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Biomedical subjects

G Holmgren

Publications and source records attributed to G Holmgren.

At least 73 records · Page 4Linked to original sources
PubMed1995

Localization of autosomal dominant cerebellar ataxia associated with retinal degeneration and anticipation to chromosome 3p12-p21.1.

We present linkage analysis on a large Swedish five-generation family of 15 affected individuals with autosomal dominant cerebellar ataxia (ADCA) associated with retinal degeneration and anticipation. Common clinical signs in this family include ataxia, dysarthria and severely impaired vision with the phenotype ADCA type II. Different subtypes of ADCA have proven difficult to classify clinically due to extensive phenotypic variability within and between families. Genetic analysis of a number of ADCA type I families shows that heterogeneity exists also genetically. During the last few years several types of ADCA type I have been localized and to date six genetically distinct forms have been identified including SCA1 (6p), SCA2 (12q), SCA3 and Machado-Joseph disease (MJD) (14q), SCA4 (16q), and finally SCA5 (11). We performed a genome-wide search of the Swedish ADCA type II family using a total of 270 microsatellite markers. Positive lod scores were obtained with a number of microsatellite markers located on chromosome 3p12-p21.1. Three markers gave lod scores over 3 with a maximum lod score of 4.53 achieved with the marker D3S1600. The ADCA type II gene could be restricted to a region of 32 cM by the markers D3S1547 and D3S1274.

Cerebellar Ataxia↗
PubMed1995

Occupational and other risk factors for clinically overt familial amyloid polyneuropathy.

Amyloidosis is associated with the deposition of amyloid substance in various tissues of the body. In several forms of familial amyloid polyneuropathy, mutated transthyretin is the main fibril component. The disease is inherited as an autosomal dominant trait with onset in adult life, but few carriers develop symptoms. The aim of the present investigation was to screen for additional factors that might be necessary for the development of familial amyloid polyneuropathy. We conducted a case-control study involving 51 male and 30 female cases of clinically overt familial amyloid polyneuropathy and 306 male and 317 female population controls. We considered occupational exposures, disease histories, and medical treatments as potential determinants of risk for clinically overt disease. We found an odds ratio of 5.4 for dressmakers. Low and high levels of exposure to organic solvents resulted in an odds ratio of 2.1 and 11.8, respectively. A history of prostatic hyperplasia, cholecystic disease, or appendectomy was also a risk factor, possibly as a consequence of anesthesia.

Adult↗
PubMed1995

Outcome of pregnancy in women with myotonic dystrophy and analysis of CTG gene expansion.

Pregnancy outcome was investigated in 32 women with clinically obvious myotonic dystrophy. The results indicated that there are two groups of women, those whose children have the adult type of myotonic dystrophy and those whose children have the congenital type. The overall perinatal mortality was 14%. Polyhydramnios was an obvious sign of the congenital type. No subclinical gene carrier was found among the children. We conclude that prenatal diagnosis should be offered to women with myotonic dystrophy, particularly to those who have previously given birth to a child with the congenital type.

Chromosomes, Human, Pair 19↗
PubMed1995

Hereditary myopathy with lactic acidosis, succinate dehydrogenase and aconitase deficiency in northern Sweden: a genealogical study.

A hereditary myopathy with lactic acidosis during physical exercise, low physical work capacity, and paroxysmal myoglobinuria (HML), called "Myopathy with deficiency of succinate dehydrogenase and aconitase" (McKusick 255125) has been described in 19 members of nine families who lived in two geographically separate areas in northern Sweden. By using the unique Swedish historical archives, including Catechetical Meeting Records from a number of northern Swedish parishes, it has been possible to trace ancestors of the nine families including all known 19 cases back in time to some key couples, who lived up to 300 years ago (that is seven to ten generations). No common single couple or common links between families in the past was found in these registers as a support for a single or several mutations that had developed far back in time. The mode of inheritance in this family is most likely autosomal recessive. This material will be used for the chromosomal localisation of the gene.

Acidosis, Lactic↗
PubMed1995

Adult onset idiopathic torsion dystonia is excluded from the DYT 1 region (9q34) in a Swedish family.

A gene (DYT1) for early onset idiopathic torsion dystonia was mapped to chromosome 9q34 in non-Jewish and Jewish families. The DYT1 gene region has been excluded in other families with adult onset and cervical or cranial onset idiopathic torsion dystonia from the United States, Great Britain, and France. The role of DYT1 in a Swedish family with adult onset idiopathic torsion dystonia in four generations was examined. The disease seems to be inherited in an autosomal dominant mode with reduced penetrance in this family. There were 10 affected family members, with a mean age of onset of 27 (range 18 to 50) years. The disease showed variable expression, with focal, multifocal, and generalised forms of dystonia in different family members. Genetic analysis excluded the chromosomal region containing the DYT1 locus as being responsible for dystonia in this family.

Adolescent↗
PubMed1994

Fine mapping of Best's macular dystrophy localizes the gene in close proximity to but distinct from the D11S480/ROM1 loci.

The Best's macular dystrophy (BMD) gene has previously been mapped to the 11q13 region. In this study, recombination data localizes the BMD gene to the 6-cM genetic interval between the markers Fc epsilon RI and D11S480/ROM1 in a large Swedish 12-generation BMD family. Mutation analyses of the candidate gene ROM1 did not reveal any mutations that could explain the disease phenotype. However, one recombination event between intragenic ROM1 polymorphisms and the BMD phenotype was detected. Therefore, it is highly unlikely that mutations in the ROM1 gene cause BMD. Identification of the disease gene will elucidate the pathophysiological mechanism in BMD, which may also be of importance in other retinopathies such as age-related macular degeneration.

Alleles↗
PubMed1994

The gene for diffuse palmoplantar keratoderma of the type found in northern Sweden is localized to chromosome 12q11-q13.

Hereditary palmoplantar keratoderma is characterized by hyperkeratosis of the skin of palms and soles. An autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma, frequently complicated by fungal infections, is encountered in northern Sweden with a prevalence of 0.3-0.55%. We have examined two families with this type of palmoplantar keratoderma and localized the causative genetic defect to a 14 cM interval on chromosome 12q11-q13, a region known to contain the keratin type II gene cluster as well as the retinoic acid receptor gamma gene. The palmoplantar keratoderma variant investigated in this study is thus genetically different from epidermolytic palmoplantar keratoderma, which recently has been shown to result from mutations in the gene for the type I keratin 9.

Chromosome Mapping↗
PubMed1994

Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q.

Amelogenesis imperfecta (AI), is an inherited odontological disease which affects the formation of enamel. We report a linkage analysis study performed on three Swedish families, where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained. Recombinations localized the ADAI locus to a chromosome region which contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

Amelogenesis Imperfecta↗
PubMed1994

Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy.

OBJECTIVES: To describe the evolution of nutritional and neurological complications in a Swedish population of patients with familial amyloidotic polyneuropathy, and to identify prognostic factors and useful tests for monitoring the progress of the disease. DESIGN: Prospective and retrospective study of patients with familial amyloidotic polyneuropathy. SETTING: Tertiary referral centre. SUBJECTS: Twenty-seven patients with familial amyloidotic polyneuropathy, and a symptomatic onset before the age of 50. MAIN OUTCOME MEASURES: Age at onset, duration of disease before death, serum albumin, body mass index (BMI), duration and grade of peripheral neuropathy and gastrointestinal disturbances. Faecal fat, xylose test and 75selenohomocholic acid-taurine (SeHCAT) test were used for assessment of malabsorption. RESULTS: Thirteen patients died during the study period after a disease duration of between 9 and 18 years (mean 13). A short time interval between the onset of neurological and of gastrointestinal symptoms had greater impact on survival than age at onset in this selected group of patients (r = 0.65; P = 0.017). Malnutrition was evaluated by multiplying the [body weight (kg)/height2 (m)] with the serum albumin to compensate for oedema. This modified body mass index (mBMI) was significantly correlated to the number of years before death (r = 0.89; P < 0.0005) and to the duration of gastrointestinal symptoms (r = -0.66; P < 0.0005), but not to duration of disease (r = -0.2; P = 0.20). Polyneuropathy was graded according to functional capacity from I to IV (PND score) and was correlated to the number of years before death and mBMI, but not to serum albumin. The SeHCAT test for bile acid malabsorption was significantly correlated to the duration of gastrointestinal symptoms and to mBMI (r = -0.67; P = 0.0003 and r = -0.62; P = 0.003, respectively). CONCLUSION: The investigation disclosed that a short time interval between the onset of neurological and of gastrointestinal symptoms is associated with a decreased survival time. The mBMI was closely related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. The mBMI appears to be well suited to monitoring disease progress and gives prognostic information.

Adult↗
PubMed1994

The gene for familial dystonia with myoclonic jerks responsive to alcohol is not located on the distal end of 9q.

A gene (DYT1) for susceptibility to early-onset torsion dystonia in Ashkenazi Jewish and Gentile kindreds is situated on chromosome 9q32-q34 in a 6-7 cM span between markers AK1 and ASS. To determine whether transmission of familial dystonia with myoclonic jerks responsive to alcohol was consistent with a gene in this region, we studied the 37 members of a Swedish family, of whom 20 were so affected. A lod score of < -2.00 from a two-point linkage analysis with six DNA markers covering a 30 cM span from D9S26 to D9S10 that included the region of the DYT gene indicated that this gene is not located in this region, and that two or more autosomal loci are responsible for hereditary dystonia in humans.

Alcohols↗
PubMed1994

Geographical distribution of TTR met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate.

The first Swedish case of familial amyloidotic polyneuropathy (FAP) was published in 1965. The same transthyretin (TTR met30) mutation as that seen in Japanese, Portuguese, and other populations was also found in Swedish FAP patients. More than 350 patients with clinical manifestations of FAP have been diagnosed in northern Sweden, most of them originating from the areas around Skellefteå and Piteå. The mean age of onset is 56 years, much later than in patients from Japan and Portugal. To estimate the frequency of the TTR met30 mutation in the counties of Västerbotten and Norrbotten, sera from 1276 persons aged 24 to 65 years, randomly sampled from a health programme (MONICA), were screened with the monoclonal antibody FD6. In 19 persons, 13 females and six males, a positive reaction was seen in an Elisa test using this antibody. DNA analysis confirmed the TTR met30 mutation and showed that 18 were heterozygous and one homozygous for this mutation. Other mutations were not looked for in this study. The mean TTR met30 carrier frequency in the area was 1.5% ranging from 0.0 to 8.3% in 23 subpopulations. There was a notable discrepancy between the regional distribution of the TTR met30 allele and the morbidity rate for FAP. The estimated number of TTR met30 gene carriers in a total population of 500,000 in the area is approximately 7500. The penetrance of the TTR met30 mutation shows considerable variation between families, and the overall diagnostic (predictive) value in this population is as low as around 2%.

Adult↗
PubMed1994

Charcot-Marie-Tooth disease in northern Sweden: pedigree analysis and the presence of the duplication in chromosome 17p11.2.

Sixty-seven patients in 29 families with the diagnosis of Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy in northern Sweden were examined by pedigree and DNA analysis for the CMT1a duplication within chromosome 17p11.2. There were 39 patients in nine families with Charcot-Marie-Tooth type 1 and autosomal dominant inheritance and in all these cases the duplication was seen. In six patients in three families with Charcot-Marie-Tooth type 1 the pedigrees strongly suggested autosomal recessive inheritance. In two patients DNA analysis was not informative but in the others no duplication was shown. There were also 11 "sporadic" patients and one pair of sibs classified as Charcot-Marie-Tooth type 1, but there was no duplication shown although in four patients DNA analysis was not informative. In nine patients with Charcot-Marie-Tooth type 2 from five families and in 13 unaffected relatives of Charcot-Marie-Tooth patients the CMT1a duplication was not found.

Adolescent↗
PubMed1994

Familial clustering of multiple sclerosis in a northern Swedish rural district.

A small rural district in the most northerly province of Sweden was found to have a very high occurrence of multiple sclerosis. A total of 12 patients with multiple sclerosis among 4744 inhabitants were identified (five females, seven males), corresponding to a prevalence of 253/100,000. Many of the patients were related and a further 21 cases with multiple sclerosis (14 females, seven males), mostly living in the neighbouring area, have family ties to the district. A genealogical investigation showed that 22 of the 33 patients identified had ties of kinship and thus, to our knowledge, the largest aggregation of multiple sclerosis in a family is presented.

Adolescent↗
PubMed1994

Strong founder effect for the fragile X syndrome in Sweden.

We analyzed the FRAXAC2 and DXS548 microsatellites in normal and fragile X chromosomes from Sweden and the Czech Republic in order to investigate a possible founder effect for chromosomes carrying a fragile X mutation. We report a much stronger linkage disequilibrium between the marker haplotypes and the disease in Swedish fragile X chromosomes than in Czech and most other previously studied Caucasian populations. Two haplotypes accounted for 64% of Swedish fragile X chromosomes and for only 14% of normal chromosomes. Neither of these two haplotypes was found in Czech chromosomes, but the most common Swedish fragile X haplotype is the same as that reported to be predominant in Finnish fragile X patients. Linkage disequilibrium was observed in the Czech fragile X chromosomes but the haplotypes were more diverse and similar to those observed in other Caucasian populations. The most prevalent Swedish fragile X haplotype was traced back from affected males to common ancestors in the early 18th century. This indicates an apparently silent segregation of fragile X alleles through up to nine generations. The geographical distribution of the two major at-risk haplotypes in Sweden suggests that they were present among early settlers in different parts of the country.

Chi-Square Distribution↗
PubMed1993

Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis.

Familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant disorder. Progressive peripheral and autonomic neuropathy are associated with neural and visceral deposition of amyloid, derived most commonly from the Met-30 variant of the plasma protein transthyretin. We have reported previously that orthotopic liver transplantation causes prompt replacement of variant transthyretin by the donor wild-type in the plasma. We now report clinical outcome 1-2 years after transplantation. Three of the first four patients have improved general wellbeing, walking ability, and bowel function, and one of them has regained normal bladder and bowel function. There has been little objective improvement in peripheral neuropathy. The fourth patient, who had the most severe neurological deficits and a complicated postoperative course, has not improved but there has been no further deterioration in contrast to the inexorable progression before transplantation. Quantitative scintigraphy with radiolabelled serum amyloid P component showed visceral amyloid deposits in all three patients studied; in two who were followed serially the deposits regressed after transplantation in association with the clinical improvement. Another FAP patient who was also monitored prospectively for 2 years but who did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition. Liver transplantation does therefore have important benefits in FAP during the first 2 years after surgery. Neurological decline is halted and amyloid deposits can be mobilised. The best timing and long-term results of the procedure must now be established.

Adult↗
PubMed1993

The x-ray crystal structure refinements of normal human transthyretin and the amyloidogenic Val-30-->Met variant to 1.7-A resolution.

The x-ray crystal structures of normal human transthyretin (prealbumin) and the amyloidogenic Val-30-Met variant have been refined at 1.7-A resolution to R-values of 0.168 and 0.179, respectively, for 19,882 and 20,362 reflections (Fobs > 2.0 sigma). Standard deviations for stereochemical parameters are 0.018 and 0.022 A for bond distances, 0.030 and 0.038 A for angle distances, and 0.035 and 0.070 A for planar 1-4 distances. The newly refined normal structure shows improvement over the original structure of Blake and Swan (Blake, C. C. F., and Swan, I. D. A. (1971) J. Mol. Biol. 61, 217-224) in stereochemistry and in the conformation of the loop regions. Residues Arg-103, Thr-123, Asn-124, and Pro-125 have now been resolved, and residues 1-9 and 126-127 have been modeled with the aid of simulated annealing refinement. The functional form of transthyretin is a tetramer, having a cylindrical cavity which will bind thyroxine and an exterior binding site for the complex of retinol with retinol-binding protein. The monomer is a beta barrel flattened to become more like a sandwich with residue 30 in the interior. The methionyl for valyl substitution forces the beta sheets of the monomer as much as 1 A apart, resulting in a distortion of the thyroxine-binding cavity, in agreement with the independent observations that the Met-30 variant has low affinity for thyroxine.

Amino Acid Sequence↗