Monitoring phenylalanine concentrations in the follow-up of phenylketonuria patients:An inventory of pre-analytical and analytical variation

Background: Reliable measurement of phenylalanine (Phe) is a prerequisite for adequate follow-up of phenylketonuria (PKU) patients. However, previous studies have raised concerns on the intercomparability of plasma and dried blood spot (DBS) Phe results. In this study, we made an inventory of differences in (pre-)analytical methodology used for Phe determination across Dutch laboratories, and compared DBS and plasma results. Methods: Through an online questionnaire, we assessed (pre-)analytical Phe measurement procedures of seven Dutch metabolic laboratories. To investigate the difference between plasma and DBS Phe, participating laboratories received simultaneously collected plasma-DBS sets from 23 PKU patients. In parallel, 40 sample sets of DBS spotted from either venous blood or capillary fingerprick were analyzed. Results: Our data show that there is no consistency on standard operating procedures for Phe measurement. The association of DBS to plasma Phe concentration exhibits substantial inter-laboratory variation, ranging from a mean difference of −15.5% to +30.6% between plasma and DBS Phe concentrations. In addition, we found a mean difference of +5.8% in Phe concentration between capillary DBS and DBS prepared from venous blood. Conclusions: The results of our study point to substantial (pre-)analytical variation in Phe measurements, implicating that bloodspot Phe results should be interpreted with caution, especially when no correction factor is applied. To minimize variation, we advocate pre-analytical standardization and analytical harmonization of Phe measurements, including consensus on application of a correction factor to adjust DBS Phe to plasma concentrations

Improving a Rare Metabolic Disorder Through Kidney Transplantation: A Case Report of a Patient With Lysinuric Protein Intolerance.

Lysinuric protein intolerance (LPI) is a rare metabolic disorder with reduced renal and intestinal reabsorption of ornithine, lysine, and arginine. It is due to variants in SLC7A7, the gene encoding y+L amino acid transporter 1 (y+LAT1), which lead to urea cycle defects with protein intolerance. Chronic kidney disease in lysinuric protein intolerance is common and can progress to kidney failure and initiation of kidney replacement therapy. Kidney transplantation could in theory improve urine levels and, consequently, plasma levels of these amino acids and therefore improve clinical symptoms, as well as protein intolerance, in patients with lysinuric protein intolerance. However, data on kidney transplantation in patients with lysinuric protein intolerance are limited, and up until now no data on clinical and biochemical improvement after kidney transplantation have been reported. In this case report we describe a rare case of kidney transplantation in a lysinuric protein intolerance patient with substantial improvement in protein tolerance; in plasma and urine levels of ornithine, lysine, and arginine; and in lysinuric protein intolerance symptoms

TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood

BACKGROUND: Type 3 hereditary haemochromatosis (HH) is a rare iron overload disorder caused by variants in the transferrin 2 receptor (TFR2) gene. We aim to present characteristics of patients diagnosed with TFR2-HH in the Netherlands, in order to increase knowledge and awareness of this disease. METHODS: We collected clinical, biochemical and genetic data from four patients from three families diagnosed with HH type 3 in the Netherlands between 2009 and 2016. RESULTS: Three women and one man diagnosed with HH type 3 presented with arthralgia and elevated ferritin levels and transferrin saturation (TSAT) at ages 25-41 years. The hepcidin/ferritin ratio as measured in three patients was low. Liver iron content in two patients as assessed by MRI or liver biopsy was highly increased (250 and 362.7 mumol iron/g dry weight, respectively, reference 100 mumol/g form an indication for analysis of the TFR2 gene. Although type 3 HH is extremely rare, awareness of the disease among physicians is important in order to achieve an early diagnosis and prevent complications, such as liver damage

Variable workup calls for guideline development for type 2A hereditary haemochromatosis

Item does not contain fulltex

Impact of newborn screening for very-long-chain acyl-CoA dehydrogenase deficiency on genetic, enzymatic, and clinical outcomes

Contains fulltext : 203474.pdf (publisher's version ) (Open Access

Iron refractory iron deficiency anemia: a heterogeneous disease that is not always iron refractory

TMPRSS6 variants that affect protein function result in impaired matriptase-2 function and consequently uninhibited hepcidin production, leading to iron refractory iron deficiency anemia (IRIDA). This disease is characterized by microcytic, hypochromic anemia and serum hepcidin values that are inappropriately high for body iron levels. Much is still unknown about its pathophysiology, genotype-phenotype correlation, and optimal clinical management. We describe 14 different TMPRSS6 variants, of which 9 are novel, in 21 phenotypically affected IRIDA patients from 20 families living in the Netherlands; 16 out of 21 patients were female. In 7 out of 21 cases DNA sequencing and multiplex ligation dependent probe amplification demonstrated only heterozygous TMPRSS6 variants. The age at presentation, disease severity, and response to iron supplementation were highly variable, even for patients and relatives with similar TMPRSS6 genotypes. Mono-allelic IRIDA patients had a milder phenotype with respect to hemoglobin and MCV and presented significantly later in life with anemia than bi-allelic patients. Transferrin saturation (TSAT)/hepcidin ratios were lower in IRIDA probands than in healthy relatives. Most patients required parenteral iron. Genotype alone was not predictive for the response to oral iron. We conclude that IRIDA is a genotypically and phenotypically heterogeneous disease. The high proportion of female patients and the discrepancy between phenotypes of probands and relatives with the same genotype, suggest a complex interplay between genetic and acquired factors in the pathogenesis of IRIDA. In the absence of inflammation, the TSAT/hepcidin ratio is a promising diagnostic tool, even after iron supplementation has been given. Am. J. Hematol. 91:E482-E490, 2016. (c) 2016 Wiley Periodicals, Inc