Search

Background: Polycystic liver disease (PLD) is a common extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). Bile acids may play a role in PLD pathogenesis. We performed a post-hoc exploratory analysis of bile acids in ADPKD patients, who had participated in a trial on the effect of a somatostatin analogue. Our hypothesis was that serum bile acid levels increase in PLD, and that lanreotide, which reduces liver growth, may also reduce bile acid levels. Furthermore, in PLD, urinary excretion of bile acids might contribute to renal disease. Methods:With liquid chromatography-mass spectrometry, 11 bile acids in serum and 6 in urine were quantified in 105 PLD ADPKD patients and 52 age-, sex-, mutation- and eGFR-matched non-PLD ADPKD patients. Sampling was done at baseline and after 120 weeks of either lanreotide or standard care. Results: Baseline serum levels of taurine- and glycine-conjugated bile acids were higher in patients with larger livers. In PLD patients, multiple bile acids decreased upon treatment with lanreotide but remained stable in untreated subjects. Changes over time did not correlate with changes in liver volume. Urine bile acid levels did not change and did not correlate with renal disease progression. Conclusion: In ADPKD patients with PLD, baseline serum bile acids were associated with liver volume. Lanreotide reduced bile acid levels and has previously been shown to reduce liver volume. However, in this study, the decrease in bile acids was not associated with the change in liver volume.

Two siblings, presenting with a neurometabolic phenotype, were identified with 5, 10-methenyltetrahydrofolate synthetase (MTHFS) deficiency. Whole genome sequencing in both patients demonstrated an homozygous MTHFS variant NM_006441.3(MTHFS):c.434G > A, p.Arg145Gin, which has been described before. At baseline, both patients showed moderate hyperhomocysteinemia, decreased 5-methyltetrahydrofolate (5MTHF), and increased 5-formyltetrahydrofolate (5-FTHF) in whole blood. In CSF, 5MTHF levels were in the low-normal range and 5-FTHF was strongly increased. In our novel enzyme assay, MTHFS activity was deficient in cultured fibroblasts in both sisters. Oral treatment was initiated with escalating dose of 5-methyltetrahydrofolate (5MTHF) up to 12 mg and hydroxycobalamin 5 mg daily. Plasma homocysteine normalized and 5MTHF became elevated in the blood of both patients. The elevated 5FTHF levels increased further on treatment in blood and CSF. This regimen resulted in some clinical improvement of patient 1. In patient 2, the clinical benefits of 5MTHF supplementation were less obvious. It seems plausible that the alleviation of the deficient 5MTHF levels and normalization of homocysteine in blood are of some clinical benefit. On the other hand, the very high levels of 5FTHF may well be detrimental and may prompt us to decrease the dose of 5MTHF. In addition, we hypothesize that the crippled MTHFS enzyme may destabilize the purinosome, which is presumably not ameliorated by 5MTHF.

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective: To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods: Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results: Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions: Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.

beta-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyses the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, ammonia and CO2. To date, only a limited number of genetically confirmed patients with a complete beta-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 10 newly identified beta-ureidopropionase deficient individuals. Patients presented mainly with neurological abnormalities and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine. Analysis of UPB1, encoding beta-ureidopropionase, showed 5 novel missense variants and two novel splice-site variants. Functional expression of the UPB1 variants in mammalian cells showed that recombinant beta-ureidopropionase carrying the p.Ala120Ser, p.Thr129Met, p.Ser300Leu and p.Asn345Ile variant yielded no or significantly decreased beta-ureidopropionase activity. Analysis of the crystal structure of human beta-ureidopropionase indicated that the point mutations affect substrate binding or prevent the proper subunit association to larger oligomers and thus a fully functional beta-ureidopropionase. A minigene approach showed that the intronic variants c.[364 + 6 T > G] and c.[916 + 1_916 + 2dup] led to skipping of exon 3 and 8, respectively, in the process of UPB1 pre-mRNA splicing. The c.[899C > T] (p.Ser300Leu) variant was identified in two unrelated Swedish beta-ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated.

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine–tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal–Wallis tests with post-hoc Mann–Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions “working memory”, “plan and organize” and “monitor”, ASEBA dimensions “social problems” and “attention problems”, and for the SSRS “assertiveness” scale (all p values <0.001). To conclude, TT1 patients showed cognitive impairments on all domains studied, and appeared to be significantly more affected than PKU patients. More attention should be paid to investigating and monitoring neurocognitive outcome in TT1 and research should focus on explaining the underlying pathophysiological mechanism.

INTRODUCTION: We examined associations between nutritional biomarkers and clinical progression in individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD)-type dementia. METHODS: We included 528 individuals (64 ± 8 years, 46% F, follow-up 2.1 ± 0.87 years) with SCD (n = 204), MCI (n = 130), and AD (n = 194). Baseline levels of cholesterol, triglycerides, glucose, homocysteine, folate, vitamin A, B12, E and uridine were measured in blood and S-adenosylmethionine and S-adenosylhomocysteine in cerebrospinal fluid. We determined associations between nutritional biomarkers and clinical progression using Cox proportional hazard models. RESULTS: Twenty-two (11%) patients with SCD, 45 (35%) patients with MCI, and 100 (52%) patients with AD showed clinical progression. In SCD, higher levels of low-density lipoprotein (LDL) cholesterol were associated with progression (hazard ratio [HR] [95% confidence interval (CI)] 1.88 [1.04 to 3.41]). In AD, lower uridine levels were associated with progression (0.79 [0.63 to 0.99]). DISCUSSION: Our findings suggest that LDL cholesterol and uridine play a—stage-dependent—role in the clinical progression of AD.

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium. Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups. Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.