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The risks of developing energy or nutrient deficits are of great concern in infants and children with the rare lymphoedema cholestasis syndrome 1 (LCS1)/Aagenaes syndrome. In adolescents and adults, it is not known whether LCS1 patients need specific dietary advice outside periods of cholestasis. The primary objective of the present study was to evaluate the progression of the liver disease and nutritional status in patients with LCS1 over a period of nine years. Dietary and biochemical data were obtained for patients and healthy controls in two cross-sectional studies, a baseline (2000) and a follow-up study (2009). Thirteen patients above 18 years of age with LCS1 (65%) were included (six females). Dietary intake and biochemical measures were stable in the patients from baseline until follow-up. Compared to healthy controls, the patients had significantly higher serum levels of alkaline phosphatase (p = .015 and p = .002), gamma-glutamyltransferase (p = .001 and p .001), total bile acids (p = .037 and p = .016), and fibrinogen (p = .046 and p .001) and lower albumin (p = .033 and p .001) and α-tocopherol (p = .011 and p = .003) at baseline and follow-up. Despite stable liver function, the presence of a low grade of hepatobiliary dysfunction in these patients was suggested. Patients with LCS1 had a nutritional status similar to healthy controls, with no clinical deterioration of liver function during the nine-year period. The findings presented in this paper support that more than 50% of patients with LCS1 can expect a normal lifespan.

Aim: To examine the association between skipping meals and snacking events and dietary and clinical characteristics in children and adolescents using modern insulin treatment. Methods: Dietary intake was recorded for 4 d in food diaries in 655 young diabetic patients. Number of meals and snacking events was recorded in a separated questionnaire, while clinical data were obtained from case record forms. Skipping meals refer to consuming a main meal (e.g., breakfast) five times a week or less. Results: Modern insulin treatment may favor a more flexible lifestyle. This study shows that there are fewer young diabetic patients who skip meals than non-diabetic controls (p

Objective. To investigate the prognosis of liver disease in Aagenaes syndrome (lymphoedema cholestasis syndrome 1 (LCS1)), which is an autosomal recessive inherited syndrome consisting of neonatal cholestasis with intermittent cholestatic episodes in childhood into adulthood and development of lymphoedema. Forty Norwegian patients are known to have this condition, 25 of whom are alive. A clinical description of the liver disease is supplied with a case-control study. Material and methods. In this paper we review the course of the liver disease in the Norwegian cohort of patients and present results from a case-control study in the patients above 10 years of age. The case-control study was performed on 15 patients without clinical cholestasis (itching and sometimes jaundice) at the time of the study. An evaluation of 11 patients above 15 years of age without chronic biochemical cholestasis (increased alkaline phosphatase (ALP), gammaglutamyl transferase (GGT) and/or serum bile acids) was also carried out. For each patient one randomly identified control person was included (15 in one study, 11 in the other). Results. Cirrhosis with either transplantation or death in infancy or early childhood occurred in six patients; slowly developing cirrhosis occurred in three patients. Two patients may be in the process of developing cirrhosis. Significantly increased ALP and GGT levels were found in patients with normal liver biochemistry in the preceding years when compared with the case control group. Additionally, albumin was found to be lower in older patients. Conclusions. Compared with that for other types of hereditary neonatal cholestasis, patients with LCS1 have a relatively good prognosis. More than 50% can expect a normal life span.

Lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome) is the only known form of hereditary lymphedema associated with cholestasis. A locus, LCS1, has recently been mapped to chromosome 15q in a Norwegian kindred. In a consanguine Serbian Romani family with a neonate who had a combination of lymphedema and cholestasis with features atypical for Norwegian LCS, haplotype and linkage analysis of markers spanning the LCS1 region argue that a second LCS locus may exist. The infant may represent an instance of a previously undescribed lymphedema-cholestasis syndrome. ( J Pediatr 2003;142:441-7 )

The characterizations of primary lymphedemas in different hereditary diseases are often published as case reports. In this study, 17 out of 20 Norweigian adult patients with lymphedema cholestasis syndrome 1 (LCS1)/Aagenaes syndrome were examined. The patients exhibited lymphedema and sporadic cholestasis. Individual clinical variations are described.Lymphedema was classified from Grade I to IV by clinical examinations and ultrasound B-mode scanning. To support the clinical findings, direct segmental multifrequency bioelectrical impedance analysis (DSM-BIA) was included and was compared to healthy matched controls. The lymphedema was similar to other hereditary lymphedemas, with more pronounced fluid retention in the lower extremities. It was generally more extensive, as it also included lymphedema in the arms, face, and trunk. Limited tissue fibrosis was observed, even after long-standing lymphedema.Approximately one-third of the patients had severe forms of lymphedema in the limbs (grades III and IV) and their conditions required close followup. A more frequent use of compression in the upper extremities is advised.

The increase in blood glucose in insulin-dependent diabetics after different fruit meals was investigated. Apple, banana and orange loads were compared with an equal amount of glucose dissolved in water. The postprandial blood glucose responses to pure glucose, apple and banana were almost identical, while the response after orange was somewhat weaker. We therefore conclude that though these fruits contain considerable amounts of fructose, they represent an important source of rapidly absorbable carbohydrate and should mainly be used in mixed meals.

Dietary fibre may retard glucose absorption in normal and diabetic subjects. It is, however, unclear which type of fibre would be most suitable for this purpose. We therefore studied whether pectin differs from fibre from barley (85 %) and citrus (15%) (Dumovital®) in its effect on postprandial blood glucose responses. Eight insulin-dependent diabetics fasted overnight and were then given a meal without their morning insulin. The basic meal, composed of 90 g white bread and 120 g jam (total carbohydrate 105 g), was given three times: alone, with 15 g pectin and with 15 g Dumovital fibre. Blood glucose was measured for three hours. The tests showed that pectin administration considerably inhibited the postprandial rise in blood glucose, while Dumovital showed no such effect. Barley/citrus fibre (a mixture of cellulose, hemicellulose, lignin and pectin) has not the same inhibiting effect on postprandial rise in blood glucose as pure pectin in insulin-dependent diabetics. Thus, the specific type of fibre must be considered when prescribing dietary fibre to diabetics.

The molecular basis of a patient with 5α-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 5α-reductase type 2 gene, alanine 228 for threonine. The heterozygous parents are first cousins of Pakistani origin. Am. J. Med. Genet. 80:269–272, 1998. © 1998 Wiley-Liss, Inc.

We present a Norwegian family, followed since 1967, with a chromosome 6q24 duplication in two siblings with neonatal diabetes, in their non-diabetic father, and in a female (third generation) with adult-onset diabetes. The parents (first generation) were healthy and non-consanguineous. After a miscarriage, the couple had two infants with birth weights of 1780 and 1620 g, respectively, both of whom died on their second day of life. Patient I (male, weight 1840 g at term) had a blood glucose level of 33 mmol/L on day 6. He was treated with insulin for 3 months. In adult life he had permanent diabetes, treated with oral hypoglycemic agents. At 43 yr of age, there were no diabetic late complications. Patient II (female, birth weight 1440 g at term) had an increasing blood glucose of 55 mmol/L on day 13. She received insulin treatment for 12.5 months. Subsequently, she was successfully treated with sulfonylurea (tolbutamide) for 10 yr. At 11 yr of age, insulin was again considered necessary. At 40 yr of age, no diabetic late complications were detected. Patient III had a birth weight of 2630 g at term and no diabetic symptoms as a neonate. She had insulin-requiring diabetes from age 19. We conclude that (i) neonatal diabetes with chromosome 6q24 duplications may become a permanent disease in adult life; (ii) this chromosome anomaly may also be associated with adult-onset diabetes; (iii) sulfonylurea treatment may be attempted, and (iv) late diabetic complications may be absent, even after more than 40 yr.

summary Background&Aims: Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. Methods: Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. Results: The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p ¼ 0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of a-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. Conclusions: The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and a-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.

(1998). Hereditary Cholestasis with Lymphoedema (Aagenaes Syndrome, Cholestasis-Lymphoedema Syndrome): New Cases and Follow-up from Infancy to Adult Age. Scandinavian Journal of Gastroenterology: Vol. 33, No. 4, pp. 335-345.

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%.

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 antibodybound 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.

Japn, Norway, Israel and the United States have studied have studied the epidemiology of IDDM in children by a similar method of data collection. Afterwards, the data were compared. Available data demonstrated that children in Norway, the United States and Israel were almost 20,15 and 5 times more likely respectively to develop IDDM than children in Japan. Although there was a samll difference in sex ratio, incidence in the smaller age group, and incidence of slowly progressing type IDDM between Japan and the other three countries, the other descriptive epidemiology of IDDM was quite similar, despite the large difference in the incidence and prevalence of IDDM. Therefore, it seems that the difference in the incidence would not be primarily environmental and could be related to the number of individuals susceptible to diabetes. It was hypothesized that the difference in incidence may be linked to the difference in prevalence of HLA type among the children in those four countries. However, it cannot be fully explained nby HLA difference. Other genetic markers associated with the developing IDDM musrt be evaluated.

The most important aspects of the diet for diabetic children are: 1. The timing of the meals. For the main meals, the time of the school meal and of the family dinner should be followed. Smaller meals will be necessary in between, with a total of about 6 meals daily. 2. The size of the meals and total amount of energy must be adjusted to the need of the children, and to the insulin type, dose and time of injection. A reasonable variation in energy intake is supported. Extra intake related to exercise will not only be taken on the days of exercise but also on the day after. This is supported by our own investigation. The appetite of the children should also be used in this regulation. Newer studies are summarized about the change in absorbability of starch by heating and cooking, and the effect on blood glucose of potatoes, rice and bread, different fruits and sorbitol. A long-term study of different fibres in bread is presented. A decrease both in mean bloodglucose and HbAl was found to be induced both by bran and by guar. The practical accomplishment of the diet is a larger problem than the theoretical ones.

Summary Two siblings have been described who developed a fatal metabolic acidosis during the first days of life. The acidosis was found to be caused by an accumulation of lactic acid in the second sibling. In the first sibling, no determination of lactic acid was performed, but the similarities in clinical, biochemical and pathological findings combine very strongly to suggest an identical condition. The children died at the age of 100 and 177 hours. The main pathological findings were confined to the brain, the thymus and the liver. Softening of the white matter was pronounced with delayed myelination. Organized bilateral paraventricular cystic spaces were found. Fatty changes were pronounced in the liver. In some respects these children differ from those previously reported with congenital lactic acidosis.

An inherited disorder characterized by a combination of lymphoedema and intrahepatic cholestasis is described in a Norwegian kindred. The jaundice is evident soon after birth, and recurrent episodes occur throughout life. The oedema starts at about school age and subsequently progresses; it is due to hypoplasia of the lymph vessels of the lower extremities. The cause of the cholestasis has not been established, but a structural intrahepatic developmental defect is suggested.

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.

In the recent years Alagille and coworkers (3) and Watson & Miller (7) have described a condition with cholestasis and hepatic ductular hypoplasia combined with peripheral pulmonary stenosis and some other malformations of which a characteristic facies and columnar malformations were the most consistent.

Ten insulin-dependent diabetic subjects were given the following tests in randomized order: 50 g glucose dissolved in water, 250 g raw and cooked potato (equal to 50 g carbohydrate), 270 g raw and cooked carrot (equal to 25 g carbohydrate), and 4 h of fasting. Blood glucose was measured for 4 h following the tests. The postprandial blood glucose responses after pure glucose and cooked potato were almost similar (90-min values: glucose 8.8mmol/L, cooked potato 8.0 mmol/L), while the response after raw potato was considerably slower and weaker (90-min value: 3.3 mmol/L). There were no differences between the postprandial blood glucose responses after raw and cooked carrot (90-min values: raw carrot 3.2 mmol/L, cooked carrot 2.8 mmol/L), but the responses were statistically different from blood glucose values during fasting alone (90-min value: 0.8 mmol/L). The study shows that cooking is responsible for the rapid increase in blood glucose after ingestion of cooked potato, while no such phenomenon is seen aftercooking of carrots.

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.

Since Sharp first showed the relationship between α-1 antitrypsin deficiency and cholestasis in infancy and cirrhosis in childhood in 1969 (5), a substantial number of reports have appeared from different parts of the world, all confirming Sharp’s work. In many parts of the world this is now one of the major causes of intrahepatic cholestasis in infancy. Depending on the frequency of the Pi Z gene, the frequency of Pi ZZ infants in children with neonatal intrahepatic cholestasis will be around 15–30%, and the other way round, between 10 and 15% of children with Pi type ZZ seem to develop liver disease in infancy (4).

Healthy individuals were given different carbohydrate-rich test meals (each with an energy content of 300 kcal) after a standardization period. Plasma glucose and insulin were measured during the tests. When compared with an ordinary oral glucose load, potato had a post-prandial plasma glucose and insulin response not statistically different from the glucose load, the bread group had a weaker and slower response than the potato group, and rice had a response between the two other groups. Gastric emptying, the availability of the starch for digestion and differences in the carbohydrate content are discussed as possible explanations for these differences.

One of a group of studies designed to delineate the perinatal and infant mortality problem in the United States, this new report from the National Center for Health Statistics presents an analysis of the problem in Norway. The study focuses on the sizable decreases in late neonatal and postneonatal mortality rates and the considerably smaller decrease in the perinatal rate. Changes in several parameters of infant loss and their influences on the infant and perinatal mortality trends are discussed, including such risk factors as legitimacy status, maternal age and parity, seasonal, and urban-rural differences.