Novel mutations in the KCNJ10 gene associated to a distinctive ataxia, sensorineural hearing loss and spasticity clinical phenotype.

KCNJ10 encodes the inward-rectifying potassium channel (Kir4.1) that is expressed in the brain, inner ear, and kidney. Loss-of-function mutations in KCNJ10 gene cause a complex syndrome consisting of epilepsy, ataxia, intellectual disability, sensorineural deafness, and tubulopathy (EAST/SeSAME syndrome). Patients with EAST/SeSAME syndrome display renal salt wasting and electrolyte imbalance that resemble the clinical features of impaired distal tubular salt transport in Gitelman's syndrome. A key distinguishing feature between these two conditions is the additional neurological (extrarenal) manifestations found in EAST/SeSAME syndrome. Recent reports have further expanded the clinical and mutational spectrum of KCNJ10-related disorders including non-syndromic early-onset cerebellar ataxia. Here, we describe a kindred of three affected siblings with early-onset ataxia, deafness, and progressive spasticity without other prominent clinical features. By using targeted next-generation sequencing, we have identified two novel missense variants, c.488G>A (p.G163D) and c.512G>A (p.R171Q), in the KCNJ10 gene that, in compound heterozygosis, cause this distinctive EAST/SeSAME phenotype in our family. Electrophysiological characterization of these two variants confirmed their pathogenicity. When expressed in CHO cells, the R171Q mutation resulted in 50% reduction of currents compared to wild-type KCNJ10 and G163D showed a complete loss of function. Co-expression of G163D and R171Q had a more pronounced effect on currents and membrane potential than R171Q alone but less severe than single expression of G163D. Moreover, the effect of the mutations seemed less pronounced in the presence of Kir5.1 (encoded by KCNJ16), with whom the renal Kir4.1 channels form heteromers. This partial functional rescue by co-expression with Kir5.1 might explain the lack of renal symptoms in the patients. This report illustrates that a spectrum of disorders with distinct clinical symptoms may result from mutations in different parts of KCNJ10, a gene initially associated only with the EAST/SeSAME syndrome.

Selección del mejor lugar de estimulación tras cirugía cardiaca evaluando la asincronía con strain tras diferentes estimulaciones / Selecting the best site for pacing leads after cardiac surgery by evaluating the asynchrony of myocardial deformation observed with different pacing sites

Introducción y objetivos. Implantar electrodos transitorios en ventrículo derecho (VD) tras cirugía cardiaca es habitual. El objetivo es estudiar en pacientes intervenidos el efecto de la estimulación en diferentes localizaciones ventriculares en la sincronía, analizando la deformación miocárdica (strain), y en la eficacia cardiaca. Métodos. En 19 pacientes se midió la asincronía interventricular (diferencia en el tiempo al comienzo del strain entre VD y ventrículo izquierdo [VI]: TE DI) y la intraventricular (desviación estándar [TE DE] y máxima diferencia en el tiempo de comienzo del strain en las seis caras del VI [TE MD]). Estas estimaciones y el gasto cardiaco (GC) mediante Doppler se determinaron tras la estimulación en VD en tres diferentes segmentos del VI. Resultados. La estimulación en VD fue la que más aumentó los parámetros de asincronía respecto al estudio basal: TE DI, 59,8 ± 40,5 frente a 28,23 ± 56,9 ms (p = 0,002); TE DE, 53,2 ± 34,4 frente a 36,6 ± 34,9 ms (p = 0,007); TE MD, 135,3 ± 82,9 frente a 90,5 ± 87,4 ms (p = 0,007). La estimulación en VI produjo menos asincronía (estimulación en segmento anterior del VI: TE DI, 17,2 ± 53,8 ms; TE DE, 35,8 ± 17,9 ms; TE MD, 91,3 ± 45,2 ms (sin significación estadística respecto a basal). El GC tras la estimulación en VD fue menor que tras estimulación en la cara anterior del VI: 4,36 ± 1 frente a 4,7 ± 1 (p = 0,001). Conclusiones. La estimulación en VI produce menos asincronía que en VD. Asimismo, la estimulación en la cara anterior del VI consigue mayor GC que la estimulación en VD. Estos datos indican que se debería modificar la localización de los electrodos transitorios tras cirugía cardiaca (AU)

Introduction and objectives. After cardiac surgery, temporary pacing leads are routinely implanted in the right ventricle (RV). The objective was to investigate the effect of different ventricular pacing locations on cardiac synchrony (by evaluating myocardial deformation, or strain) and efficiency in patients undergoing cardiac surgery. Methods. Interventricular asynchrony (i.e. the difference in the time of onset of deformation between right and left ventricles; TE-R/L) and intraventricular asynchrony (i.e. the standard deviation and maximum difference in the time of onset of deformation in six segments of the left ventricle [LV]; TE-SD and TE-MD, respectively) were assessed in 19 patients. Doppler echocardiography was used to evaluate these parameters and cardiac output after pacing in the RV and in three different LV segments. Results. Pacing in the RV resulted in the greatest increases in asynchrony parameters from baseline: TE- R/L 59.8 ms (standard deviation [SD] 40.5 ms) vs. 28.23 ms (SD 56.9 ms), P=.002; TE-SD 53.2 ms (SD 34.4 ms) vs. 36.6 ms (SD 34.9 ms), P=.007; and TE-MD 135.3 ms (SD 82.9 ms) vs. 90.5 ms (SD 87.4 ms), P=.007. Pacing in the LV resulted in less asynchrony: for anterior LV pacing, TE-R/L was 17.2 ms (SD 53.8 ms), TE-SD was 35.8 ms (SD 17.9 ms), and TE-MD was 91.3 ms (SD 45.2). The change from baseline was not significant. Cardiac output was lower after RV pacing than after anterior LV pacing: 4.36 (SD 1) vs. 4.70 (SD 1); P=.001. Conclusions. Pacing in the LV produced less asynchrony than RV pacing. In addition, anterior LV pacing resulted in a higher cardiac output than RV pacing. These findings suggest that the location normally used for temporary leads after cardiac surgery should be changed (AU)

Selecting the best site for pacing leads after cardiac surgery by evaluating the asynchrony of myocardial deformation observed with different pacing sites.

INTRODUCTION AND OBJECTIVES: After cardiac surgery, temporary pacing leads are routinely implanted in the right ventricle (RV). The objective was to investigate the effect of different ventricular pacing locations on cardiac synchrony (by evaluating myocardial deformation, or strain) and efficiency in patients undergoing cardiac surgery. METHODS: Interventricular asynchrony (i.e. the difference in the time of onset of deformation between right and left ventricles; Tε-R/L) and intraventricular asynchrony (i.e. the standard deviation and maximum difference in the time of onset of deformation in six segments of the left ventricle [LV]; Tε-SD and Tε-MD, respectively) were assessed in 19 patients. Doppler echocardiography was used to evaluate these parameters and cardiac output after pacing in the RV and in three different LV segments. RESULTS: Pacing in the RV resulted in the greatest increases in asynchrony parameters from baseline: Tε-R/L 59.8 ms (standard deviation [SD] 40.5 ms) vs. 28.23 ms (SD 56.9 ms), P=.002; Tε-SD 53.2 ms (SD 34.4 ms) vs. 36.6 ms (SD 34.9 ms), P=.007; and Tε-MD 135.3 ms (SD 82.9 ms) vs. 90.5 ms (SD 87.4 ms), P=.007. Pacing in the LV resulted in less asynchrony: for anterior LV pacing, Tε-R/L was 17.2 ms (SD 53.8 ms), Tε-SD was 35.8 ms (SD 17.9 ms), and Tε-MD was 91.3 ms (SD 45.2). The change from baseline was not significant. Cardiac output was lower after RV pacing than after anterior LV pacing: 4.36 (SD 1) vs. 4.70 (SD 1); P=.001. CONCLUSIONS: Pacing in the LV produced less asynchrony than RV pacing. In addition, anterior LV pacing resulted in a higher cardiac output than RV pacing. These findings suggest that the location normally used for temporary leads after cardiac surgery should be changed.

An XX male with an intratubular undifferentiated germ cell neoplasia.

OBJECTIVE: To report a case of a 46,XX male with an intratubular undifferentiated germ cell neoplasia within an extra-abdominal gonad. DESIGN: Case report. SETTING: Molecular, cytogenetic, pathologic, and clinical units of three tertiary hospitals. PATIENT(S): A male with ambiguous genitalia at birth and descended testes observed in a pediatric endocrinology setting. INTERVENTION(S): Physical examination, hormonal assays, cytogenetic investigation, molecular analysis, surgical intervention for biopsies and bilateral orchiectomy, and pathologic evaluation. MAIN OUTCOME MEASURE(S): Pathologic evaluation with immunostaining for placental alkaline phosphatase and C-kit. RESULT(S): Conventional chromosome analysis revealed a 46,XXq- karyotype, and fluorescence in situ hybridization experiments with the SRY probe found a signal at the short arm of the deleted X chromosome. Molecular analysis indicated the presence of a portion of the short arm of the Y chromosome including the proto-oncogene TSPY. Pathologic evaluation of the gonads revealed an intratubular undifferentiated germ cell neoplasia. CONCLUSION(S): This is the first case of a 46,XX male with descended testes in whom an intratubular undifferentiated germ cell neoplasia developed. When proposals of management in this subgroup of disorders of sexual differentiation are formulated, the risk of germ cell malignancy must be taken into account.

Role of insulin-like growth factor I signaling in neurodegenerative diseases.

Disturbed trophic support to neurons has long been considered a potential mechanism in neurodegeneration. Recent evidence indicates that intracellular trophic signaling may be compromised in several neurodegenerative diseases. Changes in the levels of insulin-like growth factor I (IGF-I), a trophic hormone with multiple neuroprotective actions, have recently been observed in several human neurodegenerative illnesses. Therefore analysis of IGF-I pathways could help provide greater insight into trophic disturbances to neurons. However, neurodegenerative diseases with similar clinical manifestations show either high or low levels of circulating IGF-I. This apparently puzzling observation can be explained if we consider that IGF-I input to target neurons is disrupted by either lower IGF-I availability or by reduced cell sensitivity to IGF-I. The latter disturbance may be associated with high IGF-I levels. We hypothesize that in the majority of neurodegenerative diseases compromised IGF-I support to neurons emerges as part of the pathological cascade during the degenerative process and contributes to neuronal demise. In addition, loss of IGF-I input to specific neuronal populations might be the cause of a small group of neurodegenerative diseases.