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Quantitative urinary amino acid excretion has been studied in 23 adult patients with mild phosphate diabetes (MPD), in 22 adult control patients with various renal disorders and in 15 children, 7--19 years old, with atopic disorders (normal controls). Statistically significant increases in urinary excretion of glutamine (p < 0.01), glycine (p < 0.01) and cystine (p < 0.05) were found in the MPD patients compared to the normal controls. The urinary excretion of glutamine was significantly increased while the increases in cystine and glycine excretions were non-significant when MPD patients were compared to the control patients. In addition to clinical signs and analyses of plasma and urinary phosphate, a quantitative evaluation of urinary amino acids might be a tool in the diagnosis of MPD. The significance of the increased urinary amino acid excretion in MPD is discussed.

DNA fragments complementary to cloned sequences encoding HLA-D region class II antigen alpha- and beta-chains were determined by genomic blotting with DNA from HLA-typed members of 22 complete families, 12 of which had a proband with insulin-dependent diabetes mellitus (IDDM). Analysis of genotypes showed that the DNA sequences were linked to HLA-DR and permitted confirmation of recombinations in two families. Digestion with the restriction enzymes BamHI, EcoRI, and PstI and hybridization with an HLA-D region beta-chain cDNA probe confirmed a BamHI 3.7 kilobase (kb) fragment present at low frequency among diabetic individuals and a BamHI 3.2 kb fragment that was also decreased among the diabetic subjects compared with siblings (P less than 0.05) as well as nonrelated control siblings (P less than 0.02) and their parents (P less than 0.01). BamHI 12.0 kb (P less than 0.05) and 5.8 kb (P less than 0.02, P less than 0.02), EcoRI 20 kb (P less than 0.05, P less than 0.02), and PstI 6.0 kb (P less than 0.05) fragments were more frequent in diabetic individuals compared with nonrelated control siblings or their parents, respectively. Analysis of individual haplotypes revealed that HLA-DR4-containing chromosomes were heterogeneous among controls but that the diabetic individuals showed a similar pattern of restriction fragment length polymorphism. Genomic blotting of blood lymphocyte DNA with a cDNA clone encoding the chain of HLA-D region class II antigens permits detection of fragments that are strongly associated with IDDM.

CuZn superoxide dismutase, Mn superoxide dismutase, catalase and glutathione peroxidase activities in lymphocytes and erythrocytes were studied in 9 children with insulin-dependent diabetes mellitus (IDDM) as well as in 21 healthy children. The mean erythrocyte CuZn superoxide dismutase and glutathione peroxidase were statistically significantly lower in the IDDM group compared with the controls although almost all IDDM results fell within the mean ± 2 sd limits of the controls. The small differences found can hardly be assigned biological significance. Erythrocyte catalase as well as lymphocyte CuZn superoxide dismutase and Mn superoxide dismutase did not differ from the controls.

The clinical features of eight cases of primary hyperoxaluria have been summarized. The possibility of different phenotypes is discussed. A reduction, but no normalization, of the oxalate formation during pyridoxine therapy was found. A renal transplantation performed in one of the patients failed because of the formation of nephrocalcinosis.

Genomic DNA from 17 Swedish patients with familial amyloidotic polyneuropathy (FAP), and 50 healthy controls were tested with a cDNA transthyretin probe. In seven of the patients, FAP was not reported in either of their parents. All 50 controls showed restriction fragments of 6.6 kb and 3.2 kb after cleavage with Nsil, while the 17 FAP patients showed RFLP markers of 5.1 and 1.5 kb. These observations indicate the same methionine for valine substitution at position 30 in Swedish patients with FAP as seen in patients with FAP from Japan, Portugal and FAP-patients of Swedish descent from USA. However, the mean onset of FAP symptoms for the 17 Swedish patients was found to be significantly later than for the patients from Japan, Portugal and USA.

In an epidemiological investigation of mental retardation in the county of Vasterbotten in Sweden the mother of five severely mentally retarded children was found to have untreated phenylketonuria (PKU). None of the children had PKU. The maternal PKU may have been a cause of the mental retardation, retarded intrauterine growth and different types of malformations. There is now an increasing number of girls with PKU in whom dietary treatment has been carried out and already withdrawn. These girls require thorough information on the high risk of serious fetal damage before they become pregnant. Dietary treatment should be introduced before any conception.

Eleven families including 35 cases with fra(X) mental retardation (MR) were traced genealogically using the Research Archives at Umeå University. Seven of the cases were women with fra(X). All of the families originated partly or totally from the county of Västerbotten. It was possible to link 7 of the index families to common ancestors over an 8-11 generation span. The remaining 4 families were not traced to the same ancestors. However, they were linked together pair-wise over a 7-8 generation span. Transmission of the fra(X) mutation was studied in these families. In the pedigree analyses, priority was given to maternal transmission. In 2 families the fra(X) mutation was transmitted solely through females over 7 or 8 generations respectively. Within 9 families the mutation was transmitted by males in 2-5 generations in order to reach common ancestors.

Reduced glutathione (GSH) in whole blood was studied in 15 insulin-dependent juvenile diabetic patients at onset of diabetes (group A). In 5 of these patients the blood GSH concentration was followed during the first month after onset. The blood GSH content was also analyzed in 16 children with insulin-dependent diabetes mellitus (IDDM) with a duration of diabetes of more than 2 years (group B), and in a control group of 76 healthy children (group C). The GSH levels in groups A, B and C were 48.3 +/- 5.7, 47.1 +/- 4.6 and 47.6 +/- 4.3 mg/100 ml erythrocytes, respectively. Thus, there were no significant differences between the patients and the control group. In group A, there were no significant differences in blood GSH values at onset and 1 month later.

A t(6;9) was seen in bone marrow aspirates from two patients with sarcoidosis who developed acute myeloid leukemia. This is a new observation not previously reported.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56-year-old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR-met30-gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR-met30-gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.

A new cloned DNA probe (U6.2), which recognizes polymorphisms near the locus for the fragile-X syndrome, was isolated. No recombinations were observed between the probe and the disease locus, although recombinations were observed with several other probes known to be located close to the fragile site. The locus defined by the probe, DXS304, cosegregated with the fragile-X phenotype in 29 informative meioses (zeta = 4.97, tau = 0.00). The degree of polymorphism at this locus and its proximity to the fragile-X locus makes it useful for carrier diagnosis and as a new starting point for attempts to clone the gene responsible for the disease.

A clinical study was performed on 14 patients with diastrophic dysplasia (DD), including three pairs of sibs. Six of these patients, including two pairs of sibs, died shortly after birth of respiratory and circulatory insufficiency. We consider these six patients to represent a special lethal variant of DD. In all infants with the lethal variant of DD the birth weight was lower than in those with the non-lethal variant. There were also roentgenological differences between these two groups. Overlapping in joints and dislocation of the cervical spine were seen in all the lethal cases. In addition, four of the six patients with lethal DD cases had a congenital heart defect, and none in the non-lethal group.

A significantly lower frequency of atopies was found in diabetic children and their relatives compared to a control group of non-diabetic individuals.

X-linked mental retardation (MR) associated with a fragile X chromosome was found in two Swedish families. The fragile X chromosome was demonstrated in 5/5 boys with mental retardation. Clinical data on four of these boys are presented. In one of the families, the mental retardation was associated with macro-orchidism, large hands and large, folded ears. In the other family, macro-orchidism was not seen, possible because the boys were younger. Fragile site X chromosomes were also seen in three obligate carriers. A summary of earlier published cases of X-linked MR associated with the fragile X chromosome is given.

Fragile-X mental retardation (FRAX-MR) is one of the more common X-linked disorders affecting 1 in 1,500 newborn males. This disease is characterized by the expression of fragile site in the region q27.3 of the X-chromosome of affected boys when their lymphocytes are cultured in folate deficient medium. In most patients there is macroorchidism postpubertally. The clinical diagnosis of carrier females based on the expression of fragile site in Xq27.3 is usually difficult and sometimes impossible. About half of the carrier females escape diagnosis by this method. Furthermore, prenatal diagnosis is not always feasible. Using Restriction Fragment Length Polymorphism (RFLP) and cloned DNA segments from the region Xq27-Xqter as probes, we have investigated Swedish families with FRAX-MR in three generations. Interesting observations, previously unreported to our knowledge, have been made in some patients and carrier mothers, using one of the probes which is localized to the distal end of Xq. The significance of these findings and the linkage of the disease locus to the different probes used in this study is presented.

Two main diabetic groups were investigated, viz. one consisting of 19 diabetic children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) (median age 10 years) where a prospective study was made, and one where a retrospective examination was performed of 73 patients (median age 14 years) with a mean duration of IDDM of 7 years; 83 healthy school children (median age 13 years) served as controls. In both groups of diabetic children more zinc was excreted in the urine than in the controls. At onset of IDDM, serum and blood clot zinc concentrations were reduced with a gradual increase towards normal within 1 month of insulin therapy. The zinc concentrations in hair did not differ from those of the controls. No correlation were found between zinc levels in serum, blood clots, urine and hair on one hand and the concentrations of albumin and glucose in serum and urine on the other.

Two monozygotic twin brothers, 55 years of age, are carriers of the TTR Met 30 gene. Twin no. 1 had onset of typical FAP symptoms seven years ago, while twin no. 2 is absolutely healthy. The twins have the same educational background, are working in the same industry and are living in the same area. The progress of symptoms in twin no. 1 was rather rapid with polyneuropathy, gastrointestinal and heart symptoms. Liver transplantation was per-formed in twin no. 1 in 1993, with a successful result. The discordance of FAP symptoms in identical twins might indicate that environmental factors are of importance for the onset of FAP symptoms. The possible importance of environmental factors is indicated by a population study made in the same area. The TTR Met 30 gene carrier frequency is 1.6 per cent, while the frequency of FAP patients in the same area is only 0.05 per cent, indicating a gene penetrance of only about 5 per cent. To our knowledge this is the first report of discordant symptoms in monozygotic twin...

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.

We have developed a quick and reliable diagnostic method for detecting variant forms of transthyretin (TTR); namely, centrifugal concentration followed by electrospray ionization mass spectrometry (ESI-MS). Argentinian patients from three families with neuropathic amyloidosis and their relatives were screened for mutated TTR by ESI-MS. In order to facilitate transportation, we investigated the impact storage had on lyophilized anti-TTR-antibody precipitates' mass spectra. For this investigation, plasma samples from three Swedish patients with known TTR amyloidosis were analysed. We detected identical, additional peaks corresponding to a variant form of TTR in 10 members of the families, and also in a lyophilized sample sent unfrozen by mail from Argentina. All except one symptomatic subject had additional peaks, the exception having undergone a liver transplantation for the disease. All patients were early onset cases, i.e. below 35 years of age, and family history suggests an aggressive, rapidly progressing disease. Lyophilized anti-TTR-antibody precipitates stored at room temperature for 1 week exhibited only minor differences compared with plasma samples stored at -70 degrees C. In a new Argentinian study on familial amyloidotic polyneuropathy, the variant TTR was quickly identified and typed by ESI-MS. To facilitate transportation, dry-frozen samples can be used and the quality of the spectra is similar to that of samples stored at -70 degrees C.

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.

An extraneous ninhydrin-positive spot on high-voltage paper electrophoresis (HVPE) was observed in urine samples collected from children receiving paracetamol medication. Interference by this derivative has not previously been reported. This extraneous spot could simulate an abnormal peptiduria.

The plasma insulin level and glucose tolerance were studied In five patients with homocystinuria. Two of them showed a marked hyperinsulinemia and a concomitant pathologic glucose tolerance, while the remaining three showed a normal glucose tolerance, two of them, however, had plasma insulin values in the upper level of the normal range. These preliminary results support the earlier hypothesis that the pancreatic islets β-cells are particularly sensitive to an imbalance in the sulfhydryl levels of the organism since homocystinurics have an increased plasma methionine level due to an inborn error of the methionine metabolism.

SINCE the discovery of genetically controlled slow and fast transferrin variants in human beings1,2, data on the frequencies of the different transferrin phenotypes have been collected from various populations. It was noted that slow variants seemed to occur mainly in Negroes and Australian Aborigines and fast variants in White people.

Cultured skin fibroblasts from two patients with Sjogren-Larsson syndrome (SLS) and from a normal control were analyzed for trienoic and tetraenoic fatty acids. In addition, we assayed desaturation of [ l - 14 C]linoleic acid in cells from four patients and four controls. There was no significant effect of the disease on the composition of polyunsaturated fatty acids or on the rate of linoleic acid desaturation in fibroblasts. The results indicate the presence of Δ 5 - and Δ 6 -fatty acid desaturases in cells from SLS patients.

The aim of the present study was to examine the fatty acid patterns of plasma phospholipids, cholesteryl esters, triglycerides and free fatty acids in patients with Sjögren-Larsson syndrome in order to detect whether absorption or metabolism is essential fatty acids may be abnormal. The fatty acid patterns were analyzed by gas liquid chromatography. The proportions of 23 fatty acids were calculated. The parameters used for assessment of the essential fatty acid metabolic status were calculated and compared with those from a group of institutionalized mentally retarded patients and from a group of healthy controls. There was no significant difference in either the fatty acid components or parameters used to evaluate the essential fatty acid metabolic study when the mentally retarded and control groups were compared. The relative concentration of linoleic acid (18:2 omega 6) in plasma phospholipids in patients with Sjögren-Larsson syndrome did not differ significantly from that of the healthy or mentally retarded controls, indicating that the Sjögren Larsson syndrome does not involve a dietary essential fatty acid deficiency or a defect in absorption of linoleate. In the phospholipids of Sjörgren-Larsson syndrome patients, the metabolites derived from linoleic acid were found to be significantly lower than in health controls, suggesting the metabolic defect. The total products of delta 6 desaturation were reduced to 3% of that in controls, whereas the products of delta 5 and delta 9 desaturation were not noticeably affected in the patients with Sjögren-Larsson syndrome. All individuals with Sjörgren-Larsson syndrome exhibited decreased products of delta 6 desaturation which also affected subsequent metabolites in the metabolite sequence.