RESUMEN
PURPOSE: Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10, implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. METHODS: We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients (n = 407) and unrelated controls (n = 284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy (n = 153), childhood absence (n = 84), juvenile myoclonic (n = 111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n = 59) and all were of European ancestry. RESULTS: SNP rs#1130183 (C > T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel-Haenszel chi square = 5.65, d.f. = 1, P = 0.017, odds ratio 0.52, 95% CI 0.33-0.82. CONCLUSION: The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Canales de Potasio de Rectificación Interna , Canales de Potasio/genética , Convulsiones/genética , Distribución de Chi-Cuadrado , Intervalos de Confianza , Frecuencia de los Genes/genética , Genotipo , Humanos , Oportunidad Relativa , Sitios de Carácter Cuantitativo/genéticaRESUMEN
PURPOSE: We attempted to confirm recent findings of Kanemoto et al. that demonstrated a positive association (p < 0.017) between a polymorphism in the promoter region of the interleukin 1-beta (IL-1beta) gene and the clinical phenotype of temporal lobe epilepsy with hippocampal sclerosis (TLE+HS). METHODS: We determined the frequency of this polymorphism in a group of 61 TLE+HS patients of European ancestry and compared it with that found in 119 ethnically matched control subjects. RESULTS: Analysis of genotype and allele frequencies showed no statistically significant difference in the distribution of the polymorphism between the two groups (p = 0.10). CONCLUSIONS: These data suggest that this IL-1beta promoter polymorphism does not act as a strong susceptibility factor for TLE+HS in a population of individuals of European ancestry.
Asunto(s)
Epilepsia del Lóbulo Temporal/genética , Variación Genética , Interleucina-1/genética , Fragmentos de Péptidos/genética , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/epidemiología , Etnicidad/genética , Europa (Continente)/etnología , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad , Genotipo , Hipocampo/patología , Humanos , Interleucina-1beta , Fenotipo , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Esclerosis , Estados Unidos/epidemiología , Población Blanca/genéticaRESUMEN
We report medullary injury during adenoidectomy in two children who received injections of local anesthetic agents into the operative bed. Initial manifestations included hemiparesis, nystagmus, and ataxia. Magnetic resonance imaging showed hemorrhagic, paramedian medullary lesions in both patients. The mechanism of injury is likely to be injection of fluid into the medulla.
Asunto(s)
Adenoidectomía/efectos adversos , Anestésicos Locales/efectos adversos , Tronco Encefálico/lesiones , Inyecciones/efectos adversos , Paresia/etiología , Adenoidectomía/métodos , Ataxia/etiología , Niño , Preescolar , Epinefrina/administración & dosificación , Humanos , Lidocaína/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Nistagmo Patológico/etiología , Medición de RiesgoRESUMEN
A large body of evidence suggests that genetic factors influence liability to many common neurodevelopmental disorders. Examples include Tourette syndrome, attention-deficit hyperactivity disorder, autism, and dyslexia. Characterization of the genetic component of susceptibility to these conditions at a molecular level should improve classification, elucidate fundamental neurobiologic mechanisms of disease, and suggest novel approaches to treatment. Susceptibility loci for complex traits could be identified by detecting linkage to a well-mapped genetic marker or by detecting association with a putative high-risk allele at a candidate locus. This article reviews the principles underlying these complementary approaches, and notes recent progress in specific conditions. As the molecular epidemiology of susceptibility to common neurodevelopmental disorders emerges, it might be increasingly possible to identify "high-risk" and "low-risk" genotypes. Clinicians should understand the nature of this kind of information in order to appreciate its power as well as its limitations.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Genética Médica/métodos , Enfermedades del Sistema Nervioso/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno Autístico/genética , Dislexia/genética , Femenino , Ligamiento Genético/genética , Marcadores Genéticos , Genotipo , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Linaje , Fenotipo , Síndrome de Tourette/genéticaRESUMEN
Recent application of genetic analysis to rare, hereditary epilepsies has resulted in the identification of mutations in genes encoding ion channels or functionally related proteins in several human and animal syndromes. Reviewed here are selected human and murine epilepsies that result from ion channel mutations. In humans, three autosomal-dominant disorders--benign familial neonatal convulsions, nocturnal frontal lobe epilepsy, and "generalized epilepsy with febrile seizures plus"--result from mutations affecting voltage-sensitive potassium channels, a central nicotinic acetylcholine receptor, and a voltage-sensitive sodium channel, respectively. In mice, four genetically distinct, autosomal-recessive models of absence epilepsy are caused by mutations in genes encoding three types of calcium channel subunits and a sodium-hydrogen ion exchanger. These findings suggest that variation in genes encoding ion channels could determine susceptibility to common human epilepsies.
Asunto(s)
Epilepsia/genética , Canales de Potasio/genética , Canales de Sodio/genética , Aberraciones Cromosómicas/genética , Trastornos de los Cromosomas , Epilepsia/diagnóstico , Humanos , Recién Nacido , Mutación Puntual/genética , Receptores Colinérgicos/genética , Receptores Nicotínicos/genéticaRESUMEN
We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease. The disorder is characterized by slow progression, distal limb amyotrophy, and pyramidal tract signs associated with severe loss of motor neurons in the brain stem and spinal cord. The gene for this disorder, classified as a form of juvenile amyotrophic lateral sclerosis (ALS), is designated "ALS4." We performed a genomewide search and detected strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34. The highest LOD score (Z) was obtained with D9S1847 (Z=18.8, recombination fraction of .00). An analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, on chromosome 9q34, that define an approximately 5-cM interval that harbors the ALS4 gene. These results extend the degree of heterogeneity within familial ALS syndromes, and they implicate a gene on chromosome 9q34 as critical for motor-neuron function.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Cromosomas Humanos Par 9 , Genes Dominantes , Ligamiento Genético , Adolescente , Edad de Inicio , Anciano , Anciano de 80 o más Años , Mapeo Cromosómico , Intercambio Genético , Femenino , Humanos , Masculino , LinajeRESUMEN
Epileptic disorders affect about 20-40 million people worldwide, and 40% of these are idiopathic generalized epilepsies (IGEs; ref. 1). Most of the IGEs that are inherited are complex, multigenic diseases. To address basic mechanisms for epilepsies, we have focused on one well-defined class of IGEs with an autosomal-dominant mode of inheritance: the benign familial neonatal convulsions (BFNC; refs 2,3). Genetic heterogeneity of BFNC has been observed. Two loci, EBN1 and EBN2, have been mapped by linkage analysis to chromosome 20q13 (refs 5,6) and chromosome 8q24 (refs 7,8), respectively. By positional cloning, we recently identified the gene for EBN1 as KCNQ2 (ref. 9). This gene, a voltage-gated potassium channel, based on homology, is a member of the KQT-like family. Here we describe an additional member, KCNQ3. We mapped this new gene to chromosome 8, between markers D8S256 and D8S284 on a radiation hybrid map. We screened KCNQ3 for mutations in the large BFNC family previously linked to chromosome 8q24 in the same marker interval. We found a missense mutation in the critical pore region in perfect co-segregation with the BFNC phenotype. The same conserved amino acid is also mutated in KVLQT1 (KCNQ1) in an LQT patient. KCNQ2, KCNQ3 and undiscovered genes of the same family of K+ channels are strong candidates for other IGEs.
Asunto(s)
Epilepsia Generalizada/genética , Mutación , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 8 , Femenino , Variación Genética , Humanos , Canal de Potasio KCNQ3 , Masculino , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Homología de Secuencia de AminoácidoRESUMEN
Several X-linked disorders affect females disproportionately or exclusively. These including focal dermal hypoplasia, oral-facial-digital syndrome type I (ref. 3) and epilepsy with bilateral periventricular heterotopias. X-linked dominant inheritance with male lethality is probably responsible for sex-limited expression of these disorders, as affected women have frequent spontaneous abortions and the sex ratio of their live offspring is often skewed. The same inheritance pattern has been proposed for Rett syndrome, Aicardi syndrome and microphthalmia with linear skin defects, but in these sporadic conditions, evidence of male lethality is lacking. We investigated an unusual family with epilepsy and mental retardation limited to females (EFMR, #121250 in ref. 9); this disorder is transmitted both by females and by completely unaffected carrier males. Assignment of the EFMR disease locus (EFMR) to the X chromosome indicates that selective involvement of females in X-linked disease may in some instances result from male sparing rather than male lethality.
Asunto(s)
Epilepsia/genética , Impresión Genómica , Discapacidad Intelectual/genética , Cromosoma X , Corteza Cerebral/patología , Mapeo Cromosómico , Epilepsia/patología , Femenino , Genes Dominantes , Marcadores Genéticos , Humanos , Discapacidad Intelectual/patología , Escala de Lod , Masculino , Linaje , Recombinación Genética , Caracteres SexualesRESUMEN
Two autosomal dominant forms of benign idiopathic epilepsy of early life have been described: benign neonatal familial convulsions and benign infantile familial convulsions. Herein we describe a pedigree with familial convulsions in which the age of onset is intermediate between that seen in these two disorders. Two genes responsible for benign neonatal familial convulsions have been mapped to chromosome 20q and to chromosome 8q. Previously, the chromosome 20q benign neonatal familial convulsions locus had been excluded in this pedigree. Further linkage analysis in our laboratory revealed that the chromosome 8 benign neonatal familial convulsions locus also is not responsible for seizures in this pedigree. These results indicate that there are at least three loci responsible for autosomal dominant benign epilepsies of early life.
Asunto(s)
Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 8/genética , Convulsiones/genética , Edad de Inicio , Aberraciones Cromosómicas/fisiopatología , Trastornos de los Cromosomas , Femenino , Ligamiento Genético , Marcadores Genéticos , Haplotipos , Humanos , Lactante , Recién Nacido , Escala de Lod , Masculino , Linaje , Reacción en Cadena de la Polimerasa , Recombinación Genética , Remisión Espontánea , Convulsiones/etiologíaRESUMEN
Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg271 by a glutamine (R271Q) in one case and a leucine (R271L) in the other. Here, 5 additional hyperekplexia families are shown to have the most common G-to-A transition mutation at nucleotide 1192. Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times). In 2 additional families, a third mutation is also presented that changes a tyrosine at amino acid 279 to a cysteine (Y279C). Five patients with atypical clinical features and equivocal or absent family history of hyperekplexia and 1 patient with a classical presentation but not family history are presented in whom a mutation in the GLRA1 gene was not detected. Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.
Asunto(s)
Análisis Mutacional de ADN , Rigidez Muscular/genética , Reflejo de Sobresalto/genética , Secuencia de Bases , Exones , Haplotipos , Humanos , Lactante , Datos de Secuencia Molecular , Polimorfismo GenéticoRESUMEN
Hereditary hyperekplexia, an autosomal dominant neurologic disorder characterized by an exaggerated startle reflex and neonatal hypertonia, can be caused by mutations in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). Spasmodic (spd), a recessive neurologic mouse mutant, resembles hyperekplexia phenotypically, and the two disease loci map to homologous chromosomal regions. Here we describe a Glra1 missense mutation in spd that results in reduced agonist sensitivity in glycine receptors expressed in vitro. We conclude that spd is a murine homologue of hyperekplexia and that mutations in GLRA1/Glra1 can produce syndromes with different inheritance patterns.
Asunto(s)
Mutación , Mutación Puntual , Receptores de Glicina/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario/genética , Humanos , Ratones , Ratones Endogámicos A , Ratones Mutantes Neurológicos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Ratas , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido NucleicoRESUMEN
We report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bell-shaped chest, diastasis recti, short fingers, and mild developmental delay.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 5 , Anomalías Múltiples/diagnóstico , Amniocentesis , Humanos , Lactante , Cariotipificación , MasculinoRESUMEN
We report a patient who developed paroxysmal kinesigenic dystonia shortly after initiation of therapy with methylphenidate for presumed attention deficit-hyperactivity disorder. Attacks persisted long after methylphenidate was discontinued and responded completely to treatment with carbamazepine. Though it is possible that methylphenidate caused this syndrome in our patient, it is more likely that the stimulant triggered the onset of a genetically determined disorder.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Distonía/inducido químicamente , Metilfenidato/efectos adversos , Metilfenidato/uso terapéutico , Adolescente , Carbamazepina/administración & dosificación , Carbamazepina/uso terapéutico , Distonía/tratamiento farmacológico , Humanos , MasculinoRESUMEN
Hereditary hyperekplexia, or familial startle disease (STHE), is an autosomal dominant neurologic disorder characterized by marked muscle rigidity of central nervous system origin and an exaggerated startle response to unexpected acoustic or tactile stimuli. Linkage analyses in several large families provided evidence for locus homogeneity and showed the disease gene was linked to DNA markers on the long arm of chromosome 5. Here we describe the identification of point mutations in the gene encoding the alpha 1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families. All mutations occur in the same base pair of exon 6 and result in the substitution of an uncharged amino acid (leucine or glutamine) for Arg271 in the mature protein.
Asunto(s)
Cromosomas Humanos Par 5 , Exones/genética , Enfermedades del Sistema Nervioso/genética , Mutación Puntual/genética , Receptores de Glicina/genética , Reflejo de Sobresalto/genética , Secuencia de Aminoácidos , Animales , Cricetinae , Familia , Femenino , Ligamiento Genético , Humanos , Masculino , Datos de Secuencia Molecular , Polimorfismo GenéticoRESUMEN
The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first few weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but we have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder.
Asunto(s)
Cromosomas Humanos Par 8 , Epilepsia Generalizada/genética , Espasmos Infantiles/genética , Secuencia de Bases , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 20 , Ligamiento Genético , Variación Genética , Humanos , Lactante , Recién Nacido , Escala de Lod , Datos de Secuencia Molecular , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
Hyperekplexia, or startle disease (STHE), is an autosomal dominant neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to sudden, unexpected acoustic or tactile stimuli. STHE responds dramatically to the benzodiazepine drug clonazepam, which acts at gamma-aminobutyric acid type A (GABA-A) receptors. The STHE locus (STHE) was recently assigned to chromosome 5q, on the basis of tight linkage to the colony-stimulating factor 1-receptor (CSF1-R) locus in a single large family. We performed linkage analysis in the original and three additional STHE pedigrees with eight chromosome 5q microsatellite markers and placed several of the most closely linked markers on an existing radiation hybrid (RH) map of the region. The results provide strong evidence for genetic locus homogeneity and assign STHE to a 5.9-cM interval defined by CSF1-R and D5S379, which are separated by an RH map distance of 74 centirays (roughly 2.2-3.7 Mb). Two polymorphic markers (D5S119 and D5S209) lie within this region, but they could not be ordered with respect to STHE. RH mapping eliminated the candidate genes GABRA1 and GABRG2, which encode GABA-A receptor components, by showing that they are telomeric to the target region.
Asunto(s)
Cromosomas Humanos Par 5 , Síndrome de la Persona Rígida/genética , Secuencia de Bases , Línea Celular Transformada , Mapeo Cromosómico , Clonazepam/uso terapéutico , ADN de Cadena Simple , Femenino , Ligamiento Genético , Haplotipos , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Receptores de GABA-A/efectos de los fármacos , Síndrome de la Persona Rígida/tratamiento farmacológicoRESUMEN
We describe a boy with an interstitial deletion of 7q [46,XY,del(7)(pter-->q11.21::q11.23-->qter)] and severe mental retardation, bilateral inguinal hernias, plagiocephaly, and mildly abnormal facial appearance. This is the 21st case report involving a proximal 7q deletion, but the first report of this specific deletion in the absence of Zellweger syndrome. Specific genotype-phenotype correlations are still not possible for this region of chromosome 7.
Asunto(s)
Anomalías Múltiples/genética , Deleción Cromosómica , Cromosomas Humanos Par 7 , Discapacidad Intelectual/genética , Bandeo Cromosómico , Cara/anomalías , Hernia Inguinal/genética , Humanos , Lactante , MasculinoRESUMEN
Familial startle disease (also known as hyperekplexia and congenital "stiff-man" syndrome) is an autosomal dominant disorder characterized by an exaggerated startle reaction of sudden, unexpected auditory or tactile stimuli; affected neonates also have severe and occasionally fatal hypertonia. We recently encountered a large, five-generation family with startle disease, and treated 16 patients (including 1 neonate) with clonazepam; all experienced dramatic and sustained improvement. We performed systematic linkage analysis in this family, and found tight linkage between the disease locus and a polymorphic genetic marker locus (colony-stimulating factor receptor, or CSF1R) that has been physically mapped to chromosome 5q33-q35. The maximum odds ratio favoring linkage over nonlinkage is greater than 10,000,000:1 (lod score, 7.10) at 3% recombination. Several genes encoding neurotransmitter receptor components have been physically mapped to the subtelomeric region of chromosome 5q, and are thus candidates for the startle disease gene. The availability of additional large pedigrees with startle disease should facilitate identification and characterization of the gene for this disorder.