Reliability of home-based, motor function measure in hereditary neuromuscular diseases.

Objective To evaluate the reliability of the motor function measure (MFM) scale in the assessment of disease severity and progression when administered at home and clinic and assess its correlation with the Paediatric Outcomes Data Collection Instrument (PODCI). Methods In this prospective study, two assessors rated children with hereditary neuromuscular diseases (HNMDs) using the MFM at the clinic and then 2 weeks later at the patients' home. Intraclass correlation coefficient (ICC) was calculated for the reliability of the MFM and its domains. The reliability of each item was assessed and the correlation between MFM and three domains of PODCI was evaluated. Results A total of 48 children (5-17 years of age) were assessed in both locations and the MFM scale demonstrated excellent inter-rater reliability (ICC, 0.98). Weighted kappa ranged from excellent to poor. Correlation of the home-based MFM with the PODCI domain 'basic mobility and transfers' was excellent, with the 'upper extremity' domain was moderate, but there was no correlation with the 'happiness' domain. Conclusion The MFM is a reliable tool for assessing patients with HNMD when used in a home-based setting.

[The amygdala and its relation to autism, behavioural disorders and other neurodevelopmental disorders]. / La amígdala y su relación con el autismo, los trastornos conductuales y otros trastornos del neurodesarrollo.

The amygdala is related with the recognition of the emotional meaning of stimuli, long-term memory, the orientation of social stimuli and the perception of gaze orientation. It plays a fundamental role in the recognition of faces, especially those expressing fear, and makes it possible to comprehend different emotional states, which will facilitate an appropriate social cognition. Dysfunctions of the amygdala have been associated to a number of different neurodevelopmental disorders as well as neurocognitive and behavioural disorders in specific neurogenetic entities. A number of studies focused on the amygdalic complex have allowed researchers to understand many pathophysiological aspects and to formulate new hypotheses regarding their origins. Given that the disorders or conditions in which the role of the amygdala has been evoked are becoming increasingly more extensive, this article refers the reader to those that have aroused the most interest in recent years. Thus, they can be divided into two groups: developmental and behavioural disorders (autism, anxiety disorders, bipolar disorder, alexithymia and anorexia nervosa) and specific neurogenetic entities (fragile X, Rett, Prader-Willi and Williams syndromes), in which structural or dysfunctional alterations have been observed that may be related with their neurocognitive and behavioural symptoms. It is important to remember that the amygdala is a highly connected structure that forms truly functional networks and has been associated to different disorders with varied explanations and includes several different pathophysiological phenomena. Its role must not, therefore, be simplified in a reductionistic manner, but also placed upon a hierarchy of dysfunctions in other areas that interact with it.

TITLE: La amigdala y su relacion con el autismo, los trastornos conductuales y otros trastornos del neurodesarrollo.La amigdala esta relacionada con el reconocimiento del significado afectivo del estimulo, la memoria a largo plazo, la orientacion del estimulo social y la percepcion de orientacion de la mirada. Desempeña un papel fundamental en el reconocimiento de caras, en especial la de temor, y permite la comprension de diversos estados emocionales, los cuales facilitaran una adecuada cognicion social. Disfunciones de la amigdala se han relacionado con diversos trastornos del neurodesarrollo y con alteraciones neurocognitivas y conductuales en entidades neurogeneticas especificas. Multiples estudios focalizados en el complejo amigdalino han permitido comprender muchos aspectos fisiopatologicos y formular nuevas hipotesis en relacion con su genesis. Dado que los trastornos o entidades en que se ha evocado el papel de la amigdala son cada vez mas extensos, este articulo remite a aquellos que han despertado mayor interes en los ultimos años, dividiendolos en dos grupos: trastornos del desarrollo y conductuales (autismo, trastornos de ansiedad, trastorno bipolar, alexitimia y anorexia nerviosa), y entidades neurogeneticas especificas (sindromes del cromosoma X fragil, Rett, Prader-Willi y Williams), en las cuales se han comprobado alteraciones estructurales o disfunciones que pueden relacionarse con la sintomatologia neurocognitiva y conductual de estas. Es importante recordar que la amigdala es una estructura altamente conectada que conforma verdaderas redes funcionales, se ha asociado a diversos trastornos cuya explicacion es variada e incluye diversos fenomenos fisiopatologicos, por lo que no debe simplificarse de una forma reduccionista su papel, sino tambien jerarquizar disfunciones de otras areas que interactuan con ella.

[Hypotonic syndrome in the newborn infant]. / Síndrome hipotónico del lactante.

Hypotonia is understood to refer to a pronounced decrease in muscle tone that affects normal motor development and that may affect the axial muscles as well as those of the limbs and, sometimes, the face. It is a very challenging clinical picture because it consists in a fairly wide range of conditions that affect different areas of the central and peripheral nervous system and may be the expression of pathologies that can be either benign or of an uncertain prognosis. These cover myopathies, metabolic disorders, diseases based on genetic causes, pathologies affecting the endocrine glands and progressive or chronic diseases, among other aetiologies. The important development of medicine today has made a number of tools available to the examiner with which to refine or pronounce a diagnosis. Such instruments include the developments achieved in genetic research, together with studies conducted in imaging and optical and electronic microscopy. However, in spite of having all this material available for use, it is still the clinical features that allow a rational use to be made of these advances to be able to point towards the possible causation, topographic location and developmental control. It is useful, for the diagnostic approach and the use of auxiliary methods, to know the topographic location of the disorder, whether it is situated in the brain, the cerebellum, the stem, the spinal cord, the peripheral nerves, the myoneural junction or the muscle.

TITLE: Sindrome hipotonico del lactante.Entendemos como hipotonia la disminucion acentuada del tono muscular que afecta al desarrollo motor normal y que puede afectar a la musculatura axial y de los miembros y, en ocasiones, a la facial. Es un cuadro que genera un gran desafio ya que, en su universo, comprende una serie bastante amplia de condiciones que afectan a distintas areas del sistema nervioso, tanto central como periferico, y que pueden ser expresion de patologias de corte benigno o de pronostico reservado. Abarcan miopatias, alteraciones metabolicas, enfermedades de corte genetico, endocrinopatias y enfermedades progresivas o cronicas, entre otras causas. El gran desarrollo de la medicina actual ha logrado poner a disposicion del examinador multiples herramientas que permiten afinar o aseverar el diagnostico, entre las que destacan los desarrollos logrados en las investigaciones geneticas, asi como los estudios de imagenes y de microscopia optica y electronica. Sin embargo, pese a toda esta oferta, sigue siendo la clinica la que permite usar racionalmente estos avances y orientar hacia la posible etiologia, localizacion topografica y control evolutivo. Es de utilidad, para el enfoque diagnostico y la utilizacion de metodos auxiliares, que la localizacion topografica de la afectacion ya este esta ubicada en el cerebro, el cerebelo, el tallo, la medula, los nervios perifericos, la union mioneural o el musculo.

Ciliary biology: understanding the cellular and genetic basis of human ciliopathies.

Motile cilia have long been known to play a role in processes such as cell locomotion and fluid movement whereas the functions of primary cilia have remained obscure until recent years. To date, ciliary dysfunction has been shown to be causally linked to a number of clinical manifestations that characterize the group of human disorders known as ciliopathies. This classification reflects a common or shared cellular basis and implies that it is possible to associate a series of different human conditions with ciliary dysfunction, which allows gaining insight into the cellular defect in disorders of unknown etiology solely based on phenotypic observations. Furthermore, to date we know that the cilium participates in a number of biological processes ranging from chemo- and mechanosensation to the transduction of a growing list of paracrine signaling cascades that are critical for the development and maintenance of different tissues and organs. Consequently, the primary cilium has been identified as a key structure necessary to regulate and maintain cellular and tissue homeostasis and thus its study is providing significant information to understand the pathogenesis of the different phenotypes that characterize these human conditions. Finally, the similarities between different ciliopathies at the phenotypic level are proving to be due to their shared cellular defect and also their common genetic basis. To this end, recent studies are showing that mutations in a given ciliary gene often appear involved in the pathogenesis of more than one clinical entity, complicating their genetic dissection, and hindering our ability to generate accurate genotype-phenotype correlations.

Clinical and biological phenotype of a patient with familial glucocorticoid deficiency type 2 caused by a mutation of melanocortin 2 receptor accessory protein.

Familial glucocorticoid deficiency (FGD) is a rare inherited disorder which may be caused by mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) named FGD type 1 or by mutations in the MC2R accessory protein (MRAP) named FGD type 2. We report the case history of a male patient from birth until adulthood with FGD type 2, confirmed by a mutation of the MRAP gene.

New diseases derived or associated with the tight junction.

The space between neighboring epithelial cells is sealed by the tight junction (TJ). When this seal is leaky, such as in the proximal tubule of the kidney or the gallbladder, substances may cross the epithelium between the cells (paracellular pathway). Yet, when TJs are really hermetic, as is the case in the epithelium of the urinary bladder or the colon, substances can mainly cross the epithelium through the transcellular pathway. The structure of the TJ involves (so far) some 50-odd protein species. Failure of any of these components causes a variety of diseases, some of them so serious that fetuses are not viable. A fast-growing number of diseases are recognized to depend or involve alterations in the TJ. These include autoimmune diseases, in which intestinal TJs allow the passage of antigens from the intestinal flora, challenging the immune system to produce antibodies that may cross react with proteins in the brain, thyroid gland or pancreas. TJs are also involved in cancer development, infections, allergies, etc. The present article does not catalogue all TJ diseases known so far, but describes one of each type as illustration. It also depicts the efforts being made to find pharmaceutical agents that would seal faulty TJs or release their grip to allow for the passage of large molecules through the upper respiratory and digestive tracts, such as insulin, thyroid, appetite-regulatory peptide, etc.

Inv dup (15): is the electroclinical phenotype helpful for this challenging clinical diagnosis?

OBJECTIVE: To study the electroclinical phenotype in 5 patients with large supernumerary marker chromosome referred as inv dup (15), in an attempt to analyze the electroclinical spectrum in order to determine if the binomial epilepsy-EEG is stereotyped enough to corroborate this challenging diagnosis. METHODS: Five patients with large inv dup (15) were submitted to EEG and/or V-EEG, with a minimum duration of 2h. Two certified neurophysiologists analyzed all EEG tracings simultaneously, blinded to clinical and molecular data. Epilepsy was characterized by detailed history and a standard questionnaire according to International League Against Epilepsy guidelines and corroborated by V-EEG findings. RESULTS: Epilepsy started during infancy in 4 patients, in 3 with spasms. Spasms were easily controlled in one but not in others. Epilepsy evolved with generalized seizures in two patients and, generalized and focal in one. Currently, 3 patients present refractory epilepsy and two are seizure-free. In one patient, only one isolated episode suggestive of a secondary generalized tonic-clonic event occurred at the age of 12 years without recurrence. Regarding the EEG, patients had distinct features, except for two patients with very high amplitude fast activity, resembling recruiting rhythm. Despite good seizure outcome in 3 patients, EEGs remained remarkably abnormal with frequent epileptiform discharges over poorly organized background. CONCLUSIONS: Our data showed a heterogeneous electroclinical phenotype with generalized and partial epilepsy, presenting distinct degrees of severity and refractoriness. SIGNIFICANCE: Our findings suggest that it is not possible to delineate an electroclinical phenotype in this neurogenetic syndrome. Therefore, inv dup (15) remains as a diagnostic challenge and epilepsy and EEG features are valuable only when inserted in the proper clinical context.

Alterações ecocardiográficas em doenças genéticas / Echocardiographic features of genetic diseases

A identificação ecocardiográfica de cardiopatias em indivíduos com alterações genéticas e em familiares pode representar um avanço muito grande no manuseio dessas anomalias. Apresentamos de maneira resumida, as mais importantes doenças genéticas associadas a alterações cardiovasculares morfológicas e/ou funcionais, e suas correspondentes alterações ecocardiográficas. Em seguida discutimos sobre o valor do método no rastreamento de familiares com doenças genéticas

Mutação no exon 20 do gene da elastina em mulheres com incontinência urinária de esforço decorrente de fatores extrínsecos à uretra / Mutation in exon 20 elastin women with extra urethral stress urinary incontinence

A incontinência urinária de esforço (IUE) é uma condição de alta prevalência em mulheres, representando um problema de saúde pública. Indícios de que desordens difusas do tecido conectivo, talvez de origem genética, possam estar implicadas na gênese da IUE têm sido descritos, como maior prevalência dessa afecção em mulheres com síndromes genéticas / Stress urinary incontinence (SUI) is a high prevalent condition in women and represents a public helth problem. It has been described signs that diffuse disorders of connective tissue, perhaps by genetic causes, may be involved in SUI genesis, as increased prevalence in women with others affections, such as varicose veins and hernia...

Genética molecular y la fisiopatología de las enfermedades hereditarias / Molecular genetics and the pathophysiology of hereditary disease

El ADN, la molécula de la información genética tiene 2 funciones fundamentales: i) Replicarse y transmitirse sin errores, sea desde el cigoto hasta las 10 células de un individuo adulto, o para transmitirse a través de las generaciones; y ii) Contener en su secuencia de bases la información de las decenas de miles de genes que codifican todas las proteínas de nuestro organismo. Los avances de la biología molecular han permitido determinar las mutaciones (errores) en genes que producen proteínas anómalas, o que son expresadas en cantidades anormales en diversas patologías genéticas. En este manuscrito se presentan algunos ejemplos de estas enfermedades y se esboza el impacto de las mutaciones a diferentes niveles para explicar sus fenotipos.

Channelopathies: ion channel defects linked to heritable clinical disorders.

Electrical signals are critical for the function of neurones, muscle cells, and cardiac myocytes. Proteins that regulate electrical signalling in these cells, including voltage gated ion channels, are logical sites where abnormality might lead to disease. Genetic and biophysical approaches are being used to show that several disorders result from mutations in voltage gated ion channels. Understanding gained from early studies on the pathogenesis of a group of muscle diseases that are similar in their episodic nature (periodic paralysis) showed that these disorders result from mutations in a gene encoding a voltage gated Na(+) channel. Their characterisation as channelopathies has served as a paradigm for other episodic disorders. For example, migraine headache and some forms of epilepsy have been shown to result from mutations in voltage gated Ca(2+) channel genes, while long QT syndrome is known to result from mutations in either K(+) or Na(+) channel genes. This article reviews progress made in the complementary fields of molecular genetics and cellular electrophysiology which has led to a better understanding of voltage gated ion channelopathies in humans and mice.

Alcohol-sensitive hereditary essential myoclonus with dystonia: a study of 6 Brazilian patients.

We present the clinical profile of a group of patients with myoclonus and dystonia sensitive to alcohol and address these cases in the context of essential myoclonus. Six patients from 4 families were selected: 4 men and 2 women with myoclonus affecting predominantly the arms. Active movements of these segments elicited the dystonic and myoclonic movements. A marked improvement with alcohol intake was seen. Laboratory findings including EEG, SSEP, and cranial CT and MRI were normal. Surface EMG recording showed bursts with duration of 30-112 ms in 3 patients. One patient showed a triphasic recording pattern (agonist-antagonist-agonist) of ballistic type. Our findings suggest that the myoclonus-dystonia disorder is present in Brazilian patients.

[Ionic-channel diseases]. / Enfermedades de los canales iónicos.

This review illustrates several hereditary diseases caused by mutations in genes which encode various ion channels activated by voltage or neurotransmitters. Many physiological processes depend upon the proper functioning of plasma membrane ion channels and this is most apparent in absorptive and secretory epithelia, and in electrically excitable tissues such as nerve and muscle. By combining the information from electrophysiological recordings with molecular biological techniques, further insight can be gained into the gene expression and protein structure of ionic channels. This combination has resulted in a structure-function analysis revealing the molecular substructures of the ionic channels responsible for the processes of permeation and selectivity of activation and inactivation and different types of block. Using molecular biologic tools, these abnormal channels can be identified and their molecular defects defined. Advances in these areas now provide the basis for a rational approach to the classification and treatment of these disorders of membrane excitation.

Enfermedades de los canales ionicos / Ionic-channel diseases

Este trabajo clasifica diversas enfermedades causadas por un anormal funcionamento en los canales iónicos activados por voltaje o neurotransmisores. Numerosos procesos fisiológicos dependen del normal funcionamiento de canales iónicos, funciones que son más aparentes en los epitelios absortivos y secretorios y en los tejidos excitables como nervio y músculo. Los estudios que combinan los registros electrofisiológicos con la biologia molecular han aclarado la estructura de las proteínas constituyentes de los canales iónicos y la expresión de los mismos. Estos estudios han revelado diversas estructuras responsables de los procesos de permeación, selectividad, activación, inactivación y bloqueo de los canales iónicos. Por medio de estos estudios los canales anormales y sus efectos moleculares pueden ser identificados. Los recientes avances en esta área permiten una clasificación más racional para las enfermedades de los canales iónicos y los resultados podrían ser útiles para su tratamiento en el futuro.

Enfermedades de los canales ionicos / Ionic-channel diseases

Este trabajo clasifica diversas enfermedades causadas por un anormal funcionamento en los canales iónicos activados por voltaje o neurotransmisores. Numerosos procesos fisiológicos dependen del normal funcionamiento de canales iónicos, funciones que son más aparentes en los epitelios absortivos y secretorios y en los tejidos excitables como nervio y músculo. Los estudios que combinan los registros electrofisiológicos con la biologia molecular han aclarado la estructura de las proteínas constituyentes de los canales iónicos y la expresión de los mismos. Estos estudios han revelado diversas estructuras responsables de los procesos de permeación, selectividad, activación, inactivación y bloqueo de los canales iónicos. Por medio de estos estudios los canales anormales y sus efectos moleculares pueden ser identificados. Los recientes avances en esta área permiten una clasificación más racional para las enfermedades de los canales iónicos y los resultados podrían ser útiles para su tratamiento en el futuro. (AU)

Enfermedad de Caroli / Caroliïs disease

La enfermedad de Caroli es una causa poco común de colangitis recurrente secundaria a obstrucción ductal segmentaria. Dicha entidad, cuya transmisión es de carácter autosómico recesivo, se caracteriza por la dilatación sacular de los conductos biliares intrahepáticos, que predispone a la estasis de bilis, y precipitación de cristales que contribuyen a la obstrucción del árbol biliar con la formación de cálculos intraductales. El diagnóstico se apoya en imágenes tomográficas y ultrasonográficas; sin embargo, el estudio de elección para estudiar el árbol biliar es la colangio-pancreatografía retrógrada endoscópica. El tratamiento consiste en la administración de antibióticos y en la remoción de los litos de la vía biliar. Cuando la enfermedad se limita a un solo lóbulo hepático, debe de efectuarse lobactomía. Se presenta el caso de un paciente masculino de 42 años de edad, con cuadro de colangitis, en el que posteriormente se demostró dilatación quística de los conductos biliares intrahepáticos. Se expone la metodología diagnóstica seguida y el tratamiento adoptado

Angioplastía coronaria directa y neuroleptoanalgesia en el tratamiento del infarto agudo del miocardio / Direct coronary angioplasty and neuroleptanalgesia in the treatment of acute myocardial infarction

Presentamos el caso de un paciente de 55 años, con infarto agudo del miocardio de localización anterior, de 3 horas de evolución, con dolor de pecho muy severo, refractario al tratamiento clásico, Se administró neuroleptoanalgesia en infusión logrando quitar el dolor y la ansiedad en unos cuantos minutos. También se observó disminución de la elevación del segmento ST en forma significativa. Hubo mejoría clínica y heomodinámica. La arteriografía coronaria demostró enfermedad coronaria multivascular y oclusión total de la arteria descendente anterior. Se practicó angioplastía coronaria directa de la arteria responsable del infarto. La revascularización total fue diferida para más adelante. La neuroleptoanalgesia en el tratamiento de pacientes con infarto agudo del miocardio que van a ser sometidos a angioplastía de urgencia es de gran utilidad, ya que seda al paciente y facilita el trabajo del operador