Gösta Holmgren

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.

Coexpression of the sis and myc proto-oncogenes in developing human placenta suggests autocrine control of trophoblast growth

First trimester human placentas actively express the sis proto-oncogene, the structural gene for the B chain of platelet-derived growth factor (PDGF). Using the in situ hybridization technique, the 4.2 kb c-sis transcript has been localized to the cytotrophoblastic component, especially the highly proliferative and invasive cytotrophoblastic shell, paralleling the distribution of c-myc transcripts in early placenta. Explants of first trimester placenta release significant levels of PDGF-like activity into the medium under apparent developmental control. Moreover, cultured trophoblasts display abundant high-affinity PDGF receptors and respond to exogenous authentic PDGF by an activation of the c-myc gene and DNA synthesis. The developing human placenta may therefore represent a case of autocrine growth regulation in a normal tissue, in which cells bearing receptors for a growth factor can also synthesize and respond to that factor.

The epidemiology of diabetes in Swedish children 0-14 years--a six-year prospective study.

SummarySince 1 July 1977, all newly diagnosed diabetic children in Sweden aged 0–14 years have been reported to a central register. During the first 6 years, 2300 newly diagnosed diabetic children out of a population of 1.6 million children were registered. The degree of certainty was close to 100%. The mean of the yearly incidence rate for the whole 6 year period was 23.6 per 100000. The prevalence of insulin dependent diabetes mellitus on 1 July 1980 was 1.48 per 1000 and 1.52 on 1 July 1983. Comparing the first and second 3-year periods, an increase was found (22.7–25.1 per 100000). This increase was consistent when analyzing incidence rates by age, sex, and geographical distribution. Cumulative incidence rates revealed a risk of developing diabetes by the age of 15 years of 3.6 per thousand for boys and 3.2 per thousand for girls. The higher incidence for boys was consistent throughout the study period. Seasonal variations in the incidence rate were also consistent, showing yearly incidence peaks in the autumn and winter months. Incidence peaks were noted for both sexes in the pubertal ages. Age- and sex-standardized morbidity ratios varied significantly within the country. 12.8% of the probands had a first degree relative with Type 1 diabetes, and it was twice as common that this relative was a father as a mother. The high and rapidly increasing incidence of Type 1 diabetes in a genetically stable population such as Sweden calls for case-control studies directed towards the identification of environmental pathogens.

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

Abstract. 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.

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%.

Familial Amyloidotic Polyneuropathy in Sweden: Geographical Distribution, Age of Onset, and Prevalence

Familial amyloidotic polyneuropathy (FAP) in Swedish patients is associated with the same transthyretin mutation (TTRMet30) as in Portuguese, Japanese, Brazilian and Majorcan patients. Yet, the age of onset of FAP is much later in Sweden than in other populations. We have studied 239 cases of FAP from northern Sweden, their geographical distribution, differences in age of onset, and estimated prevalence and incidence rates. Cases and families concentrate mainly in two areas, around the towns of Skellefteå and Piteå. Mean age of onset was found to be later in the Piteå (58.8 +/- 10.8) than in the Skellefteå area (54.4 +/- 13.5). Unusually high figures were found for prevalence rates (91 x 10(-5) and 104 x 10(-5), respectively) in 1985. Mean yearly incidences were 3.1 x 10(-5) and 4.4 x 10(-5), respectively, over the period 1985-1989.

Community-Based Study of Neurological Disorders in Rural Central Ethiopia

Between 1986 and 1988 a door-to-door survey was conducted on a stable rural population of 60,820 in central Ethiopia. Trained lay health workers made a complete census and identified cases with symptoms and signs of neurological disorders, using specially designed questionnaires which, in a previous pilot study, were found to have a sensitivity of 91% and specificity of 85%. Neurological disorders in the rural population were epilepsy, postpoliomyelitis paralysis, mental retardation, peripheral neuropathy (mainly due to leprosy), and deaf-mutism with prevalence rates (cases/100,000 population) of 520, 240, 170, 150 and 130, respectively. The prevalence rates of the other less common neurological disorders were 62 for hemiparesis (15 of which were for cerebrovascular accidents), 20 for cerebral palsy, 16 for optic atrophy, 12 for perceptive deafness, 10 for tropical spastic paraparesis, 7 for Parkinsons disease and 5 for motor neuron disease, ataxia and chorea/athetosis. Among related non-neurological conditions, blindness, locomotor disability and deafness were predominant. The significance and role of such a neuroepidemiological study in laying the strategies for the prevention of neurological disorders and rehabilitation of patients are discussed in the context of a developing country.

Identification of a susceptibility locus for migraine with and without aura on 6p12.2-p21.1

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

Clinical and electroencephalographic characteristics of epilepsy in rural Ethiopia: a community-based study.

A community-based epidemiological study of neurological disorders was performed in a rural area in Ethiopia. The most prevalent neurological disorder identified was epilepsy, found in 316 persons. The prevalence of epilepsy was 5.2/1000 inhabitants at risk, 5.8 for males, 4.6 for females. The highest age-specific prevalence was found for ages 10-19 years. Generalized tonic-clonic seizures were the most common seizure type and occurred in 81%. On clinical grounds, partial seizures occurred in 20% and in 29% of these secondary generalization followed. During seizures, 8.5% had been injured by burns and 5.7% by trauma. Eighty-four percent had seizures at least monthly. Seizures occurred in 4.8% of siblings. Traditional treatment with local herbs, holy water and amulets was the most common. Only 1.6% had been treated with recognized antiepileptic drugs. Mental retardation was the most common associated disorder, found in 7.9% of the persons with epilepsy. During a period of 2 years, 8 persons died of status epilepticus and 1 from severe burns as a result of falling into a domestic fire during a seizure. EEG was recorded in 73%. Epileptiform activity occurred in 18%.

Fragile site X chromosomes and X-linked mental retardation in severely retarded boys in a northern Swedish county. A prevalence study

In an unselected series of 96 severely mentally retarded boys (IQ < 50) born 1959–70 in a northern Swedish county, six had a fragile site on the distal end of the X chromosome (FraXq 28). The prevalence of the fragile X syndrome in severely retarded boys was 6 %. Next to trisomy 21, this fragile X syndrome appears to be the most common single cause of severe mental retardation in boys.