Synaptic defects in type I spinal muscular atrophy in human development.

Childhood spinal muscular atrophy is an autosomal recessive neuromuscular disorder caused by alterations in the Survival Motor Neuron 1 gene that triggers degeneration of motor neurons within the spinal cord. Spinal muscular atrophy is the second most common severe hereditary disease of infancy and early childhood. In the most severe cases (type I), the disease appears in the first months of life, suggesting defects in fetal development. However, it is not yet known how motor neurons, neuromuscular junctions, and muscle interact in the neuropathology of the disease. We report the structure of presynaptic and postsynaptic apparatus of the neuromuscular junctions in control and spinal muscular atrophy prenatal and postnatal human samples. Qualitative and quantitative data from confocal and electron microscopy studies revealed changes in acetylcholine receptor clustering, abnormal preterminal accumulation of vesicles, and aberrant ultrastructure of nerve terminals in the motor endplates of prenatal type I spinal muscular atrophy samples. Fetuses predicted to develop milder type II disease had a similar appearance to controls. Postnatal muscle of type I spinal muscular atrophy patients showed persistence of the fetal subunit of acetylcholine receptors, suggesting a delay in maturation of neuromuscular junctions. We observed that pathology in the severe form of the disease starts in fetal development and that a defect in maintaining the initial innervation is an early finding of neuromuscular dysfunction. These results will improve our understanding of the spinal muscular atrophy pathogenesis and help to define targets for possible presymptomatic therapy for this disease.

Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy.

We studied spinal muscular atrophy (SMA) during human development to identify possible delays or alterations in fetal movements detectable by ultrasound. We evaluated 29 pregnancies at risk for severe SMA performing 2D-ultrasound around 11-14 weeks, prior to prenatal molecular testing of the SMN1 gene. We charted the occurrence of generalized body movements, isolated movements of arms and legs, head movements, startle and hiccup. Fetuses were diagnosed as healthy (n=12), carriers (n=10) or affected (n=7) according to the SMN1 molecular testing results obtained. SMN2 copies were also tested in the seven affected fetuses, six of whom showed two SMN2 copies and one a unique SMN2 copy. The movements under study were observed in all recordings, regardless of group and the SMN2 copies. At the gestational age examined, we did not observe a qualitative early limitation of movements in fetuses with SMA, even in cases predicted to develop a severe neonatal form.

[Information systems in health and health indicators: an integrating perspective]. / Sistemas de Información en Salud e indicadores de salud: una perspectiva integradora.

Health Information Systems (HIS) are the core support to decision-making in health organizations. Within HIS, health indicators (HI) reflect, numerically, events measured in the health-illness continuum. The integrated health information system is intended to standardize, integrate and organize all the information available in health information systems through an accessible and secure repository, and to conveniently distribute information for decision-making. To standardize information it is necessary to define standards and semantic information to enable us to identify concepts and relate them uniquely to each other. The definition of a catalog of entities (DEA) with concepts, attributes and domains will enable the configuration of the information system, so there will be a catalog of entities (concepts of information and domains). Based on operational systems, analytical systems enabling management and strategy in the management of organizations will be built. The maximum level of analysis is the Balanced Score Card (BSC), which is established as the strategic tool for managers. It is necessary for the organization an integrated information system to plan, manage, evaluate and therefore provide managers with a decision tool for strategic and tactical decision-making in short and medium term.

Sistemas de Información en Salud e indicadores de salud: una perspectiva integradora / Information systems in health and health indicators: an integrating perspective

Los Sistemas de Información en Salud (SIS) constituyen el núcleo principal de soporte para la toma de decisiones en las instituciones sanitarias. Dentro de los SIS, los indicadores de salud (IS) reflejan numéricamente los acontecimientos medidos en el continuum salud-enfermedad. El sistema integrado de información en salud tiene por objetivo normalizar, integrar y organizar toda la información en salud disponible en sus sistemas de información, en un repositorio accesible y seguro, así como la distribución de la información de la forma más conveniente, para facilitar la toma de decisiones. Para normalizar la información hace falta definir estándares de información y semánticos que nos permitan identificar los conceptos de forma unívoca y relacionarlos entre sí. La definición de un catálogo de entidades (DEA) detallando conceptos, atributos y dominios, facilitará la configuración del sistema de información; por lo tanto, se dispondrá de un catálogo de entidades (conceptos de información y dominios de la misma). A partir de los sistemas operacionales se construirán los sistemas analíticos que permitirán constituir instrumentos que faciliten la gestión y la estrategia de la dirección en las organizaciones. El máximo nivel de análisis constituye el cuadro de mando integral (CMI) o Balanced Score Card (BSC), que se constituye como la herramienta estratégica para la dirección. La organización ha de disponer de un sistema integrado de información que permita planificar, gestionar, evaluar y, por lo tanto, facilitar a la dirección un instrumento de decisión táctico y estratégico para la toma de decisiones a corto y medio plazo (AU)

Health Information Systems (HIS) are the core support to decision-making in health organizations. Within HIS, health indicators (HI) reflect, numerically, events measured in the health-illness continuum. The integrated health information system is intended to standardize, integrate and organize all the information available in health information systems through an accessible and secure repository, and to conveniently distribute information for decision-making. To standardize information it is necessary to define standards and semantic information to enable us to identify concepts and relate them uniquely to each other. The definition of a catalog of entities (DEA) with concepts, attributes and domains will enable the configuration of the information system, so there will be a catalog of entities (concepts of information and domains). Based on operational systems, analytical systems enabling management and strategy in the management of organizations will be built. The maximum level of analysis is the Balanced Score Card (BSC), which is established as the strategic tool for managers. It is necessary for the organization an integrated information system to plan, manage, evaluate and therefore provide managers with a decision tool for strategic and tactical decision-making in short and medium term (AU)

Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene.

Spinal muscular atrophy (SMA) is caused by mutations in the SMN1 gene. We have studied the molecular pathology of SMA in 745 unrelated Spanish patients using PCR-RFLP, SMN gene dosage analysis, linkage studies, long-range PCR and direct sequencing. Our systematic approach allowed us to complete genetic testing and risk assessment in 736 SMA patients (98.8%). Females were more frequently affected by the acute form of the disease (type I), whereas chronic forms (type II-III) predominated in males (p<0.008). Absence of the SMN1 gene was detected in 671 patients (90%), and hybrid SMN1-SMN2 genes were observed in 37 cases (5%). Furthermore, we detected 13 small mutations in 28 patients (3.8%), four of which were previously identified in other populations (c.91dupT; c.770_780dup11; p.Tyr272Cys and p.Thr274Ile), while five mutations were found to date only in Spanish patients (c.399_402delAGAG, p.Ile116Phe, p.Gln136Glu, c.740dupC and c.834+2T>G). The c.399_402delAGAG mutation accounted for 1.9% of all Spanish SMA patients. Finally, we discovered four novel mutations: c.312dupA, c.411delT, p.Trp190X and p.Met263Thr. Our results confirm that most SMA cases are due to large genetic rearrangements in the repetitive region of the SMA locus, resulting in absence-dysfunction of the SMN1 gene. By contrast, ancestrally inherited small mutations are responsible for only a small number of cases. Four prevalent changes in exons 3 and 6 (c.399_402delAGAG; c.770_780dup11; p.Tyr272Cys; p.Thr274Ile) accounted for almost 70% of our patients with these subtle mutations. An SMN-SMN dimer model featuring tight hydrophobic-aromatic interactions is proposed to explain the impact of mutations at the C-terminal end of the protein.

Marker and real-time quantitative analyses to confirm hemophilia B carrier diagnosis of a complete deletion of the F9 gene.

Approximately 3% of hemophilia B patients have major deletions in the F9 gene, half of which are complete. Marker and quantitative PCR analyses were employed for carrier diagnosis in a family of a mentally retarded hemophilia B patient with a total deletion of the F9 gene and neighbor genes. Both methodologies allowed the confirmation of carrier or non-carrier status.

Two independent mutations of the SMN1 gene in the same spinal muscular atrophy family branch: lessons for carrier diagnosis.

PURPOSE: We present the results of carrier studies in 33 relatives of the paternal branch of a spinal muscular atrophy patient with homozygous absence of the SMN1 gene. METHODS AND RESULTS: Once linkage and quantitative analyses were performed, a number of first-, second- and third-degree relatives were identified as carriers given that they shared the at-risk haplotype and showed one SMN1 copy. In the fourth-degree relatives, linkage analysis demonstrated discordance with the quantitative results because the members with one copy were carriers of the mutation, but in a different haplotype background. We concluded that two independent mutations were present in this branch of the family. Furthermore, the combination of both methods of analysis allowed us to identify carriers with two SMN1 genes in one chromosome and none in the remaining chromosome. CONCLUSIONS: Carrier testing in spinal muscular atrophy should be performed by employing both quantitative and linkage analyses in order to guarantee accurate carrier identification.

Should gamete donors be tested for spinal muscular atrophy?

OBJECTIVE: To report two cases of spinal muscular atrophy (SMA) after artificial insemination and to discuss why genetic screening of the disease may be justified in gamete donors. DESIGN: Case report. SETTING: Academic departments of genetics and obstetrics. PATIENT(S): A 32-year-old woman with two successive assisted pregnancies. INTERVENTION(S): Molecular studies of the SMN1 (survival motor neuron), the determining gene of the disease. MAIN OUTCOME MEASURE(S); Prenatal testing to detect a homozygous deletion of the SMN1 gene; carrier diagnosis by quantitative analysis to detect a single or double dose of exon 7 in the SMN1 gene. RESULT(S): After a first assisted pregnancy, an SMA child with a homozygous deletion of the SMN1 gene was born. In the second assisted pregnancy, using sperm from a different donor, a fetus with a homozygous deletion of SMN1 was detected. Carrier status in the donor was confirmed by a single dose of SMN1 in the quantitative analysis. CONCLUSION(S): Genetic screening of SMA carrier status by quantitative analysis of the SMN1 gene should be performed in gamete donors when the recipient is a known carrier. Cost-benefit analysis should be made to consider the inclusion of the test in prospective gamete donor programs.