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Patients with cholestasis-lymphedema syndrome (CLS) suffer severe neonatal cholestasis that usually lessens during early childhood and becomes episodic; they also develop chronic severe lymphedema. The genetic cause of CLS is unknown. We performed a genome screen, using DNA from eight Norwegian patients with CLS and from seven unaffected relatives, all from an extended pedigree. Regions potentially shared identical by descent in patients were further characterized in a larger set of Norwegian patients. The patients manifest extensive allele and haplotype sharing over the 6.6-cM D15S979-D15S652 region: 30 (83.3%) of 36 chromosomes of affected individuals carry a six-marker haplotype not found on any of the 32 nontransmitted parental chromosomes. All Norwegian patients with CLS are likely homozygous for the same disease mutation, inherited from a shared ancestor.

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The molecular basis of a patient with 5alpha-reductase deficiency was investigated in this study. This disease is a rare form of male pseudohermaphroditism with virilization during puberty. The child was raised as a girl, but had a male gender identity early in life. The diagnosis was set at the age of 13 years when the virilization process began. Hypospadias repair was performed and he changed to a male gender. DNA sequence analysis disclosed a homozygous mutation in exon 4 of the 5alpha-reductase type 2 gene, alanine 228 for threonine. The heterozygous parents are first cousins of Pakistani origin.

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Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue-specificity. This heterogeneity is suspected to be largely due to mutations affecting different subunits and isoforms of phosphorylase kinase. The gene of the ubiquitously expressed beta subunit, PHKB, was a candidate for involvement in autosomally transmitted phosphorylase kinase deficiency of liver and muscle. To identify such mutations, the complete PHKB coding sequence was amplified by RT-PCR of RNA isolated from blood samples of patients and analyzed by direct sequencing of PCR products. The characterization of mutations was complemented by PCR of genomic DNA. In one female and four male patients, we identified five independent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss of exon 8. Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.

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A Norwegian programme for treatment and selective screening of familial hypercholesterolaemia has been developed which takes into account family history and levels of hypercholesterolaemia. The programme includes recommendations on when and whom to screen for familial hypercholesterolaemia. With regard to treatment, special emphasis is placed on diet. The working group suggests that small lipid clinics with a dietitian should be established in some paediatric departments.

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We have investigated the effect of long-term strict glycaemic control on peripheral and autonomic nerve function in 45 IDDM patients (age 18-42 years, diabetes duration 7-23 years) without clinical signs of neuropathy or other neurological disease. They were randomly assigned to treatment either with continuous insulin infusion, multiple injections (4-6 times daily), or conventional treatment (twice daily) for 4 years and followed prospectively for 8 years. Motor and sensory nerve conduction velocities were measured at the start and after 8 years. Autonomic nerve function tests were performed only once, after 8 years. A significant reduction of nerve conduction velocity was observed during 8 years in patients with mean HbA1 more than 10% (n = 12, group mean 10.9%, range 10.1-13.2%) compared to patients with HbA1 less than 10% (n = 33, group mean 9.0%, range 7.5-9.9%). Change of motor nerve conduction velocity in the peroneal nerve was: -4.8 +/- 4.9 (SD) vs -2.2 +/- 5.3 m/s (p < 0.01). Change of motor nerve conduction velocity in the posterior tibial nerve was: -6.8 +/- 5.7 vs- 3.9 +/- 5.1 m/s (p < 0.05). No significant changes were observed in the ulnar nerve. Change of sensoric nerve conduction velocity in the sural nerve was: -8.9 +/- 8.0 vs -4.6 +/- 5.3 m/s (p < 0.05). Multiple regression analysis showed that a change in HbA1 of 1% resulted in a 1.3 m/s change in nerve conduction velocity during 8 years.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hereditary intrahepatic cholestasis with lymph oedema is now a well defined autosomal recessive inherited syndrome. More than 75% of the known cases (about 40) are Norwegian, and most of these came from a few communities in the south-western part of Norway. Cholestasis is present prior to or shortly after birth. With modern treatment the cholestasis usually improves considerably during the first two years of life, but periods of recurrent cholestasis occur later. In some cases, lymph oedema is present at birth, but usually comes to light during childhood. Lymph oedema needs continuous treatment. As a rule, the prognosis for the liver disease is good, but cirrhosis has developed in about 15% of the Norwegian cases. As for the pathogenesis of the cholestasis, the hypothesis is that the cause is an anomaly of the lymph function.

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Continuous subcutaneous insulin infusion (CSII) and multiple injections (MI) have been shown to have metabolic advantages in highly-selected insulin-dependent diabetics (IDDs), but there have been few comparative studies in self-selected IDDs. With MI, the optimal insulin preparation for overnight insulin delivery has not been defined. We compared conventional 2-3 injection therapy (CT), CSII and MI with human isophane insulin (MI/human isophane) and human ultralente insulin (MI/human ultralente), respectively, at bedtime in self-selected IDDs. Of 275 IDDs who were invited to participate, 52 individuals (18.9%) entered the study. Most indices of glycaemic control showed better values on CSII and also on MI compared to CT, but the differences were small. Fasting blood glucose was higher on MI/human ultralente than on MI/human isophane. Only one subcutaneous abscess and one case of ketoacidosis requiring hospitalization occurred on CSII. Serious hypoglycaemic episodes were non-significantly increased on intensified therapy. Most patients clearly preferred intensified insulin therapy; approximately one half CSII.

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In insulin dependent diabetics microalbuminuria predicts proteinuria which is associated with an extremely high relative mortality rate. We studied the connection between long term blood glucose levels and microalbuminuria. One hundred and twenty-seven patients between 10-20 yr of age were screened for microalbuminuria. Twenty patients with both persistent microalbuminuria (greater than 15 micrograms/min albumin in at least two out of three timed overnight urine samples) and greater than 4 measurements of glycosylated hemoglobin A1 yearly for 5 yr, were included in the study. These 20 patients were matched with respect to sex, age and duration of diabetes against the normoalbuminuric diabetics. The patients with microalbuminuria had significantly higher mean 5-yr glycosylated hemoglobin A1 values than those with normoalbuminuria, 12.4 and 10.5% respectively (p less than 0.01). The data indicate a logarithmic association between mean 5 yr glycosylated hemoglobin A1 values and the urinary albumin excretion rate. The study points to a strong association between long term blood glucose levels and microalbuminuria in adolescents.

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A new syndrome in two siblings with primordial birdheaded nanism, progressive ataxia, goiter, primary gonadal insufficiency and insulin resistant diabetes mellitus is presented. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon and insulin all working through cell membrane receptors were elevated. A generalized cell membrane defect was suggested to be the pathophysiological abnormality in these patients.

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A 13 year old boy, with a five year history of diabetes mellitus, developed a severe neuropathy and a transient deterioration of a background retinopathy after initiation of improved glycaemic control. This followed a long period of extremely poor metabolic control, with growth retardation and weight loss.

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A pilot project for neonatal screening for cystic fibrosis (CF) by measuring trypsin-like immunoreactivity (TLI) in liquid serum or plasma samples was carried out in Norway from May 1982 to December 1984. A total of 72,320 newborns was screened. Twelve infants were recalled for sweat testing; 11 were confirmed to have CF. One infant had normal sweat sodium and chloride levels and no clinical symptoms. The incidence of CF in this study was 1:6574, and the recall rate for second blood samples was 0.6%. No false-negative cases have yet been reported. The level of TLI was affected by the use of heparin in plasma preparation, being reduced by about 20% as compared to serum levels.

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Urinary albumin was studied in 45 patients with insulin-dependent diabetes in a 4-year prospective randomized trial, comparing continuous sc insulin infusion (CSII), multiple insulin injections, and conventional treatment with twice daily injections. Strict blood glucose control was obtained with CSII and multiple injections, better than with conventional treatment (2P less than 0.01): mean glycosylated haemoglobin (% HbA1 +/- SEM) after 4 years: CSII 9.0 +/- 0.4%; multiple injections 9.4 +/- 0.4%; conventional treatment 10.5 +/- 0.5. A total of 696 24-h urine specimens were collected. After 4 years of CSII from the time of randomization, urinary albumin excretion was reduced (26 +/- 5 to 16 +/- 4 mg/24 h, mean +/- SEM, 2P less than 0.01), when compared with conventional treatment (2P = 0.01), when compared with conventional treatment (2P = 0.01) where no change was observed (21 +/- 4 to 22 +/- 6 mg/24 h, n.s.). The reduction observed during multiple injection treatment was not significant (17 +/- 3 to 14 +/- 3 mg/24 h). Long-term near-normoglycaemia may influence the mechanisms leading to albuminuria in diabetes, if introduced at an early stage of the disease.

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We studied urinary albumin excretion in 2 different groups of teenage diabetics, one with HbA1 less than 10% (n = 15) and another with HbA1 greater than 13% (n = 17). We found a highly significant difference between the 2 groups regarding the albumin excretion rate (AER) in overnight urines. Median value 15.8 micrograms/min (range 4.9-80.5) and 4.2 micrograms/min (range 1.0-12.6) in the high and low HbA1 group respectively. In a reference group of 19 healthy teenagers, the median AER was 4.9 micrograms/min (range 0.5-15.0). 59% of the patients in the high HbA1-group had values above the upper range in the reference group, 15 micrograms/min, and one had positive Albustix. In contrast, no difference in AER was observed between the low HbA1-group and the reference group. We did not find any correlation between AER and duration of diabetes, but the one patient with gross proteinuria had had diabetes for 14 years. No significant difference between the groups regarding blood pressure or retinopathy was found. Thus, AER was elevated in a large proportion (59%) of poorly regulated diabetic teenagers regardless of diabetic duration. This fact questions the value of employing moderately elevated urinary albumin excretion rate in teenage diabetics as a marker for later development of clinical diabetic nephropathy.

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Forty-five insulin-dependent diabetics were randomized to 1 yr treatment with either continuous subcutaneous insulin infusion (CSII), multiple insulin injections (MI), or continued conventional treatment. The CSII group used regular insulin only, the MI group used 4-6 premeal injections of regular insulin and intermediate insulin at night, and the conventional group used two daily injections of combined regular and intermediate insulin. Only highly purified porcine insulin was used. Near normoglycemia was obtained during CSII and MI but not during conventional treatment. Antibodies against insulin were measured in serum samples by measuring the binding of iodinated porcine insulin to serum after removal of free and antibody-bound insulin from the samples by acid charcoal. The percent binding of 125I-labeled insulin increased significantly during MI and CSII, in contrast to conventional treatment. Nineteen patients had sufficient binding capacity for Scatchard analysis. In the CSII and MI groups, high- or low-affinity antibodies or both were induced. When insulin was administered subcutaneously during MI or CSII for 1 yr, the insulin antibody production increased, in contrast with conventional treatment.

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