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Biomedical subjects

G Holmgren

Publications and source records attributed to G Holmgren.

At least 91 records · Page 5Linked to original sources
PubMed1993

Modifications of transthyretin in amyloid fibrils: analysis of amyloid from homozygous and heterozygous individuals with the Met30 mutation.

The finding of individuals homozygous for FAP I (familial amyloidotic polyneuropathy, transthyretin TTRMet30) with amyloid deposits in the vitreous body, gave us access to a unique material lacking wild type transthyretin and contaminating proteins. Amyloid TTR is modified in several ways. Besides the full-length protein and its dimer form, two smaller bands were identified by SDS-PAGE and protein sequencing. One corresponded to a peptide starting at amino acid Thr49, the other was a mixture of two peptides starting at positions 1 and 3 in a 3:1 ratio. Upon reduction the amount of the TTR dimer decreased, the monomer amount increased, and the resulting monomers became available for carboxymethylation. Moreover, the mobility of the small band, which includes Cys10, increased upon reduction. This cysteine seemed to be involved in an interchain disulfide bridge both between intact TTR molecules and between small fragments. The same pattern was found in heterozygous fibril material although smaller amounts of the truncated peptides were found. Fibrils were formed both from normal and mutated TTR in heterozygotes. The significance of our results for amyloid formation is discussed.

Amino Acid Sequence↗
PubMed1993

Striatal [11C]-N-methyl-spiperone binding in patients with focal dystonia (torticollis) using positron emission tomography.

Specific binding of [11C]-N-methyl-spiperone to striatal dopamine D2 receptors was assessed using positron emission tomography (PET) in 6 patients with adult-onset focal dystonia (predominantly spasmodic torticollis) and in 5 healthy subjects. No significant difference in average specific striatal tracer uptake between patients and healthy subjects was found. However, in the 5 patients showing lateralisation of clinical signs a trend to higher striatal tracer uptake in the contralateral hemisphere was observed.

Adolescent↗
PubMed1993

Diagnostic radioimmunoassay and DNA-analysis in Swedish and Japanese patients with familial amyloidotic polyneuropathy. Homozygosity for the TTR met30 gene.

Eighteen Swedish patients with familial amyloidotic polyneuropathy were tested for the met30 mutation of the transthyretin (TTR) (prealbumin) gene by RFLP analysis of genomic DNA using the restriction enzyme NsiI. The results confirmed previous findings that the Swedish variant of familial polyneuropathy has the same valine by methionine substitution at position 30, as seen in patients with FAP from Japan, Portugal or patients of Swedish descent from USA. However, two of the patients were homozygous, totally lacking the wild type allele. Measurable serum values for the variant transthyretin (TTR) was detected with a RIA-method in all the 18 Swedish FAP patients studied with a mean concentration of 12.1 +/- 5.1 (SD) mg/100 ml, (11.0 +/- 4.1 when the two homozygotes were excluded). In 45 Japanese patients the mean was 9.2 +/- 2.7 mg/100 ml. The variant TTR was not detected in the healthy controls. The value for the variant TTR was nearly twice that high in the two homozygous patients, 21.14 and 21.16 mg/100 ml, respectively. There was no correlation between the serum levels of variant TTR and the duration of disease or levels of serum albumin in the FAP-patients.

Adolescent↗
PubMed1993

Silver-like syndrome and a small deletion on chromosome 13.

A female child is described with features of Silver's syndrome, including pre- and postnatal growth delay, triangular face, hypertelorism, clinodactyly and developmental delay. In all lymphocytes analyzed, a small deletion was found in chromosome 13. The karyotype was 46,XX,del(13)(q22-32).

Chromosome Aberrations↗
PubMed1993

Familial amyloidotic polyneuropathy in Sweden: a pedigree analysis.

Extended genealogical studies were performed on the heredity patterns in Swedish patients with familial amyloidotic polyneuropathy (FAP) using Swedish historical archives. The population studied included 239 patients: 109 patients were linked to five large pedigrees and 80 patients belonged to 30 smaller pedigrees or nuclear families. In the remaining 50 cases, no genealogical links were found. Differences in mean ages of onset between the different pedigrees were found, although a considerable variation within the pedigrees was also present. There was a tendency for later ages of onset among older generations than younger ones: descendants of affected mothers seem to be more prone to anticipation in age of onset than descendants of affected fathers. Furthermore, there seems to be a tendency for earlier ages of onset among patients with a carrier mother than a carrier father. Some extended pedigrees, from the Skellefteå and Piteå areas, are presented in detail. The former go back into the middle of the 17th century. One important conclusion is that the mutational event may have occurred in late mediaeval times.

Adult↗
PubMed1992

Alteration in molecular structure which results in disease: the Met-30 variant of human plasma transthyretin.

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 A resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 A. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.

Amino Acid Sequence↗
PubMed1992

Fracture patterns in malignant osteopetrosis (Albers-Schönberg disease).

We report the occurrence and distribution of 17 fractures in four patients with malignant, autosomal recessive osteopetrosis. The frequency of the disease in the Caucasian population is in the order of 1 per 20,000, of which the vast majority suffer from a mild autosomal dominant form. The patients have been followed up for 17-22 years and have multiple handicaps. Their case histories indicate that the lower extremity is the most common site for pathological fractures. The traumata were all caused by common accidents, usually falls. Conservative treatment was successful, with normal healing time in the four cases presented.

Adolescent↗
PubMed1992

The gene for Best's macular dystrophy is located at 11q13 in a Swedish family.

A large Swedish family with more than 250 cases of Best's macular dystrophy has been clinically and genetically studied. The gene was traced to a couple born in central Sweden in the 17th century. Highly significant evidence for genetic linkage to DNA markers on chromosome 11q13 was detected. A lod score of 15.12 was obtained at recombination fraction 0.01 with DNA marker INT2 (also called FGF3). The retinally expressed gene ROM1, which maps to the same chromosomal region is a candidate for this genetic disease.

Chromosomes, Human, Pair 11↗
PubMed1992

Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences.

Familial amyloidotic polyneuropathy (FAP) with a mutation in position 30 of transthyretin (TTR) (previously called prealbumin) is an autosomal dominant inherited disorder characterized by varying degrees of peripheral neuropathy, nephropathy, gastrointestinal problems, and vitreous amyloid. We have earlier diagnosed homozygosity for the TTR-Met30-gene using Southern analysis in four Swedish individuals. We have found it possible to detect homozygosity for the Met-30 mutation by amplifying discrete regions of the TTR-gene using polymerase chain reaction (PCR), and the amplification products restricted with NsiI analysed by gel electrophoresis. Clinical data on seven homozygous individuals, including three new cases, are presented.

Aged↗
PubMed1992

The first case of familial amyloidotic polyneuropathy (FAP Met30) in the Finnish population.

Finnish hereditary amyloidosis-Meretoja (FAP type 4) is the predominating type of hereditary amyloidosis in the Finnish population, found in more than 200 individuals. We present a Finnish family with familial amyloidotic polyneuropathy (FAP Met30), a type of amyloidosis hitherto not described in the Finnish population. Genealogical tracing back to the 18th century revealed no connections with Swedish FAP families, but introduction from Sweden is the most probable origin of the FAP Met30 gene.

Aged↗
PubMed1992

Attitudes of rural people in central Ethiopia towards leprosy and a brief comparison with observations on epilepsy.

To find out public attitudes toward leprosy a door-to-door survey was carried out in 1546 sampled households in the rural farming community of Meskan and Mareko in central Ethiopia, where the prevalence of leprosy is estimated to be 1:1000. Attitudes toward leprosy were compared with attitudes to epilepsy, studied in a previously performed survey in the same community. Eighty-seven per cent of the respondents were above the age of 25, and 59.5% were females. There were slightly more Muslims (54%) than Christians. The majority of the interviewees (87%) were farmers, with an illiteracy rate of 84%. Ninety-five per cent and 83%, respectively, were not willing to employ or work with a person having the disease. Seventy-five per cent would not allow their children to associate with a playmate suffering from leprosy. Comparative analysis of attitudes in the same community showed that negative attitudes toward leprosy were stronger than those toward epilepsy, particularly with regard to matrimonial associations, sharing of accommodation, and physical contact with an affected person. The reasons for these differences appear to be the community's deeply entrenched belief that leprosy is both hereditary and contagious, expressed respectively by 48% and 53% of the respondents. In order to minimize the perpetuation of negative attitudes, there is a need to educate and impress on the population that leprosy is a treatable infectious disease which is not congenitally acquired, and that it is even curable if detected early. The study reinforces previously proposed suggestions that, in developing countries such as Ethiopia, leprosy care should be integrated into the general health services.

Adolescent↗
PubMed1991

Association of the Robin sequence with the fragile X syndrome.

We report on 4 individuals with the fragile X [fra(X)] syndrome and the Robin sequence (or elements of that sequence). To our knowledge, this association has been described in only one other boy. However, males with the fra(X) syndrome have been reported to have an increased incidence of cleft palate. We recommend that children with a cleft palate or the Robin sequence be assessed for developmental delays and a family history of mental retardation. The fra(X) syndrome may be one of the genetic causes of the Robin sequence and, when indicated, children with the sequence should be tested for fra(X).

Cleft Palate↗
PubMed1991

Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia.

The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.

Adolescent↗
PubMed1991

Attitudes of rural people in central Ethiopia towards epilepsy.

In the farming community of the sub-district of Meskan and Mareko in central Ethiopia, where the prevalence of epilepsy is known to be 5.2/1000, a door-to-door survey was undertaken in 1546 sampled households to find out public attitudes to epilepsy. Nearly 64% of the respondents were in the age group of 14-50 years, and 58.6% were women. The majority (86%) were illiterate, and 94% had incomes of a subsistence level; 89% had heard or witnessed seizures. Traditional views on the association of evil spirits and superstition was prevalent. By 45% of the interviewees, the disease was believed to be contagious through physical contacts during an attack. Although there was sympathetic concern in the community for the person suffering from epilepsy, negative attitudes were strong on matrimonial associations, sharing of accommodation and physical contacts with affected persons, particularly when there were obvious signs and frequent attacks by seizures. The study demonstrates that the rural community has very poor knowledge of the causes and nature of epilepsy, and this has resulted in social deprivations and at times, rejection of the sufferers.

Adolescent↗
PubMed1991

Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30).

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

Adult↗