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Biomedical subjects

G Holmgren

Publications and source records attributed to G Holmgren.

At least 19 recordsLinked to original sources
PubMed1998

Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation.

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin. We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls. All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset. The repeat length in SCA7 patients ranged from 40 to >200 repeats. The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported. In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with <59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically. The other two SCA7 families could not be traced back to a common ancestor. All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.

Adolescent↗
PubMed1997

Ameloblastin gene (AMBN) maps within the critical region for autosomal dominant amelogenesis imperfecta at chromosome 4q21.

Amelogenesis imperfecta (AI) is a broad group of hereditary enamel defects that is characterized by a high degree of clinical diversity. Recently, the local hypoplastic form of autosomal dominant AI (AIH2) has been mapped to human chromosome 4q in a 17.6-cM region. This locus has been further refined to a 4-Mb interval between D4S2421 and Albumin. Recently, a cDNA clone for an enamel matrix protein, ameloblastin (AMBN), has been isolated. In this report, we have isolated a PAC human genomic clone containing the human AMBN gene. The AMBN was mapped by two color fluorescence in situ hybridization using two P1 genomic clones for sequence tagged site (STS) markers, D4S400 and D4S409, which flank the critical AIH2 region. Our results place AMBN at 4q21 between D4S409 (4q13) and D4S400 (4q21). Furthermore, the AMBN PAC genomic clone was shown to contain three STS markers, D4S2604, D4S2670, and D4S2609, which are contained within the critical region defined by six Swedish families with AIH2. AMBN is therefore a strong candidate gene for AIH2.

Amelogenesis Imperfecta↗
PubMed1997

Oxidative stress is found in amyloid deposits in systemic amyloidosis.

Oxidative stress in human amyloid deposits from patients with systemic amyloidosis, such as familial amyloidotic polyneuropathy (FAP), primary amyloidosis, and secondary amyloidosis, was examined immunohistochemically by means of an affinity purified anti-hydroxynonenal (HNE) antibody to HNE, a marker of lipid peroxidation. Furthermore, the levels of thiobarbituric acid reactive substances (TBARS), which is another marker of lipid peroxidation, and the levels of protein carbonyl, a maker of protein modifications by free radicals, were determined in FAP patients and healthy controls. Affinity purified anti-HNE antibody reacted with amyloid deposits in all types of amyloid tissues examined. Significantly higher levels of TBARS and protein carbonyl were found in amyloid rich tissues of FAP patients compared with those in the control subjects. These results verify that lipid peroxidation via free radical injury occurs in amyloid deposits in systemic amyloidosis. The protein modifying properties of free radicals increase the likelihood that they play an important role in the amyloid formation process.

Adult↗
PubMed1997

Mapping of the locus for autosomal dominant amelogenesis imperfecta (AIH2) to a 4-Mb YAC contig on chromosome 4q11-q21.

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of inherited enamel defects. We recently mapped a locus for autosomal dominant local hypoplastic amelogenesis imperfecta (AIH2) to the long arm of chromosome 4. The disease gene was localized to a 17.6-cM region between the markers D4S392 and D4S395. The albumin gene (ALB), located in the same interval, was a candidate gene for autosomal dominant AI (ADAI) since albumin has a potential role in enamel maturation. Here we describe refined mapping of the AIH2 locus and the construction of marker maps by radiation hybrid mapping and yeast artificial chromosome (YAC)-based sequence tagged site-content mapping. A radiation hybrid map consisting of 11 microsatellite markers in the 5-cM interval between D4S409 and D4S1558 was constructed. Recombinant haplotypes in six Swedish ADAI families suggest that the disease gene is located in the interval between D4S2421 and ALB. ALB is therefore not likely to be the disease-causing gene. Affected members in all six families share the same allele haplotypes, indicating a common ancestral mutation in all families. The AIH2 critical region is less than 4 cM and spans a physical distance of approximately 4 Mb as judged from radiation hybrid maps. A YAC contig over the AIH2 critical region including several potential candidate genes was constructed.

Albumins↗
PubMed1997

Angioid streaks are part of a familial syndrome of dyserythropoietic anaemia (CDA III).

Congenital dyserythropoietic anaemia type III (CDA III) is a rare disease inherited in an autosomal dominant way and characterized by mild to moderate haemolytic anaemia. Most patients are adapted to their disease and have no or few complaints. Bone marrow examination shows a characteristic picture with erythroid hyperplasia and multinucleate erythroblasts. 20% of patients in a Swedish family affected with the CDA III condition have monoclonal gammopathy or multiple myeloma. By linkage and recombination analysis in the same family, the gene linked to the CDA III condition (CDAN3) has been located to chromosome 15q22. In this paper we report the observation of visual disturbances with macular degeneration and angioid streaks in six patients with CDA III and discuss the apparent association between CDA III, angioid streaks and monoclonal gammopathy. We suggest that this triad forms a previously unreported syndrome.

Adult↗
PubMed1997

Rapid screening for amyloid-related variant forms of transthyretin is possible by electrospray ionization mass spectrometry.

We have used a new and rapid method to detect three variant forms of transthyretin (TTR): methionine for valine at position 30 (Met-30), serine for cysteine at position 6 (Ser-6) and methionine for leucine at position 111 (Met-111). By using an anti-transthyretin antibody and a centrifugal concentrator, transthyretin was isolated from plasma samples and analysed for variant forms by electrospray ionization mass spectrometry. Differentiation between homozygous and heterozygous transthyretin Met-30 and Met-111 posed no problems. However, a clear separation of transthyretin Ser-6 and Met-111 peaks in one patient with concordant Ser-6 and Met-111 mutations could not be achieved. The present method enables a quick and reliable detection of variant TTR. It can be used to screen families or small populations for abnormal TTR. Knowledge of TTR polymorphism and the variable expression of different amyloidogenic mutations should be taken into consideration when applying the methods in clinical practice.

Adult↗
PubMed1996

A new simple and rapid screening method for variant transthyretin-related amyloidosis.

To screen for transthyretin (TTR) related amyloidosis rapidly and reliably, we have developed a new method using a centrifugal concentrator device and electrospray ionization mass spectrometry (ESI-MS). Only 50 microliters of serum is needed for the analysis. After preparation of the samples with anti-TTR antibody they were passed through a 1000 kDa cut off centrifugal concentrator which retained the antibody. By analyzing the obtained filtrate with ESI-MS, variant forms of TTR was detected. TTR (Met30), with a molecular weight 32.0 Da higher than the normal form of TTR, was found in all FAP patients examined. In 3 liver transplanted FAP patients, the abnormal peaks had disappeared. In conclusion, The TTR Met30 mutation was easily detected in serum samples by electrospray ionization mass spectrometry after centrifugal concentration. The proposed method is simple to perform, as no HPLC is required, and offers a possibility to screen populations for TTR related amyloidosis.

Adult↗
PubMed1996

Muscle morphology and mitochondrial investigations of a family with autosomal dominant cerebellar ataxia and retinal degeneration mapped to chromosome 3p12-p21.1.

The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders with ataxia and dysarthria as early and dominant signs. In ADCA type II, retinal degeneration causes severe visual impairment. ADCA type II has recently been mapped to chromosome 3p by three independent groups. In the family with ADCA type II studied here, the disease has been mapped to chromosome 3p12-p21.1. Histochemical examination of muscle biopsies in 5 cases showed slight neurogenic atrophy and irregular lobulated appearance or focal decreases of enzyme activity when staining for NADH dehydrogenase, succinic dehydrogenase and cytochrome oxidase. Ragged-red fibres were scarce. Electron microscopic examination showed uneven distribution of mitochondria with large fibre areas devoid of mitochondria and/or large subsarcolemmal accumulations of small rounded mitochondria, and frequent autophagic vacuoles. These vacuoles contained remnants of multiple small rounded organelles, possibly mitochondria, and had a remarkably consistent ultrastructural appearance. Biochemical investigation of mitochondrial function showed reduced activity of complex IV and slightly reduced activity of complex I in the respiratory chain in a severely affected child while no abnormalities were found in his affected uncle.

Adult↗
PubMed1996

An expanded CAG repeat sequence in spinocerebellar ataxia type 7.

Expanded CAG repeat sequences have been identified in the coding region of genes mutated in several neurodegenerative disorders, including spinocerebellar ataxia type 1 and Machado-Joseph disease. In all disorders described to date the CAG expansion codes for an elongated polyglutamine chain. An increased polyglutamine chain size leads to a more severe disease, thus correlating with the genetic anticipation seen in repeat expansion disorders. Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant spinocerebellar ataxia with anticipation and a progressive degeneration of the cerebellar cortex. Using repeat expansion detection (RED), a method in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA, we have analyzed 8 SCA7 families for the presence of CAG repeat expansions. RED products of 150-240 bp were found in all affected individuals and found to cosegregate with the disease (P < 0.000001, n = 66), indicating strongly that a CAG expansion is the cause of SCA7. On the basis of a previously established correlation between RED product sizes and actual repeat sizes in Machado-Joseph disease, we were able to estimate the average expansion size in SCA7 to be 64 CAG copies.

Chromosome Mapping↗
PubMed1996

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLO-SL): a genealogical study of Swedish families of probable Finnish background.

Four Swedish families in northern Sweden with polycystic lipomembranous osteodysplasia (PLO-SL) were studied genealogically. Historical and genealogical date provided evidence for a Finnish origin. Both parents of two of the families could be traced back to Finnish ancestors, and the other two families had a common origin in a region with a known Finnish influence, but without evidence for Finnish ancestry. PLO-SL is the first rare monogenic disease with an autosomal recessive inheritance in Sweden with a probable Finnish origin.

Bone Diseases↗
PubMed1996

Glycerol kinase deficiency in two brothers with and without clinical manifestations.

We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.

Abnormalities, Multiple↗
PubMed1995

A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13.

Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders.

Chromosome Mapping↗
PubMed1995

Liver transplantation in familial amyloidotic polyneuropathy. Follow-up of the first 20 Swedish patients.

Familial amyloidotic polyneuropathy (FAP) is an inherited fatal form of amyloidosis caused by mutant transthyretin. The disease is characterized by progressive peripheral and autonomic neuropathy. Most of the transthyretin is produced by the liver, and we have shown previously that the metabolic deficiency can be corrected by liver transplantation. In the present study, the clinical results from the first 20 patients who underwent liver transplantation for FAP in Sweden are evaluated. Three of the patients suffered from renal failure and underwent a simultaneous kidney transplantation. Fourteen of the 20 patients (70%) are alive 10-52 months after transplantation. The patients' nutritional status at the time of transplantation had a significant impact on mortality and morbidity (P < 0.007). Long-standing disease was another negative prognostic factor (P < 0.02). One year after transplantation, the nutritional status had improved (P < 0.02). Improvements were also noted in walking capacity and for gastrointestinal and urogenital symptoms. The results show that liver transplantation offers an effective means to treat patients with FAP. The procedure should preferably be performed before the nutritional status is poor and advanced organ dysfunction has developed.

Adult↗
PubMed1995

Detection of expanded CAG repeats in bipolar affective disorder using the repeat expansion detection (RED) method.

Genetic factors are of major aetiological importance in Bipolar Affective Disorder (BPAD type I and II). The exact mode of inheritance of BPAD is unknown, but the recent demonstration of anticipation suggests that dynamic mutations could be involved in the clinical expression of the disease. We have used the repeat expansion detection (RED) method to test whether the anticipation in BPAD could be explained by the presence of expanded trinucleotide repeat sequences. Using a (CTG)10 oligonucleotide a significantly higher number of expanded CAG repeats were found in the genomic DNA of two independent samples of unrelated BPAD patients of Swedish and Belgian ancestry as compared with normal controls. The difference in repeat number was more consistent if data of the two samples of patients was pooled. In this study a CAG trinucleotide repeat expansion was associated for the first time with a major psychiatric disorder. It is possible that the CAG trinucleotide repeat expansion is involved in the clinical expression of BPAD and that it is the molecular basis explaining the phenomenon of anticipation observed in this disorder.

Aged↗
PubMed1995

Haplotype analysis of common transthyretin mutations.

The most frequent transthyretin (TTR) variant associated with hereditary amyloidosis is TTR Met 30, which has its major focus in Portugal, although it also occurs in many other countries. The distribution of the mutation and its occurrence in a CpG dinucleotide lead us to question the origin of the mutation and the possibility of its having originated in Portugal. In order to investigate these questions, we studied the distribution of haplotypes associated with the Met 30 mutation in families from different European countries. All the analysed Portuguese families presented the same haplotype associated with the Met 30 mutation (haplotype I). The same was found for the Swedish and Spanish families studied. However, a distinct haplotype (haplotype III) was found in three families, one Italian, one English and one Turkish. These results suggest that, although the Portuguese Met 30 carriers might have one founder, the mutation probably recurred in populations in Europe in a similar manner to that reported in Japan. In this study, we have also analysed the haplotypes associated with other TTR variants frequent in the Portuguese population.

Amyloidosis↗