Biomedical subjects

W G Johnson

Publications and source records attributed to W G Johnson.

At least 37 records · Page 2Linked to original sources

PubMed1998

The alpha-synuclein Ala53Thr mutation is not a common cause of familial Parkinson's disease: a study of 230 European cases. European Consortium on Genetic Susceptibility in Parkinson's Disease.

We report the results of a screen of 230 European familial index cases of Parkinson's disease for the recently described Ala53Thr mutation in the alpha-synuclein gene in an autosomal dominant Parkinson's disease kindred. No mutations were found from this broad white population, and we therefore conclude that although of great interest, this mutation is a very rare cause of familial Parkinson's disease.

Adult↗

PubMed1998

Genetics of the febrile seizure susceptibility trait.

Febrile seizures are the commonest form of convulsion, occurring in 2-5% of infants in Europe and North America and 6-9% of infants in Japan. In large families, the febrile seizure susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. In the other families, inheritance appears to be multifactorial. Recent linkage studies provide evidence that regions of chromosomes 8 and 19 contain febrile convulsions (FC) susceptibility genes. This opens up the way to cloning a febrile seizure gene and determining the contributions of these gene loci to febrile seizures in the sporadic cases and the small families. Cloning a febrile seizure gene will make possible new approaches to prevention and therapy. It will also be possible to determine whether a febrile seizure gene contributes to other types of seizures.

Chromosomes, Human, Pair 19↗

PubMed1997

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Age of Onset↗

PubMed1997

Dietary and exercise interventions for juvenile obesity: long-term effect of behavioral and public health models.

We investigated the influence of nutrition and exercise interventions within cognitive/behavioral and public health formats on weight and blood lipid profiles in obese children. Compliance was also examined as well as the relationship of the compliance measures with clinical outcome variables. Three conditions were compared over 16 sessions: nutrition and eating-habit change followed by exercise (NE), exercise followed by nutrition and eating-habit change (EN), and an information control (INFO). NE and EN were presented in a cognitive/ behavioral framework which focused on the development of self-regulation whereas the INFO condition received the same material in a public health/educational model. NE and EN participants evidenced modest, yet significant, reductions in weight and blood lipids, and the impact of these two interventions endured at a five-year follow-up. In contrast, INFO participants displayed stable weight and blood lipids during the course of the program, and most remained morbidly obese at follow-up. Improved nutrition, increased physical activity and fitness were significantly correlated with weight and lipid reductions.

Adolescent↗

PubMed1997

Pelizaeus-Merzbacher-like disease: exclusion of the proteolipid protein locus and documentation of a new locus on Xq.

A large X-linked kindred with Pelizaeus-Merzbacher like disease (Pelizaeus-Merzbacher disease [PMD] lacking a proteolipid protein [PLP] mutation) was studied for linkage to 34 X-chromosome short tandem repeat polymorphism markers. Recombinational events excluded linkage to PLP and supported linkage to a 9.4-cM critical region more than 10 cM away from PLP on the X chromosome. A maximum 2-point lod score of 3.91 was observed for DXS441 at theta = 0.0. Neuropathologic study of one affected male showed intact myelin. The data thus support a different etiology for a disease that clinically resembles PMD, distinguishable phenotypically only by degree of myelin involvement. Other patients with the clinical diagnosis of PMD but without PLP mutations could have mutations at this new locus.

Adolescent↗

PubMed1997

The costs of epilepsy and cost-based evaluations of anticonvulsants.

The rapid increase in cost-related studies of epilepsy is a response to the need for information by healthcare organisations and providers who are being asked to include costs in their criteria for choosing among competing anticonvulsants. This article attempts to help non-economists to evaluate the results of research on the cost of epilepsy and cost-related evaluations of anticonvulsants. Selected articles are reviewed as examples of the types of information that they are likely to encounter. The review demonstrates that the most typical approach to the evaluation of anticonvulsants combines hypothetical patients and simulated treatments, based on expert opinions with cost data from different, noncomparable sources to estimate the costs and potential savings of competing drugs. The interpretation of the potential biases from the large array of data from different sources is extremely difficult and the comparison of different results is nearly impossible. The discussion suggests that the most important problem faced by potential consumers of cost-related research on epilepsy is the wide variance in the concepts and methods used to evaluate the cost effectiveness or cost-minimising effects of competing anticonvulsants. The importance of choices among competing anticonvulsants for costs and the well-being of patients make it imperative that researchers adopt concepts and methods that produce a much higher degree of comparability among studies than is now in practice. Some of the articles reviewed make important contributions to the achievement of that objective.

Anticonvulsants↗

PubMed1996

Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

Chromosome Mapping↗

PubMed1996

Pedigree analysis in families with febrile seizures.

Febrile seizures are the most common form of seizures, occurring in an estimated 2-5% of North American children. We carried out a systematic pedigree study of febrile seizure probands. Forty of 52 probands (77%) in a referral population selected for increased severity had more than one case per family: one family had 10 cases, one family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fit the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. Because the cases were selected for increased severity, this represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies. Simulated lod scores showed adequate power for a linkage study in the absence of heterogeneity. Individual families had simulated average lod scores as high as 2.1. However, with potential heterogeneity, assuming only 70% of families share the same disease locus, average lod scores were marginal, and a high density map of marker loci and additional families would be required to document linkage.

Databases, Factual↗

PubMed1996

The error of using returns-to-work to measure the outcomes of health care.

This article uses data from The Survey of Ontario Workers With Permanent Impairments. the world's largest survey of injured workers, to show that, as currently used, return-to-work is a misleading measure of the effectiveness of health care. The article discusses examples of two serious limitations on the use of return-to-work to measure the outcomes of health care, where health care refers to all the medical and rehabilitative services provided to a worker following a workplace injury. The first limitation is that return-to-work, like many other outcomes of health care, is influenced by factors that are not directly related to health care. Using a logit model to estimate the determinants of first absences from work after an injury, we find that socioeconomic characteristics, economic incentives, and job characteristics have a significant influence on return-to-work. The second limitation on return-to-work as an outcome measure is that the first return-to-work after an injury, like a hospital discharge, frequently marks the end of only the first of several episodes of work disability caused by the original injury. Using first post-injury returns-to-work as a proxy for recovery, we would assume that 85% of the Ontario workers recovered from their injury when, in fact, 61% had subsequent spells of work disability. We identified four mutually exclusive patterns of post-injury work and work disability. Multinomial logit estimates of the determinants of the patterns show that health care is only one of several influences on return-to-work. The results also demonstrate that if return-to-work is used to measure outcomes, it must be evaluated over a time horizon that permits multiple spells of work disability.

Bias↗

PubMed1996

PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida.

From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.

Amino Acid Sequence↗

PubMed1996

Why is the treatment of work-related injuries so costly? New evidence from California.

There is growing evidence that workers' compensation insurers are charged substantially more than health insurers for the treatment of similar injuries. The first study of the problem, conducted in Minnesota in 1987, found that both overutilization of services and price discrimination contributed to the charge differential. This article applies the Minnesota model to 1991-1993 data on health care charges and payments from California. Approximately 13,000 persons with work-related injuries are compared to approximately 3,600 persons with similar injuries that occurred off the job. Despite important differences in the populations and workers' compensation laws in California and Minnesota, workers' compensation insurers are charged more than health insurers for the treatment of similar injuries in both states. The difference in California's payments is attributable to using more health care providers and services to treat workers' compensation patients. The results do not support the hypothesis that work-related injuries cost more to treat because they are more severe than similar injuries occurring off the job.

Accidents, Occupational↗

PubMed1995

Reduced fecundity in male ALS gene-carriers.

In order to study genetic aspects in multicase families, 89 amyotrophic lateral sclerosis (ALS) and 214 Parkinson disease (PD) kindreds were analyzed in parallel studies. Obligate gene-carriers were identified as described previously [Chatkupt et al., 1992: Am J Med Genet 44:508-512]. There were fewer children per gene-carrier male (2.42) than per gene-carrier female (3.25, Student's t-test, P < .0003) for ALS but not for other diseases. The data taken together suggest that fecundity in ALS gene-carriers was reduced in males, possibly as a result of reduced fertility. Since childbearing is usually accomplished well before the onset of neurological symptoms in ALS, and since reduced fecundity was found in male ALS gene-carriers, these findings raise the possibility that an ALS gene might have a pleiotrophic effect on fertility in males occurring decades before the onset of neurological symptoms. Evidence is presented linking reactive oxygen species to reduced fertility in males. Alternatively, decreased or nonfunctional androgen receptors could play a role.

Amyotrophic Lateral Sclerosis↗

PubMed1995

Short tandem repeat polymorphism linkage studies in a new family with X-linked mental retardation (MRX20).

A family with X-linked recessive mental retardation (XLMR) without other obvious manifestations (MRX20) was studied with 14 short tandem repeat polymorphism (STRP) markers. Two-point lod scores above 3 were obtained with DXS1003, DXYS1, DXS3, and DXS458. A multipoint lod score of 4.25 was obtained with peak at DXS1003. Recombination events identify a 55.6 cM interval between DXS1068 and DXS454, while a one unit support interval identifies 40 cM between MAOA and DXS458.

Genetic Linkage↗

PubMed1995

Absence of mutations in superoxide dismutase and catalase genes in patients with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is an adult-onset, neurodegenerative disorder characterized by a selective loss of the dopaminergic cells of the substantia nigra and by progressive motor decline. Studies have shown aberrant oxidative stress metabolism within the substantia nigra and other dopaminergic regions of the brain in patients with PD. OBJECTIVE: To screen the genes of three free radical detoxifying enzymes--copper/zinc superoxide dismutase, manganese superoxide dismutase, and catalase--for mutations in patients with PD. PATIENTS AND METHODS: A total of 107 unrelated patients with PD from two PD populations (familial and sporadic) were screened for mutations in the genes of copper/zinc superoxide dismutase, manganese superoxide dismutase, and catalase by single-strand conformation analysis. The diagnosis of PD was based on the clinical observations of resting tremor, rigidity, and bradykinesia. RESULTS: No mutations were identified. However, we did identify an amino acid substitution (glycine to aspartic acid) in exon 9 of the catalase gene in one patient; decreased red blood cell catalase activity was observed in this patient. CONCLUSION: Parkinson's disease is not caused by mutations in the genes of these three detoxifying enzymes. The exon 9 variant in the catalase gene in the one family with PD is most likely a silent mutation and not the genetic cause of PD in this family.

Adult↗

PubMed1995

Parents do matter: genomic imprinting and parental sex effects in neurological disorders.

Genomic imprinting is a recently recognized phenomenon of differential expression of genetic material depending upon whether the genetic material has come from the male or female parent. This process of differential phenotypic expression involves mammalian development both in the normal and abnormal situations, resulting in parental sex effects. However, some parental sex effects may be due to other mechanisms such as mitochondrial inheritance. In the following article, evidence for genomic imprinting in experimental animals and in diseases are summarized. Relevant human neurological disorders manifesting parental sex effects discussed here include myotonic dystrophy, Huntington's disease, fragile X syndrome, spinocerebellar ataxia type 1, and neurofibromatosis type 1 and 2. A possible mechanism of imprinting involves the processes of methylation imprint and replication imprint. The knowledge of imprinting is helpful in clinical practice particularly in the areas of genetic counseling, prenatal diagnosis, and possible future gene therapy.

Animals↗

PubMed1995

Absence of linkage between familial neural tube defects and PAX3 gene.

Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene for NTD because mutations of Pax-3 cause the mouse mutant Splotch (Sp), an animal model for human NTD. Mutations in PAX3 were also identified in patients with Waardenburg syndrome type 1 (WS1). At least eight patients with both WS1 and NTD have been described suggesting pleiotropy or a contiguous gene syndrome. Seventeen US families and 14 Dutch families with more than one affected person with NTD were collected and 194 people (50 affected) from both data sets were genotyped using the PAX3 polymorphic marker. The data were analysed using affecteds only linkage analysis. The lod scores were -7.30 (US), -3.74 (Dutch), and -11.04 (combined) at theta = 0.0, under the assumption of the autosomal dominant model. For the recessive model, the lod scores were -3.30 (US), -1.46 (Dutch), and -4.76 (combined) at theta = 0.0. Linkage between PAX3 and familial NTD was excluded to 9.9 cM on either side of the gene for the dominant model and to 3.63 cM on either side of the gene for the recessive model in the families studied. No evidence of heterogeneity was detected using the HOMOG program. Our data indicate that PAX3 is not a major gene for NTD.

Base Sequence↗

PubMed1995

Friedreich ataxia.

Friedreich ataxia is an autosomal recessive ataxia with onset usually before puberty whose characteristic clinical features include progressive ataxia of gait and limbs, dysarthria, loss of joint position and vibratory sense, absent knee and ankle jerks, and Babinski signs. Foot deformity, scoliosis, diabetes mellitus, and cardiac involvement are common and characteristic. Patients survive until about age 30 years although longer survivals occur. A later onset, more slowly progressive form seems to be an allelic variant. The basic process seems to be a dying-back of neuronal processes. Using linkage mapping techniques, the classical form of Friedreich ataxia has been localized to 9q13-q21, a region on the long arm of chromosome 9. Haplotype analysis, analysis of recombinants, and physical mapping techniques, including construction of a YAC contig, have narrowed the interval for the Friedreich ataxia gene, FRDA, to a few hundred thousand base pairs. Candidate genes in the region are being studied by techniques of mutation analysis. It is likely that the Freidreich ataxia gene will be cloned soon. A condition resembling Friedreich ataxia with decreased vitamin E levels has been localized to chromosome 8 and is discussed elsewhere.

Child↗

PubMed1994

Linkage analysis of a candidate locus (HLA) in autosomal dominant sacral defect with anterior meningocele.

Sacral defect with anterior meningocele (SDAM) is a type of caudal dysgenesis. It is present at birth and becomes symptomatic later in life, usually because of obstructive labor in females, chronic constipation, rectal fistula and abscess, or meningitis. The inheritance is autosomal dominant. HLA has been implicated in caudal dysgenesis because of analogy with disorders of the T-locus complex, a tail length determining gene in mice which is linked to the major histocompatibility complex, H-2. Members of a 5-generation family with sacral defect and anterior meningocele (SDAM) were typed with polymorphic markers (dinucleotide repeats D6S89, D6S105, D6S109, and TCTE1) linked to HLA. Two-point and multipoint analysis exclude the HLA region as the location for the SDAM gene in this family.

Abnormalities, Multiple↗