articular manifestations were often associated to neurological, dermatological and cardiac pathologies. Otherwise, most patients were in Stage III. The 11.8% of the cases progressed to a recurrent chronic arthritis despite the administration of an appropriate treatment. Conclusions. Lyme disease patients showing articular manifestations should be included in the diagnosis of articular affections in areas of high risk of hard tick bite, in order to establish a suitable and early treatment and to avoid sequels (AU)

Análisis retrospectivo sobre el efecto del estimulador vagal implantado en pacientes pediátricos con epilepsia refractaria / Retrospective analysis of the effect of a vagus nerve stimulator implanted in paediatric patients with refractory epilepsy

Introducción. El estimulador vagal es una alternativa terapéutica en los pacientes con epilepsia refractaria al tratamiento con fármacos antiepilépticos que no son candidatos a cirugía de resección. Objetivo. Analizar la eficacia del estimulador vagal en los pacientes pediátricos de nuestro centro. Pacientes y métodos. Conjunto de 13 pacientes implantados entre los años 2008 y 2013. Se registró la frecuencia de crisis previa a la implantación, al año, a los dos años y al final del seguimiento. Asimismo, se recogió el número de fármacos antiepilépticos utilizados, de forma cualitativa la mejoría conductual y el cambio en la intensidad de las crisis, así como la aparición de efectos secundarios y la retirada o no del dispositivo. Resultados. Al año, a los dos años y al final del seguimiento se había producido una reducción en el número de crisis del 61%, 66,7% y 69%, respectivamente, y uno de los pacientes se encontró libre de crisis a los dos años. Al final del seguimiento, un 23% de los que habían disminuido sus crisis había experimentado una reducción superior al 90%. De forma independiente al efecto sobre el número de crisis, el 77% de los pacientes presentó una mejoría en la intensidad y duración de las crisis, y ese mismo porcentaje mostró una mejoría conductual. Los efectos secundarios aparecieron en un 30,7% de los pacientes y fueron de intensidad leve. Conclusiones. A pesar del pequeño tamaño de la muestra, nuestros resultados indican que el estimulador vagal tiene una eficacia relevante en la población pediátrica farmacorresistente, tanto sobre la frecuencia e intensidad de las crisis como sobre la conducta (AU)

Introduction. The vagus nerve stimulator is a therapeutic alternative in patients with epilepsy which is refractory to treatment with antiepileptic drugs that are not candidates for surgical resection. Aim. To analyse the effectiveness of vagus nerve stimulator in the paediatric patients of our centre. Patients and methods. Set of 13 patients implanted between 2008 y 2013. It was registered the frequency of crises prior to implantation, after a year and at the end of the monitoring period. As well, it was recorded the number of antiepileptic drugs used and in a qualitative way the behavioural improvement and the change in the intensity of the crises, besides the apparition of secondary effects and the removal or not of the device. Results. After a year, two years and at the end of the monitoring period it has been a fall in the number of crises about of 61%, 66.7% y 69% respectively, finding one patient free of crises after two years. At the end of the monitoring period, the 23% of those who had reduced their crises had experimented a reduction over 90%. Independently the effect on the number of crises, 77% of the patients presented an improvement in the intensity and the length of the crises, the same average showed a behavioural improvement. The secondary effects appeared in a 30.7% of the patients, being of mild intensity. Conclusions. Despite the small size of our sample, our results shows that the vagus nerve stimulator has a relevant efficacy over the pediatric drug resistant population, as much in the frequency and intensity of the crises, as over the behaviour (AU)

Articular manifestations in patients with Lyme disease. / Manifestaciones articulares en enfermos de Lyme.

OBJECTIVES: To determine the percentage of Lyme patients with articular manifestations in NW Spain and to know their evolution and response to treatment. PATIENTS: A retrospective study (2006-2013) was performed using medical histories of confirmed cases of Lyme disease showing articular manifestations. Clinical and laboratory characteristics, together with the treatment and evolution of the patients, were analysed. RESULTS: Seventeen out of 108 LD confirmed patients (15.7%) showed articular manifestations. Regarding those 17 patients, 64.7%, 29.4% and 5.9% presented arthritis, arthralgia and bursitis, respectively. The knee was the most affected joint. Articular manifestations were often associated to neurological, dermatological and cardiac pathologies. Otherwise, most patients were in Stage III. The 11.8% of the cases progressed to a recurrent chronic arthritis despite the administration of an appropriate treatment. CONCLUSIONS: Lyme disease patients showing articular manifestations should be included in the diagnosis of articular affections in areas of high risk of hard tick bite, in order to establish a suitable and early treatment and to avoid sequels.

Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene.

Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern).

Caracterización molecular y descripción fenotípica de dos casos con aberraciones cromosómicas recíprocas en la región de los síndromes de microdeleción/microduplicación 3q29 / Molecular characterisation and phenotypic description of two patients with reciprocal chromosomal aberrations in the region of the 3q29 microdeletion/microduplication syndromes

Introducción. Los síndromes de microdeleción y microduplicación 3q29 se caracterizan por una marcada heterogeneidad fenotípica, y el retraso del desarrollo y la discapacidad intelectual de grado leve-moderado son las manifestaciones clínicas más frecuentes. Casos clínicos. Dos pacientes con aberraciones cromosómicas recíprocas en la región 3q29. La paciente con la microdeleción 3q29 presenta dificultades de aprendizaje, microcefalia límite, dismorfismo facial leve, déficit atencional e impulsividad, y rasgos ansiosos y obsesivos. El paciente con la microduplicación 3q29 recíproca presenta dificultades de aprendizaje, dismorfismo facial leve y un perfil conductual disruptivo no asociado previamente con esta duplicación. Conclusión. Se comparan los fenotipos de estos pacientes y se revisa la bibliografía de pacientes pediátricos con microdeleciones y microduplicaciones 3q29 (AU)

Introduction. The 3q29 microdeletion and microduplication syndromes are characterised by a marked phenotypic heterogeneity, and delayed development and a mild-moderate degree of intellectual disability are the most frequent clinical manifestations. Case reports. Two patients with reciprocal chromosomal aberrations in the 3q29 region. The patient with 3q29 microdeletion presented learning disabilities, borderline microcephaly, mild facial dysmorphism, attentional deficit and impulsiveness, and anxious and obsessive traits. The patient with reciprocal 3q29 microduplication presented learning disabilities, mild facial dysmorphism and a disruptive behavioural profile that was not previously associated with this duplication. Conclusions. The phenotypes of these patients are compared and the literature about paediatric patients with 3q29 microdeletions and microduplications is reviewed (AU)

Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder.

The few proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes that have been published to date are variable in type, size and breakpoints and, therefore, encompass different chromosome bands and genes, making the establishment of genotype-phenotype correlations a challenging task. Here, microarray-based copy number analysis allowed us the detection of two novel and partially overlapping deletions in two unrelated families. In Family 1, a 4q13.1-q13.2 deletion of 3.84 Mb was identified in a mother with mild intellectual disability and in her two children, both with mild intellectual disability and attention deficit hyperactivity disorder. In Family 2, a de novo 4q13.2-q13.3 deletion of 6.81 Mb was detected in a female patient, born to unaffected parents, with a diagnosis of mild intellectual disability, behavioral disorder and facial dysmorphism. The shortest region of overlap between these two aberrations is located at chromosome 4q13.2 and includes 17 genes amongst of which we suggest UBA6 (ubiquitin-like modifier-activating enzyme 6) as a strong candidate gene for these phenotypes.

Deleción en el gen RPS6KA3 en una mujer con un fenotipo clásico del síndrome de Coffin-Lowry incluyendo episodios de caída inducidos por estímulo / Deletion of the RPS6KA3 gene in a female with a classical phenotype of Coffin-Lowry syndrome including stimulus-induced drop attacks

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Epidemiología de la enfermedad de Lyme en un área sanitaria del noroeste de España / Epidemiology of Lyme disease in a healthcare area in north-west Spain

Objetivo: Valorar la influencia de algunos factores de riesgo sobre la tasa de incidencia de la enfermedad Lyme y describir las principales manifestaciones clínicas de esta. Métodos: Se realizó un estudio retrospectivo sobre esta enfermedad (2006-2013), en una zona del noroeste de España, incluyendo solo los pacientes que cumplían los criterios de vigilancia epidemiológica de los Centers for Disease Control and Prevention de los Estados Unidos. Resultados: La tasa de incidencia varió entre 2,64 y 11,61 por 100.000 habitantes y año. Hubo diferencias significativas respecto al hábitat, la edad y la zona de residencia. Los pacientes presentaron manifestaciones neurológicas (67,59%), dermatológicas (47,22%), reumatológicas (15,74%) o cardiacas (13,88%), solas o combinadas. Conclusiones: El incremento de esta enfermedad en el noroeste de España y las diferencias observadas entre las distintas zonas de una misma área sanitaria hacen necesario plantear estudios epidemiológicos que permitan aumentar el índice de sospecha diagnóstica e implementar medidas de prevención eficaces (AU)

Objective: To evaluate the influence of some risk factors on the incidence rate of Lyme disease and the main clinical manifestations. Methods: A retrospective study of Lyme disease (2006-2013) was performed in north-west Spain; we included only patients who fulfilled the epidemiological surveillance criteria defined by the Centers for Disease Control and Prevention. Results: The incidence rate varied between 2.64 and 11.61/100,000 inhabitants/year. Significant differences were found in relation to habitat, age and area of residence. Patients showed neurological (67.59%), dermatological (47.22%), rheumatological (15.74%) and cardiac (13.88%) manifestations, alone or combined. Conclusions: Due to the increase of the disease in north-west Spain and the differences observed between the different areas, epidemiological studies are needed that increase the index of diagnostic suspicion and lead to the implementation of effective prevention measures (AU)

Clinical characterization of a male patient with the recently described 8q21.11 microdeletion syndrome.

The 8q21.11 microdeletion syndrome (OMIM # 614230) has been recently described and is primarily characterized by intellectual disability and facial dysmorphism. We describe here a male patient of 9 years 9 months of age with moderate intellectual disability and dysmorphic facial features. A high resolution copy number variation analysis, performed with the Affymetrix Cytogenetics Whole-Genome 2.7 M SNP array, allowed the identification of a heterozygous 7.069 Mb microdeletion at chromosome 8q21.11-q21.13. Clinical comparison of our patient with literature shows many similarities. However, the whole facial appearance of our patient, especially the elongated rather than rounded face and the absence of a wide nasal bridge and epicanthal folds, confers him a phenotype similar only to a subset, but not to the majority, of the hitherto described patients.

A maternally inherited 16p13.11-p12.3 duplication concomitant with a de novo SOX5 deletion in a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features.

We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant.

[Epidemiology of Lyme disease in a healthcare area in north-west Spain]. / Epidemiología de la enfermedad de Lyme en un área sanitaria del noroeste de España.

OBJECTIVE: To evaluate the influence of some risk factors on the incidence rate of Lyme disease and the main clinical manifestations. METHODS: A retrospective study of Lyme disease (2006-2013) was performed in north-west Spain; we included only patients who fulfilled the epidemiological surveillance criteria defined by the Centers for Disease Control and Prevention. RESULTS: The incidence rate varied between 2.64 and 11.61/100,000 inhabitants/year. Significant differences were found in relation to habitat, age and area of residence. Patients showed neurological (67.59%), dermatological (47.22%), rheumatological (15.74%) and cardiac (13.88%) manifestations, alone or combined. CONCLUSIONS: Due to the increase of the disease in north-west Spain and the differences observed between the different areas, epidemiological studies are needed that increase the index of diagnostic suspicion and lead to the implementation of effective prevention measures.

Síndrome de Dravet y enfermedad mitocondrial, ¿patologías comórbidas? / Dravet syndrome and mitochondrial disease, are they comorbid pathologies?

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