ABSTRACT
Rare diseases are heterogeneous life-threatening or seriously debilitating conditions that affect < 1 in 2000 individuals, and most have a genetic component. The diagnostic process is usually based on classic clinical practices, such as physical examination, personal and family history (inheritance pattern), laboratory tests and image studies, but diagnosis can be delayed several years after the initiation of symptoms. The advances in molecular genetics that have taken place in recent years have led to an important shift in medical practice and in its approach to the diagnosis and treatment of many rare diseases. The objective of this review is to promote a better understanding of the mechanisms underlying genetic diseases in humans and the tools available for their diagnosis. A practical example of X-linked hypophosphataemic rickets is described.
Subject(s)
Familial Hypophosphatemic Rickets/diagnosis , Familial Hypophosphatemic Rickets/genetics , Genetic Diseases, X-Linked/diagnosis , Genetic Predisposition to Disease , Molecular Biology/methods , Rare Diseases/diagnosis , Rare Diseases/genetics , HumansABSTRACT
Introducción: El síndrome Cornelia de Lange (SCdL) se produce por afectación de los genes que codifican proteínas reguladoras o estructurales del complejo de cohesinas. La cardiopatía congénita (CC) no es criterio mayor de enfermedad, pero afecta a numerosos individuos. El objetivo de este trabajo ha sido estudiar la incidencia y tipo de CC en pacientes con SCdL. Material y método: Se han evaluado los hallazgos cardiológicos en 149 pacientes con SCdL y su posible relación con variables clínicas y genéticas. Resultados: Un 34,9% presentan CC (defectos septales 50%, estenosis pulmonar 27%, coartación aórtica 9,6%). La presencia de CC se relaciona con hospitalización neonatal (p=0,04), hipoacusia (p=0,002), mortalidad (p=0,09) y menor hiperactividad (p=0,02); es más frecuente en pacientes HDAC8+ (60%), seguido de NIPBL+ (33%) y SMC1A+ (28,5%). Mientras que en NIPBL+ predominan los defectos septales, en HDAC8+ es más frecuente la estenosis pulmonar. Conclusiones: Los pacientes con SCdL tienen una incidencia elevada de CC, que varía según el gen afectado, siendo los hallazgos más frecuentes los defectos septales y la estenosis pulmonar. Se sugiere realizar estudio cardiológico en todos estos pacientes (AU)
Introduction: Cornelia de Lange syndrome (CdLS) is produced by mutations in genes that encode regulatory or structural proteins of the cohesin complex. Congenital heart disease (CHD) is not a major criterion of the disease, but it affects many individuals. The objective of this study was to study the incidence and type of CHD in patients with CdLS. Material and method: Cardiological findings were evaluated in 149 patients with CdLS and their possible relationship with clinical and genetic variables. Results: A percentage of 34.9 had CHD (septal defects 50%, pulmonary stenosis 27%, aortic coarctation 9.6%). The presence of CHD was related with neonatal hospitalisation (P=.04), hearing loss (P=.002), mortality (P=.09) and lower hyperactivity (P=.02), it being more frequent in HDAC8+ patients (60%), followed by NIPBL+ (33%) and SMC1A+ (28.5%). While septal defects predominate in NIPBL+, pulmonary stenosis is more common in HDAC8+. Conclusions: Patients with CdLS have a high incidence of CHD, which varies according to the affected gene, the most frequent findings being septal defects and pulmonary stenosis. Perform a cardiologic study in all these patients is suggested (AU)
Subject(s)
Humans , Male , Female , Infant, Newborn , De Lange Syndrome/epidemiology , Heart Defects, Congenital/epidemiology , Genetic Predisposition to Disease , Pulmonary Valve Stenosis/epidemiology , Prenatal Diagnosis/statistics & numerical data , Heart Septal Defects, Atrial/epidemiologyABSTRACT
INTRODUCTION: Cornelia de Lange syndrome (CdLS) is produced by mutations in genes that encode regulatory or structural proteins of the cohesin complex. Congenital heart disease (CHD) is not a major criterion of the disease, but it affects many individuals. The objective of this study was to study the incidence and type of CHD in patients with CdLS. MATERIAL AND METHOD: Cardiological findings were evaluated in 149 patients with CdLS and their possible relationship with clinical and genetic variables. RESULTS: A percentage of 34.9 had CHD (septal defects 50%, pulmonary stenosis 27%, aortic coarctation 9.6%). The presence of CHD was related with neonatal hospitalisation (P=.04), hearing loss (P=.002), mortality (P=.09) and lower hyperactivity (P=.02), it being more frequent in HDAC8+ patients (60%), followed by NIPBL+ (33%) and SMC1A+ (28.5%). While septal defects predominate in NIPBL+, pulmonary stenosis is more common in HDAC8+. CONCLUSIONS: Patients with CdLS have a high incidence of CHD, which varies according to the affected gene, the most frequent findings being septal defects and pulmonary stenosis. Perform a cardiologic study in all these patients is suggested.
Subject(s)
De Lange Syndrome/diagnosis , Heart Defects, Congenital/diagnosis , De Lange Syndrome/genetics , Female , Genetic Markers , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/genetics , Humans , Incidence , MaleABSTRACT
No disponible
Subject(s)
Humans , Male , Infant, Newborn , Cerebellopontine Angle/physiopathology , Microcephaly/genetics , Mutation/genetics , Motor Neuron Disease/genetics , Genes, Recessive/geneticsABSTRACT
We think that the main interests of this study are the report of a new mutation in gene MYBPC3 as a cause of Hypertrophic cardiomyopathy (HMC), and the verification of the fact that not always is the number of mutations related to the severity of the disease.
ABSTRACT
El asesoramiento genético es el proceso de comunicación por el que un profesional con preparación adecuada (genetista) informa al paciente (familia) sobre un diagnóstico genético y sus repercusiones físicas y psíquicas en el individuo y sus familiares, incluyendo el riesgo de recurrencia, opciones reproductivas, posibilidades de tratamiento y/o prevención y apoyo en la toma de decisiones. El cálculo del riesgo reproductivo se basa principalmente en el tipo de herencia de la enfermedad y en el caso de las enfermedades mendelianas suele ser de gran fiabilidad si el estudio genético ha confirmado el diagnóstico de sospecha (AU)
Genetic counselling is a communication process in which a profesional with the required competences (geneticist) explains the genetic condition to the patient, its physical and physiological consequences, the recurrence risk, the reproductive options and the therapeutic and preventive possibilities available, helping the consultant thorough the decision-taking-process. Recurrence risk calculation depends mainly on the mode of inheritance of the disease and, in the case of mendelian conditions is highly reliable if the diagnosis has been confirmed by the genetic test (AU)
Subject(s)
Humans , Mendelian Randomization Analysis , Genetic Counseling , Genetic Diseases, Inborn/prevention & control , Genetic Association StudiesABSTRACT
El splicing o maduración del pre-mRNA es un mecanismo que está adquiriendo gran relevancia no sólo por las posibilidades que ofrece de expansión del proteoma, sino también por su implicación en la patofisiología de las enfermedades humanas. Las mutaciones de splicing alteran el procesamiento del mRNA al afectar a las secuencias del pre-mRNA (mutaciones en cis) o a las proteínas que intervienen en el splicing (mutaciones en trans). Las secuencias que pueden verse alteradas son: las limitantes de exones e intrones, la zona de ramificación, la zona rica en pirimidinas y también otros elementos reguladores que incrementan o suprimen la selección de un exón. La comprensión en profundidad del efecto de las mutaciones sobre el splicing puede abrir la puerta a su tratamiento mediante terapia moléculas (AU)
Splicing or maturation of pre-mRNA is a mechanism that is becoming more relevant not only for its potential expansion of the proteome, but also for its involvement in the physiopathology of human diseases. Splicing mutations after the processing of mRNA by affecting pre-mRNA sequences (mutations in cis) or proteins involved in splicing (mutations in trans). The sequences that can be altered are: the limiting areas between exons and interns, the branch site, the polypirimidine tract and, finally, other regulatory elements that enhance or suppress the selection of an exon. The whole understanding of the effect of mutations on the splicing processes will help to design molecular therapy targets to correct these defects (AU)
Subject(s)
Humans , RNA Splicing/genetics , Mutation , Genetic Diseases, Inborn/genetics , Genetic Association Studies/methodsABSTRACT
La deficiencia de la HMG-CoA sintasa mitocondrial (mHS) (MIM600234) es un error innato del metabolismo de tipo autosómico recesivo que está causada por mutaciones en el gen HMGCS2. La mHS es una enzima mitocondrial que cataliza el paso de condensación de acetil-CoA con acetoacetil-CoA para forma 3-hidroxi-2-metilgutaril CoA en la ruta de síntesis de los cuerpos cetónicos. Esta deficiencia suele aparecer en la primara infancia en situaciones de ayuno y alto consumo energético. Las manifestaciones clínicas son inespecíficas e incluyen vómitos, letargia y a veces coma. Hasta la fecha, sólo se han diagnosticado a nivel clínico y genético ocho pacientes en todo el mundo (AU)
The HMG-CoA synthase mitocondrial (mHS) deficiency (OMIM 600234) is an autosomal recessive inborn error of metabolism caused by mutations in the HMGCS2 gene. mHS is a mitochondrial enzyme that cathalyzes the condensation step of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl CoA in the synthesis pathway of the ketone bodies. This deficiency frequently appears during childhood under fasting and/or high energy consumption situations. Clinical manifestations are rather inespecific and include vomiting, lethargy and, in some cases, coma. To date, only eight patients have been clinically and genetically characterized around the word (AU)
Subject(s)
Humans , Mitochondrial Proteins/deficiency , Metabolism, Inborn Errors/genetics , Hydroxymethylglutaryl-CoA Synthase/deficiency , Risk Factors , High Mobility Group Proteins/deficiencyABSTRACT
El Síndrome X Frágil (SXF) es la principal causa de retraso mental hereditario, con una incidencia aproximada de ¼.000 varones y 1/8.000 mujeres en la población general. Se hereda de forma dominante ligada al sexo. Clínicamente se caracteriza por retrasomental, fenotipo peculiar con cara alargada y pabellones auriculares grandes y despegados, hiperlaxitud articular y macroorquidismo tras la pubertad. En las mujeres afectadas las manifestaciones clínicas suelen ser menos evidentes. El mecanismo etiológico es una expansión excesiva (>200) del trinucleótido CGG en el extremo 5´ del gen FMR1, que además está metilado, dando lugar a la ausencia de la proteína FMRP (AU)
Fragile X syndrome (FXS) is considered the most common known cause of inherited mental retardation, with a frequency of approximately 1:4.000 males and 1:8.000 females in the general population. It is an X-linked dominant disorder. Characteristic clinical features included mental retardation, distinctive phenotype with long face and large prominent ears, joint laxity and macroorchidism after puberty. Affected females usually show a less severe phenotype. In the vast majority of the cases, FXS is caused by an abnormal expansion (>200) of a CGG trinucleotide repeat in the 5´- untranslated region of the FMR1 gene, which is methylated, leading to the absence of the FMRP protein (AU)
Subject(s)
Humans , Fragile X Syndrome/genetics , Intellectual Disability/genetics , Phenotype , Joint Instability/etiologyABSTRACT
La aciduria 3-hidroxi-3-metilgutárica (MIM 246450) es un error innato de metabolismo transmitido por herencia autosómica recesiva que suele manifestarse en el primer año de vida. Está causada por mutaciones en el gen HMGCL, que codifica la enzima HMG-CoA liasa humana (HL). La HL es una proteína mitocondiral que cataliza el último paso de la cetogénesis y del catabolismo de la leucina. Clínicamente, la enfermedad suele debutar la forma de episodios agudos con acidosis metabólica, hipoglucemia hipocetonémica y un patrón característico de ácidos orgánicos en orina. Hasta la fecha, se han diagnosticado genéticamente más de 100 pacientes de esta enfermedad, que tiene una especial incidencia en Arabia Saudita y en la Península Ibérica. En este trabajo revisamos el estudio molecular del gen HMGCL en 18 pacientes españoles. Aunque se han encontrado ocho mutaciones diferentes, destacan por su alta incidencia en España las mutaciones c. 109G>T y la c.504_505delCT con un 58% y un 16,6% de frecuencia alélica respectivamente. Las relaciones genotipo-fenotipo son difíciles de establecer porque la evolución de la deficiencia parece más relacionada con las causas que generan hipoglucemia (ayuno y enfermedades intercurrentes) que con un particular genotipo (AU)
3-Hydroxy-2-methyglutaric aciduria (MIM 246450) is an inborn error of metabolism transmitted by autosomal recessive inheritance that usually appears within the first year of life. The causes of this aciduria are mutations in the HMGCL gene encoding for 3-hidroxy-3-methylglutaryI coenzyme A lyase (HL). HL is a mitochondrial enzyme that catalyzes the last step of ketogenesis and leucine catabolism. Clinically, the disease appears in acute episodes with metabolic acidosis, hypoketotic hypoglycaemia and a characteristic pattern of organic acids in urine. To date more than 100 patients have been diagnosed genetically, with special incidence in Saudi Arabia and the Iberian Peninsula. In this work we review the molecular study of HMGCL gene in 18 Spanish patients. Although we have found 8 different mutations, the mutations c.109G>T and c.504_505delCT stand out as the most incidence in Spain, with 58% and 16,6% allelic frequency respectively. The genotype-phenotype correlation is difficult to establish since the evolution of deficiency seems more related to the causes of hypoglicaemia (fasting and interrecurrent diseases) than with a particular genotype (AU)
Subject(s)
Humans , /deficiency , Barth Syndrome/genetics , Genetic Association Studies/methods , Hypoglycemia/epidemiologyABSTRACT
El Síndrome de Cornelia de Lange (SCdL) es un trastorno del desarrollo hereditario caracterizado por un fenotipo facial distintivo, malformaciones en extremidades superiores y retrasado de crecimiento y psicomotor. La prevalencia oscila entre 1:45.000 y 1:62.000 nacimientos. Hasta la fecha, se han encontrado mutaciones en tres genes que codifican subunidades reguladoras o estructurales del Complejo de Cohesinas: NIPBL (5p13), SMC1A (Xp11) y SMC3 (10q25), y que afectan alrededor de un 55% de los pacientes. Clínicamente se distinguen tres fenotipos: grave, moderado y leve. El fenotipo grave sólo ha sido descrito en pacientes con mutaciones del gen NIPBL. Las bases patogénicas del síndrome no están aún aclaradas, pero parecen relacionarse con problemas de regulación de la expresión génico y/o de la cohesión cromosómica (AU)
Cornelia de Lange Syndorme (CDLS) is a congenital hereditary developmental disorder characterized by a distinctive craniofacial phenotype, upper limb malformations, and growth and developmental delay. The estimated prevalence range from 1:45.000 to 1:62.000 livebirths. Up to date, there genes that encode structural or regulator subunits of Cohesin Complex: NIPBL (5p13), SMC1A (Xp11), and SMC3 (10q25), have been found to bear mutations in approximately 55% of affected patients. Three phenotypes can be distinguished clinically: severe, moderate and mild. The severe one has been only seen in patients carrying mutations in the NIPBL gene. Although the pathogenic bases of the syndrome remain unclear, it has been hypothesized that CdLS is related to anomalies in gene expression regulations and /or chromosome cohesion (AU)
Subject(s)
Humans , De Lange Syndrome/genetics , Psychomotor Disorders/genetics , Molecular Diagnostic Techniques/methods , Gene ExpressionABSTRACT
El síndrome alcohólico fetal (SAF) se define como un defecto congénito permanente causado por el consumo excesivo de alcohol materno durante el embarazo. Se caracteriza por un crecimiento disminuido, una alteración del sistema nervioso central y un conjunto de alteraciones faciales menores. La incidencia estimada es de 0,33-2,2/1.000 recién nacidos vivos en Estados Unidos. Hasta los años noventa no hubo una serie de criterios unificados y objetivos para llegar al diagnóstico de SAF. Se presenta el caso clínico de un niño de 5 años y 10 meses con este síndrome. El objetivo de este artículo es revisar los criterios diagnósticos del SAF y su actualización
Fetal alcohol syndrome (FAS) is defined as a permanent birth defect syndrome caused by maternal alcohol abuse during pregnancy. It is characterized by growth deficiency, central nervous system (CNS) dysfunction and minor facial anomalies. The incidence in the USA has been estimated to be between 0.33 and 2.2 per 1000 live births. Until the 90s, there were no objective, standardized criteria for the diagnosis of FAS. We report the case of a boy aged 5 years and 10 months who has been diagnosed as having this syndrome. The aim of this article is to review and update the criteria for the diagnosis of FAS
