Subject(s)
Brain Diseases/genetics , Codon, Nonsense , Developmental Disabilities/genetics , Genetic Predisposition to Disease/genetics , Membrane Proteins/genetics , Phosphoric Monoester Hydrolases/genetics , Child, Preschool , Exome/genetics , Genes, Recessive , Genotype , Humans , Language Development Disorders/genetics , Magnetic Resonance Imaging , Male , Sequence Analysis, DNASubject(s)
Algorithms , Biomarkers , Causality , Clinical Trials as Topic , Drug Evaluation, Preclinical/methods , Drug-Related Side Effects and Adverse Reactions , Data Interpretation, Statistical , Drug Evaluation, Preclinical/statistics & numerical data , Humans , Reproducibility of Results , Safety , United States , United States Food and Drug AdministrationSubject(s)
Consent Forms/standards , Drug Industry/standards , Informed Consent/standards , Pharmacogenetics/standards , Clinical Trials as Topic/ethics , Clinical Trials as Topic/methods , Clinical Trials as Topic/standards , Confidentiality/ethics , Confidentiality/standards , Consent Forms/ethics , Drug Industry/ethics , Drug Industry/methods , Humans , Informed Consent/ethics , Pharmacogenetics/ethics , Pharmacogenetics/methodsABSTRACT
We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.
Subject(s)
Basal Ganglia Diseases/genetics , Ferritins/genetics , Genes, Dominant/genetics , Mutation , Protein Subunits , Adult , Age of Onset , Basal Ganglia Diseases/diagnosis , Basal Ganglia Diseases/epidemiology , Base Sequence , Brain/pathology , Chromosomes, Human, Pair 19/genetics , DNA Mutational Analysis , Female , Ferritins/metabolism , Founder Effect , Genetic Linkage , Globus Pallidus/metabolism , Globus Pallidus/pathology , Humans , Iron/metabolism , Lod Score , Magnetic Resonance Imaging , Male , Middle Aged , Molecular Sequence Data , Pedigree , Sequence Homology, Amino Acid , Terminology as TopicABSTRACT
Cerebral palsy (CP) has an incidence of approximately 1 in 750 births, although this varies between ethnic groups. Genetic forms of the disease account for about 2% of cases in most countries, but contribute a larger proportion in certain sub-types of the condition and in populations with a large proportion of consanguineous marriages. Ataxic cerebral palsy accounts for 5-10% of all forms of CP and it is estimated that approximately 50% of ataxic cerebral palsy is inherited as an autosomal recessive trait. We have identified a complex consanguineous Asian pedigree with four children in two sibships affected with ataxic cerebral palsy and have used homozygosity mapping to map the disorder in this family. A genome-wide search was performed using 343 fluorescently labelled polymorphic markers and linkage to chromosome 9p12-q12 was demonstrated. A maximum Lod score of 3.4 was observed between the markers D9S50 and D9S167 using multipoint analysis, a region of approximately 23cM. We have identified a family that segregates both ataxic CP and ataxic diplegia and have mapped the genetic locus responsible in this family to chromosome 9p12-q12. The identification of gene(s) involved in the aetiology of CP will offer the possibility of prenatal/premarital testing to some families with children affected with the disorder and will greatly increase our understanding of the development of the control of motor function.
Subject(s)
Ataxia/pathology , Cerebral Palsy/genetics , Chromosomes, Human, Pair 9/genetics , Alleles , Cerebral Palsy/pathology , Child, Preschool , Chromosome Mapping , DNA/chemistry , DNA/genetics , DNA Mutational Analysis , Family Health , Female , Genetic Linkage , Humans , Lod Score , Male , Microsatellite Repeats , PedigreeABSTRACT
Primary microcephaly is a clinical diagnosis made when an individual has a head circumference of greater than 3 standard deviations below the age and sex matched population mean, mental retardation but without other associated malformations and no apparent aetiology. The majority of cases of primary microcephaly exhibit an autosomal recessive mode of inheritance. We now demonstrate the genetic heterogeneity of this condition with the identification of a second primary microcephaly locus (MCPH2) on chromosome 19q13.1-13.2 in two multi-affected consanguineous families. The minimum critical region containing the MCPH2 locus is defined by the polymorphic markers D19S416 and D19S420 spanning a region of approximately 7.6 cM.
Subject(s)
Chromosomes, Human, Pair 19/genetics , Genes, Recessive , Genetic Linkage/genetics , Microcephaly/genetics , Adolescent , Chromosome Mapping , Family , Homozygote , Humans , MaleABSTRACT
Cerebral palsy has an incidence of approximately 1/500 births, although this varies between different ethnic groups. Genetic forms of the disease account for approximately 1%-2% of cases in most countries but contribute a larger proportion in populations with extensive inbreeding. We have clinically characterized consanguineous families with multiple children affected by symmetrical spastic cerebral palsy, to locate recessive genes responsible for this condition. The eight families studied were identified from databases of patients in different regions of the United Kingdom. After ascertainment and clinical assessment, we performed a genomewide search for linkage, using 290 polymorphic DNA markers. In three families, a region of homozygosity at chromosome 2q24-q25 was identified between the markers D2S124 and D2S148. The largest family gave a maximum LOD score of 3.0, by multipoint analysis (HOMOZ). The maximum combined multipoint LOD score for the three families was 5.75. The minimum region of homozygosity is approximately 5 cM between the markers D2S124 and D2S2284. We have shown that a proportion of autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. The identification of genes involved in the etiology of cerebral palsy may lead to improved management of this clinically intractable condition.
Subject(s)
Cerebral Palsy/genetics , Chromosomes, Human, Pair 2 , Genes, Recessive , Adolescent , Adult , Child , Chromosome Mapping , Female , Genotype , Humans , Male , Pedigree , PhenotypeABSTRACT
Primary (or "true") microcephaly is inherited as an autosomal recessive trait and is thought to be genetically heterogeneous. Using autozygosity mapping, we have identified a genetic locus (MCPH1) for primary microcephaly, at chromosome 8p22-pter, in two consanguineous families of Pakistani origin. Our results indicate that the gene lies within a 13-cM region between the markers D8S1824 and D8S1825 (maximum multipoint LOD score of 8.1 at D8S277). In addition, we have demonstrated the genetic heterogeneity of this condition by analyzing a total of nine consanguineous families with primary microcephaly.
Subject(s)
Chromosomes, Human, Pair 8 , Genes, Recessive , Microcephaly/genetics , Chromosome Mapping , Consanguinity , Family , Female , Genetic Markers , Humans , Male , Microsatellite Repeats , Pakistan/ethnology , Probability , United KingdomABSTRACT
Nine affected individuals are described from a large extended Pakistani family manifesting a syndrome characterized by a triad of varying degrees of spasticity, severe mental retardation, and visual impairment resulting from tapetoretinal degeneration. In all cases, the parents were at least first cousins, since there was complex consanguinity within the pedigree. The clinical features differ from previously reported syndromes involving pigmentary retinal degeneration and appear to represent a new recessively inherited neurodegenerative condition. Linkage to a 4-5 cM-region between markers D15S211 and D15S152 on 15q24 has been established by autozygosity mapping.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 15 , Intellectual Disability/genetics , Muscle Spasticity/genetics , Retinitis Pigmentosa/genetics , Adolescent , Adult , Child , Female , Humans , Male , Pedigree , Severity of Illness Index , SyndromeABSTRACT
We describe a highly consanguineous family, originating from Pakistan, displaying histiocytosis, joint contractures, and sensorineural deafness. The form of histiocytosis exhibited by this family does not fit readily into any of the recognized classes of this disease. It appears to represent a novel form of familial histiocytosis demonstrating autosomal recessive inheritance. Using autozygosity mapping, we have identified a homozygous region of approximately 1 cM at chromosome 11q25, in affected individuals. A maximum two-point LOD score of 3.42 (recombination fraction straight theta = .00) was obtained with marker D11S968. This is the first genetic locus to be described that is involved in the molecular pathogenesis of histiocytosis.
Subject(s)
Abnormalities, Multiple/genetics , Arthrogryposis/genetics , Chromosomes, Human, Pair 11 , Genes, Recessive , Hearing Loss, Sensorineural/genetics , Histiocytosis/genetics , Adolescent , Child, Preschool , Chromosome Mapping , Female , Genetic Linkage , Humans , Male , Middle Aged , Pedigree , SyndromeABSTRACT
Transmyocardial laser revascularization is a new treatment modality for patients with chronic angina that is refractory to traditional management. A laser is used to create full-thickness channels through areas of ischemic myocardium. Transmyocardial laser revascularization is performed in an effort to improve myocardial oxygenation, eliminate or reduce angina, and improve functional status. Transmyocardial laser revascularization currently is undergoing clinical trials. Early results have demonstrated significant reduction in anginal symptoms. Long-term efficacy of transmyocardial laser revascularization remains to be determined.
Subject(s)
Angina Pectoris/surgery , Laser Therapy/methods , Myocardial Revascularization/methods , Myocardial Revascularization/standards , History, 20th Century , Humans , Male , Middle Aged , Myocardial Revascularization/history , Patient Selection , Treatment OutcomeABSTRACT
BACKGROUND: Although preoperative education decreases the anxiety of patients and family members, the usefulness of a preoperative tour of the ICU has not been studied. In this study, the effect of an ICU tour on the anxiety levels of patients (n = 92) and family members (n = 91) before and after cardiac surgery was examined. METHODS: Using a pretest-posttest quasi-experimental design, patients and family members were assigned to a control group, which received preoperative teaching only (patients, n = 48; family members, n = 48), or to an experimental group, which received preoperative teaching with an ICU tour (patients, n = 44; family members, n = 43). Patients and family members completed two measures of anxiety, the State Trait Anxiety Inventory and a visual analog scale, before and after the intervention. After their first postoperative visit, family members completed the measures again. Repeated measures analysis of variance was used to compare anxiety levels after the intervention. In addition, patients completed the Patient Perception of the ICU Tour Questionnaire after transfer from the ICU. RESULTS: Although patients and family members had a decrease in anxiety after cardia surgery teaching, the decrease was not due to an ICU tour. However, the majority of patients who toured the ICU perceived the tour as beneficial and recommended a tour for future patients. CONCLUSIONS: ICU tours are included in many cardiac surgery educational programs. The majority of patients in this study perceived a benefit or a future benefit from an ICU tour, even though the tour did not significantly reduce the anxiety of the patients or family members.
Subject(s)
Anxiety/prevention & control , Cardiac Surgical Procedures/psychology , Intensive Care Units , Patient Education as Topic/methods , Preoperative Care/psychology , Adult , Aged , Aged, 80 and over , Clinical Nursing Research/methods , Family/psychology , Female , Humans , Male , Middle Aged , Neuropsychological Tests , United StatesABSTRACT
Non-syndromal, recessive deafness (NSRD) is the most common form of inherited deafness or hearing impairment in humans. NSRD is genetically heterogeneous and it has been estimated that as many as 35 different loci may be involved. We report the mapping of a novel locus for autosomal recessive, non-syndromal deafness (DFNB16) in three consanguineous families originating from Pakistan and the Middle East. Using multipoint analysis (HOMOZ/MAPMAKER) a maximum combined lod score of 6.5 was obtained for the interval D15S1039-D15S123. Recombination events and haplotype analysis define a 12-14 cM critical region between the markers D15S1039 and D15S155 on chromosome 15q15-q21.
Subject(s)
Chromosome Mapping , Chromosomes, Human, Pair 15 , Deafness/genetics , Female , Genes, Recessive , Humans , MaleABSTRACT
Hereditary hydronephrosis is a rare condition but several families are described in the literature. The inheritance pattern is autosomal dominant (McKusick number 143400) but the exact aetiology of the hydronephrosis is not clear. However, linkage with the HLA region on chromosome six has been shown previously. We report a family not showing linkage to this region, giving further evidence of genetic heterogeneity in this condition.
Subject(s)
Genetic Heterogeneity , Hydronephrosis/genetics , Adolescent , Adult , Female , Genes, Dominant , Humans , Infant , Infant, Newborn , Lod Score , Major Histocompatibility Complex/genetics , Male , Pedigree , Recombination, GeneticSubject(s)
Decision Making , Dissent and Disputes , Ethics , Group Processes , Life Support Care , Resuscitation Orders/psychology , Advance Directives , Aged , Ethics Committees, Clinical , Female , Humans , Life Support Care/psychology , Patient Advocacy , Patient Care Team , Professional-Family Relations , Spinal Cord Injuries/complications , Spinal Cord Injuries/nursing , Withholding TreatmentABSTRACT
Case management is the health care delivery model for the 1990s, answering the demands for provision of high quality care in a cost-effective manner. The CNS will play a pivotal role in the planning, development, implementation, and evaluation of a case management model. This article discusses practical aspects to consider when developing a case management model that meets the needs of a specific institution.
Subject(s)
Models, Nursing , Nurse Clinicians , Patient Care Planning , Humans , Managed Care ProgramsABSTRACT
Buspirone, an azospirone compound, is a nonsedative anxiolytic that has achieved wide usage since its introduction in 1987. Although relatively free of side-effects, there have been several instances of dyskinesia and dystonia associated with the use of buspirone. We report two patients with persistent movement disorders that developed after prolonged treatment with the drug. One patient developed a lasting problem of cervical-cranial dystonia and tremors after treatment with buspirone at a dosage of 40 mg/day for several weeks. Another, receiving 30 mg/day for 6 weeks, experienced an exacerbation of preexisting spasmodic torticollis and tardive dyskinesia as well as the onset of involuntary phonations. As shown by these and other examples, buspirone poses the risk for inducing or exacerbating several types of movement disorders.