Adult patient diagnosed with NADSYN1 associated congenital NAD deficiency and analysis of NAD levels to be published in: European Journal of Medical Genetics.

INTRODUCTION: Nicotinamide adenine dinucleotide (NAD) is an essential cosubstrate/coenzyme in multiple cellular redox processes and a substrate in several non-redox reactions. NADSYN1 encodes NAD synthetase 1, an enzyme in the NAD de novo synthesis pathway and the Preiss-Handler pathway, and biallelic pathogenic variants causes NAD deficiency associated with vertebral, cardiac, renal and limb defects. Szot et al. and Kortbawi et al. have reported a total of seven patients with NADSYN1 associated congenital NAD deficiency disorder with the oldest patient being seven years old. PATIENT DATA: We present a male patient age 30 with a height of 130 cm and numerous skeletal malformations including segmentation defects of the spine, rib anomalies and unequal leg length as well as bilateral ptosis, cleft palate and asymmetric dysmorphic facial features. The patient underwent surgery for an aortic stenosis due to a bicuspid valve. No malformations of the kidneys or urinary tract were identified. RESULTS: Trio exome sequencing revealed a homozygous missense variant in NADSYN1 c.1717G > A (p.Ala573Thr). Both parents were unaffected carriers of the variant. Analysis of NAD levels showed that the patient had a lower NAD pool compared to his unaffected siblings. The NAD pool rose approximately 25% after supplementation with nicotinamide, a NAD precursor for the salvage pathway. CONCLUSION: The variant was previously reported in four patients and functional analyses by Szot et al. support the pathogenicity of the variant. We report an adult patient with NADSYN1 associated congenital NAD deficiency disorder and expand the phenotypic spectrum. We also present analysis of the NAD levels before and after supplementation with nicotinamide.

Vitamin K supplementation and arterial calcification in dialysis: results of the double-blind, randomized, placebo-controlled RenaKvit trial.

BACKGROUND: Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), are prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated whether vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. METHODS: In a 2-year, double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomized to vitamin K [menaquinone-7 (MK-7), 360 µg daily] or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aortic calcification (AAC) were used to assess arterial calcification. RESULTS: Thirty-seven participants completed Year 1, and 21 completed Year 2. At Year 2, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo {mean dp-ucMGP difference: -1380 pmol/L [95% confidence interval (CI) -2029 to -730]}. There was no significant effect of vitamin K supplementation on cfPWV [mean difference at Year 2: 1.2 m/s (95% CI -0.1 to 2.4)]. CAC Agatston score increased significantly in vitamin K supplemented participants, but was not significantly different from placebo [mean difference at Year 2: 664 (95% CI -554 to 1881)]. AAC scores increased in both groups, significantly so within the placebo group at Year 1, but with no significant between-group differences. CONCLUSIONS: Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.

[Vitamin K2 influences several diseases]. / K2-vitamin har betydning ved en række sygdomme

In this paper we discuss the evidence of vitamin K2 deficiency which is a factor in several chronic diseases like diabetes, osteoporosis, cancer, inflammatory and cardiovascular diseases. This deficiency is very common in the mentioned diseases although it is rarely treated by clinicians. Randomized clinical trials have shown that patients with osteoporosis, cardiovascular diseases and cancer can benefit from vitamin K2 supplement. Further studies are needed to ascertain the effect of vitamin K2 supplement in patients with diabetes and inflammatory bowel diseases.