Early cardiomyopathy without severe metabolic dysregulation in a patient with cblB-type methylmalonic acidemia.

BACKGROUND: Cardiomyopathy is a known complication of organic acidemias but generally thought to be secondary to poor metabolic control. METHODS: Our patient was found through biochemical testing and Sanger sequencing to harbor an Icelandic founder mutation: NM_052845.4(MMAB):c.571C > T(p.Arg191Trp), leading to an early presentation (4 h after birth) of cblB-type methylmalonic acidemia (MMA). Biochemical testing of this patient suggested B-12-responsiveness and thus the patient was treated with cyanocobalamin throughout life. Informed parental consent was obtained for this report. RESULTS: Our patient had three metabolic decompensations in her life (at birth, at 1 month, and at 5 months). The first decompensation was probably linked to stress of delivery, second to rhinovirus infection, and third by co-infection of norovirus and enterovirus. At 3 months, the patient was noted to be tachypneic, although this was attributed to her underlying metabolic acidosis. At 5 months and 10 days, the patient was admitted with minor flu-like symptoms but developed severe diarrhea in hospital and upon rehydration had cardiac decompensation and was found to have undiagnosed dilated cardiomyopathy. Although, patient was treated aggressively with dextrose, hemodialysis, levocarnitine, and vasoactive agents, there was limited response to medications to treat cardiac failure, and eventually the patient passed away before turning 6 months old. CONCLUSIONS: Other than these three mild decompensations, patient had very good metabolic control, thus demonstrating that even without frequent metabolic decompensation, cardiomyopathy can be an observed phenotype in cblB-type MMA even very early in life, suggesting that this phenotype may be independent of metabolic control.

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.

[Vitamin D status before and after metabolic and bariatric surgery at Landspitali].

INTRODUCTION: Long-term results from bariatric surgery amongst individuals with obesity is considered good in general, with regard to weight loss, complications of obesity or quality of life. However, risk of nutrient deficiency might be increased. The aim of the study was to assess vitamin D status of patients before and after metabolic and bariatric surgery at Landspitali. METHODS: Data on 25(OH)D concentration and parathyroid hormone (PTH) was retrieved from medical records for patients undergoing metabolic and bariatric surgery at Landspitali from 2001-2018 (n=539). Insufficient vitamin D status was defined as 25(OH)D concentration p<45 nmol/L in 2001-2012 but p<50 nnmol/L from 2013-2018, due to changes in analytical method during the study period. Vitamin D deficiency was defined as 25(OH)D p<30 nmol/L for both time periods. Guidelines on supplement use are provided before discharge from the hospital and up to 18 months after surgery, RESULTS: Mean concentration of 25(OH)D before surgery was 51 nmol/L (SD 30 nmol/L) and 278 (52%) had insufficient vitamin D status, of which quarter of subjects were defined as being vitamin D deficient. Concentration of 25(OH)D increased after surgery in majority of subjects (85%). However, about third of those defined as having insufficient vitamin D status before surgery still had insufficient status 18 months after surgery. When comparing time periods, 2001-2012 and 2013-2018 it can be seen that insufficient vitamin D status was less common in the second period, although still persistent in about 25% of cases before surgery and 8,5% 18 months after surgery. CONCLUSION: Insufficient vitamin D status is relatively common before metabolic and bariatric surgery at Landspitali. In large majority of subjects, 25(OH)D concentration increased after surgery, following recomendations on supplement intake. The results highlight the need for greater emphasis on correcting possible nutrient deficiencies before surgery.

Gender comparison of factors associated with age-related differences in bone mineral density.

UNLABELLED: We found that age-related decline in bone mineral density (BMD) is more pronounced in women than in men, that lean mass was the most important determinant of BMD in all age groups in both sexes, and that different factors may be important for bone health of men and women and at different ages. INTRODUCTION: Multiple factors may affect bone mineral density (BMD). Our objective was to identify the correlates of age-related differences in BMD among men and women. METHODS: We performed a cross-sectional study involving 490 men and 517 women between the age of 29 and 87 years that were free of medication and diseases known to affect bone metabolism. BMD was measured at various sites using dual-energy X-ray absorptiometry, and factors possibly associated with skeletal status were assessed by direct measurements and a detailed questionnaire. RESULTS: BMD was lower with advancing age at all BMD measurement sites, the greatest difference being for the femoral neck where in women BMD was 37.5 % lower in the oldest compared to that in the youngest age group, but the difference was 22.9 % in men. Levels of free estradiol were sharply lower after age of 40 among women; free testosterone declined gradually with age among men but was not independently associated with BMD. Factors including lean mass, physical activity, ionized calcium, C-terminal telopeptide (CTX), serum sodium, free estradiol, and smoking explained a large fraction of difference in BMD in different age groups but to a varying degree in men and women. Lean mass was the strongest independent factor associated with BMD at all sites among men and women. CONCLUSIONS: Age-related decline in BMD is more pronounced in women than in men, but determinants of BMD are multiple and interrelated. Our study indicates that different factors may be important for bone health of men and women and at different ages.

Discrepancies between creatinine- and cystatin C-based equations: implications for identification of chronic kidney disease in the general population.

OBJECTIVE: Early detection and treatment of chronic kidney disease (CKD) is important for slowing the progression of the disease and decreasing the associated risk of cardiovascular disease. This study examined how two creatinine-based and two cystatin C-based equations for calculating estimated glomerular filtration rate (eGFR) perform relative to each other in identifying CKD in a large cohort of community-dwelling individuals. MATERIAL AND METHODS: A total of 1630 adults were recruited from the Reykjavik area. Each subject's eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) Study and Cockroft-Gault equations, and two cystatin C-based equations. The prevalence of decreased eGFR obtained by the four equations was compared and the relative performance of the equations examined. RESULTS: The MDRD equation labelled significantly fewer individuals as having CKD (5.3%) relative to the other equations (12.8-19.7%). Agreement between equations was limited, with up to one-third of subjects diagnosed as having CKD by the MDRD equation being classified as normal by other equations. Correlations between creatinine- and cystatin C-based equations varied with age, gender and diuretic use. CONCLUSIONS: The MDRD equation results in lower population-wide estimates of CKD relative to the other equations tested. An understanding of the performance of these equations is critical when they are used for estimating the prevalence of CKD in a population-wide setting or for diagnosing the disorder in clinical practice.

[Bone mineral density and bone turnover in systemic sclerosis]. / Beina- og kalkbúskapur sjúklinga med herslismein.

AIMS: To elucidate bone mineral density (BMD) and bone turnover in an un-selected group of patients with Systemic Sclerosis (SSc) in national based registry. MATERIAL AND METHODS: All patients who have been diagnosed with SSc in Iceland were invited to participate in the study. Participants underwent standardized interview and delivered urine and blood samples for measurements of various bone metabolites (e.g. PTH, osteocalcin, Cross Laps, PINP, IGF-1, Cystatin-C and 25-OH-vitamin-D), before they underwent measurement of BMD with DEXA (QDR 4500 Elite). RESULTS: Twenty-four individuals, 20 female and four male, of 29 diagnosed patients with SSc in Iceland accepted to participate in the study (83%). The mean age was 60 +/- 15 years. Seventeen of 20 females were postmenopausal. Twelve patients had history of fractures. Only four patients were on treatment with bisphosphonate. All measured bone metabolites were in normal ranges, but U-calcium was in the lower ranges. According to DEXA, eight patients had osteopenia (T-value = -1.0 - -2.5) and three osteoporosis (T-value <---2.5), while six patients had BMD more than one standard deviation below the mean of age matched controls. CONCLUSION: Although the majority of patients with SSc have normal bone turnover and BMD, every fourth patient may have low BMD. No single pathogenic factor was observed, however, several individuals are in calcium saving stages reflected in low urinary calcium excretion. This may be result of defects in intestinal absorption of calcium due to gastrointestinal involvement of the disease. This study does not give opportunity to evaluate effects of treatment on BMD in this group of patients. Thus, individual evaluation concerning osteoporosis is recommended in patients with SSc.

[Prevalence of secondary hyperparathyroidism (SHPT) and causal factors in adult population in Reykjavík area]. / Algengi og orsakir afleidds kalkvakaóhófs medal fullordinna á höfudborgarsvaedinu.

INTRODUCTION: SHPT is a consequence of decreased concentration of ionized calcium in blood, which may have many causes. The purpose of this study was to assess the prevalence and contributing factors of SHPT in an adult Icelandic population and explore the relationship between PTH and other variables which might explain age related increase in PTH. Such knowledge might be helpful in evaluating the results of PTH measurements. METHODS AND STUDY GROUP: The study group was a random sample of men and women in the Reykjavik area, 30-85 years of age. Serum PTH was measured by ECLIA (Roche Diagnostics), serum 25(OH)D by RIA (DiaSorin), and body composition by DXA. SHPT was defined as PTH >65 ng/l and ionized calcium <1.25 mmol/l. Inadequate vitamin D was defined as serum 25(OH)D 25-45 nmol/l and vitamin D deficiency <25 nmol/l, inadequate calcium intake <800 mg/day (from questionnaire) and reduced kidney function as serum cystatin-C >1.55 ng/l. The relationship between PTH and other variables was assessed by Spearman?s correlation coefficient and linear regression. RESULTS: Of 2,310 individuals invited 1,630 attended (70%), 586 men and 1,023 women. Further 21 were excluded because of primary hyperparathyroidism. Of the total group 6.6% did have SHPT, 7.7% of the women and 4.6% of men (p<0.01 by gender). Underlying causes were identified in 90% of cases, most commonly inadequate vitamin D (73%). Other important causes were obesity, inadequate calcium intake, reduced kidney function and furosemide intake. Many individuals did have more than one possible underlying cause. The concentration of PTH was found in a multivariate linear regression to be associated with age, ionized calcium, 25(OH)D, cystatin-C, smoking, and BMI, especially fat mass. Testosterone did have a weak negative relationship with PTH in men. CONCLUSIONS: Most cases of SHPT could be explained by known causes and far the commonest was inadequate vitamin D. The prevalence of SHPT in Iceland is probably higher than described elsewhere, possibly due to less sunlight exposure. These results would suggest that a greater intake of vitamin D is needed in Iceland. The relationship of PTH with body composition, especially fat mass, sex hormones and smoking, needs further evaluation.

Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover.

INTRODUCTION: The purpose of this study was to compare age-related differences in osteoprotegerin (OPG) in relationship with BMD and the serum bone markers osteocalcin (OC), collagen crosslinks (CTX), and tartrate-resistant acid phosphatase 5b (TRACP-5b). METHODS: Data were derived from a cross-sectional study on bone health in a random sample of community-dwelling adults aged 30 to 85 years in the Reykjavik area in Iceland. All subjects had whole body, hip, and lumbar spine BMD measured (by DXA), gave blood samples, and answered a thorough questionnaire on medications and medical history. We assessed relationships using the Spearman correlation coefficient, partial correlation, and multivariable linear regression. Men and women were analyzed separately. RESULTS: Of 2,310 subjects invited over 2 years, 1,630 participated. After excluding individuals with diseases and medications affecting bone metabolism, 517 women (age 56.1 +/- 16.9 years) and 491 men (age 58.7 +/- 14.9 years) remained for analysis. OPG increased steadily with age in both genders without a gender difference. In women, BMD at all sites declined steadily after age 50. In men, BMD remained relatively stable until age 70, after which it declined significantly. After controlling for age, BMI, and other confounding variables, OPG showed only a borderline positive relationship with whole body BMD in men (P = 0.10), but the relationship was nonsignificant in women. In multivariable models, OPG was inversely related to TRACP-5b (P = 0.002) and positively with OC (P = 0.007), the OC/TRACP-5b (P = 0.001) and OC/CTX (P = 0.02) ratios in women. Among men, multivariable models showed a positive association between OPG and OC (P = 0.05) and OC/TRACP-5b (P < 0.009). CONCLUSIONS: We conclude that serum OPG levels are associated with a profile of bone turnover markers favoring bone formation, suggesting that OPG may be protective against age-related bone loss. Longitudinal studies are needed to address that issue.

The effect of raloxifene on markers of bone turnover in older women living in long-term care facilities.

OBJECTIVES: To examine the effect of raloxifene on bone turnover in elderly women. DESIGN: Clinical intervention. SETTING: Long-term care facilities. PARTICIPANTS: Nineteen women completed the study, mean age 85 (range 76-99). INTERVENTION: Raloxifene 60 mg was given daily for 12 weeks. MEASUREMENTS: Markers of bone turnover were plasma C-telopeptides of type I collagen (CTx), urine cross-linked N-telopeptides of type I collagen (NTx) and serum tartrate-resistant acid phosphatase (TRAP 5b), plasma osteocalcin, and serum bone alkaline phosphatase. Other markers were serum 25-OH vitamin D, parathyroid hormone, ionized calcium, and phosphate. Markers were measured at baseline, after calcium and vitamin D had been taken for 6 weeks, after raloxifene had been taken for 12 weeks, and 6 weeks after raloxifene had been stopped. Paired sample t test was used to examine changes in markers at each time point. RESULTS: Plasma CTx decreased on average by 31%, urinary NTx by 35%, plasma osteocalcin by 25%, serum bone alkaline phosphatase by 15% (P<.01), and serum TRAP 5b by 10% (P<.05) on treatment. CONCLUSION: Raloxifene reduces bone turnover in elderly women living in long-term care facilities. The effect of raloxifene on bone turnover is comparable with that seen in younger postmenopausal women.

Hyperphagia modifies FA profiles of plasma phospholipids, plasma FFA, and adipose tissue TAG.

Hyperphagia was achieved by continuous intracerebroventricular infusion of a melanocortin receptor antagonist (HS024; Neosystem, Strasbourg, France) in rats. The effects of hyperphagia on FA composition and concentration of plasma phospholipids (PL), plasma FFA, and adipose tissue TAG were studied in rats for 8 d [short-term hyperphagia (STH); n = 8], or 28 d [long-term hyperphagia (LTH); n = 9]. The control rats were treated with artificial cerebrospinal fluid for 8 d (n = 8) or 28 d (n = 10). The rats were fed the same regular diet. In STH rats the plasma PL and fasting plasma FFA contained higher concentrations of saturated FA (SFA) and monounsaturated FA (MUFA), and plasma FFA contained lower n-6 PUFA than in the control rats. In LTH rats the plasma PL contained higher concentrations of SFA, MUFA, and n-3 PUFA and higher proportions of 16:1n-7 and 18:1n-9 at the expense of 18:2n-6 than in the control rats. In LTH rats the abundant dietary intake of 18:2n-6 did not enrich 18:2n-6 of the plasma PL or adipose tissue TAG. In LTH rats the fasting plasma FFA contained more than twofold higher concentrations of SFA and MUFA, and higher proportions of 16:1n-7 and 18:1n-9 at the expense of 18:2n-6 than in the control rats. This animal obesity model shows that LTH affects the FA composition and concentration of plasma PL, plasma FFA, and adipose tissue TAG, a result consistent with changes associated with increased risk of various diseases in humans. These results also demonstrate that LTH alters the FA composition of plasma PL and adipose tissue TAG in a way that does not reflect the FA composition of dietary fat.

[Assessment of age-related changes in parathyroid hormone levels by different methods.].

BACKGROUND: Current assays measuring intact PTH may not only measure the active form, PTH(1-84), but also some large breakdown products, including PTH(7-84). A new method is believed to measure only PTH(1-84). The purpose of this study was to examine whether increases in intact PTH that accompany age, weight and worsening renal function could be related to breakdown products interfering with traditional assays. METHODS: We used data from an ongoing cross-sectional study on bone health in 40-85 years old Icelanders. Over a 12 month period, 1096 subjects were invited for a DEXA scan, blood test, height and weight measurements and each subject answered a questionnaire on health and medication. For the current analysis we excluded those who were taking medications affecting bone and mineral metabolism. PTH was measured using PTH elecsys (Roche) and the new PTH cap (Scantibodies). We used kappa statistic to assess agreement with regard to levels above upper reference values for each assay and ANOVA, Pearson's and Spearman's correlation coefficients for other analysis. Women and men were analyzed separately. RESULTS: Of 746 individuals who came for the study, after exclusion, 247 women and 209 men remained for this analysis. PTH was on the average roughly 40% lower with the new PTH cap assay. The correlation between the assays was 0.787 (P<0.001) for women and 0.69 (P<0.001) for men. Kappa statistic was 0.486 (P<0.001) for women and 0.283 (P<0.001) for men, indicating fair to good agreement. PTH elecsys increased with age (P=0.03 and P=0.01 for women and men, respectively) but not PTH cap (P=0.7 and P=0.09 for women and men, respectively). PTH elecsys was positively associated with cystatin C (P<0.05 for both genders), but the correlation between PTH cap and Cystatin C was not statistically significant. The association with body mass index was similar for the two assays (r=0.16 to 0.24, P<0.05) for both genders. CONCLUSIONS: There is a significant difference between these two PTH assays. It is likely that increases in intact PTH observed with age and worsening renal function are related to large breakdown products of PTH whereas the PTH increase seen with higher weight seems to be related to PTH(1-84) itself.