Rationale: Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, leads to impaired pancreatic function and therefore reduced intestinal absorption of lipids and fat-soluble vitamins especially in patients with CF developing pancreatic insufficiency (PI). Previous studies showed that CFTR modulator therapy with lumacaftor-ivacaftor (LUM/IVA) in Phe508del-homozygous patients with CF results in improvement of pulmonary disease and thriving. However, the effects of LUM/IVA on plasma concentration of the lipid soluble vitamins A and E remain unknown. Objectives: To investigate the course of plasma vitamin A and E in patients with CF under LUM/IVA therapy. Methods: Data from annual follow-up examinations of patients with CF were obtained to assess clinical outcomes including pulmonary function status, body mass index (BMI), and clinical chemistry as well as fat-soluble vitamins in Phe508del-homozygous CF patients before initiation and during LUM/IVA therapy. Results: Patients with CF receiving LUM/IVA improved substantially, including improvement in pulmonary inflammation, associated with a decrease in blood immunoglobulin G (IgG) from 9.4 to 8.2 g/L after two years (p < 0.001). During the same time, plasma vitamin A increased significantly from 1.2 to 1.6 µmol/L (p < 0.05), however, levels above the upper limit of normal were not detected in any of the patients. In contrast, plasma vitamin E as vitamin E/cholesterol ratio decreased moderately over the same time from 6.2 to 5.5 µmol/L (p < 0.01). Conclusions: CFTR modulator therapy with LUM/IVA alters concentrations of vitamins A and vitamin E in plasma. The increase of vitamin A must be monitored critically to avoid hypervitaminosis A in patients with CF.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive upper and lower motor neuron (LMN) loss. As ALS and other neurodegenerative diseases share genetic risk factors, we performed whole-exome sequencing in ALS patients focusing our analysis on genes implicated in neurodegeneration. Thus, variants in the DHTKD1 gene encoding dehydrogenase E1 and transketolase domain containing 1 previously linked to 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth (CMT) disease type 2, and spinal muscular atrophy (SMA) were identified. In two independent European ALS cohorts (n = 643 cases), 10 sporadic cases of 225 (4.4%) predominantly sporadic patients of cohort 1, and 12 familial ALS patients of 418 (2.9%) ALS families of cohort 2 harbored 14 different rare heterozygous DHTKD1 variants predicted to be deleterious. Four DHTKD1 variants were previously described pathogenic variants, seven were recurrent, and eight were located in the E1_dh dehydrogenase domain. Nonsense variants located in the E1_dh domain were significantly more prevalent in ALS patients versus controls. The phenotype of ALS patients carrying DHTKD1 variants partially overlapped with CMT and SMA by presence of sensory impairment and a higher frequency of LMN-predominant cases. Our results argue towards rare heterozygous DHTKD1 variants as potential contributors to ALS phenotype and, possibly, pathogenesis.

This article reports a targeted metabolomic method for total plasma fatty acids (FAs) of clinical or nutritional relevance. Thirty-six saturated, unsaturated, or branched-chain FAs with a chain length of C8-C28 were quantified using reversed-phase liquid chromatography-tandem mass spectrometry. FAs in plasma (10 μL) were acid-hydrolyzed, extracted, and derivatized with DAABD-AE (4-[2-(N,N-Dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole) at 60 °C for 1 h. Derivatization resulted in a staggering nine orders of magnitude higher sensitivity compared to underivatized analytes. FAs were measured by multiple-reaction monitoring using stable isotope internal standards. With physiological and pathological analyte levels in mind, linearity was established using spiked plasma. Intra-day (n = 15) and inter-day (n = 20) imprecisions expressed as variation coefficient were ≤10.2% with recovery ranging between 94.5–106.4%. Limits of detection and limit of quantitation ranged between 4.2–14.0 and 15.1–51.3 pmol per injection, respectively. Age-stratified reference intervals were established in four categories: 18 year. This method was assessed using samples from patients with disorders affecting FAs metabolism. For the first time, C28:0 and C28:0/C22:0 ratio were evaluated as novel disease biomarkers. This method can potentially be utilized in diagnosing patients with inborn errors of metabolism, chronic disease risk estimation, or nutritional applications.