NAD deficiency, congenital malformations, and niacin supplementation

BACKGROUND: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients. METHODS: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 system. RESULTS: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects. CONCLUSIONS: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice

Relative acidic compartment volume as a lysosomal storage disorder–associated biomarker

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders

Virtual reality reduces anxiety and pain in acute hospital palliative care: service evaluation.

OBJECTIVES: Virtual reality (VR) might improve symptom management, but there is limited evidence regarding VR in palliative care. We evaluated the feasibility of VR and impact on anxiety and pain for patients in a hospital palliative care consultation service. METHODS: Patients referred to a hospital specialist palliative care team, with anxiety or pain, were offered a VR intervention (a short audiovisual experience). Participants rated anxiety and pain on a 0-10 Likert severity scale pre intervention/post intervention and completed an evaluation form. Change in symptom scores was analysed by parametric statistics. RESULTS: 28 participants used VR a total of 42 times with no adverse events. Mean pain score reduced by 29% from 4.10 (SD=2.71) pre intervention to 2.93 (SD=2.45) post intervention (t(27)=5.150, p<0.001). Mean anxiety scores reduced by 40% from 4.43 (SD=2.56) to 2.65 (SD=2.24) (t(27)=5.058, p<0.001). Patients rated the experience on average 4.75/5 and all would recommend use to a friend. VR was described as absorbing and relaxing. CONCLUSION: VR may improve anxiety and pain and was acceptable in this setting. Large-scale evaluation will generate important data on feasibility and implementation

Virtual reality reduces anxiety and pain in acute hospital palliative care: Service evaluation

Objectives: Virtual Reality (VR) might improve symptom management, but there is limited evidence regarding VR in palliative care. We evaluated the feasibility of VR and impact on anxiety and pain for patients in a hospital palliative care consultation service.Methods: Patients referred to a hospital specialist palliative care team, with anxiety or pain were offered a VR intervention (a short audio-visual experience.) Participants rated anxiety and pain on a 0-10 Likert severity scale pre/post intervention and completed an evaluation form. Change in symptom scores was analysed by parametric statistics. Results: 28 participants used VR a total of 42 times with no adverse events. Mean pain score reduced by 28% from 4.10 (SD = 2.71) pre intervention, to 2.93 (SD=2.45) post intervention (t(27)=5.150, p<0.001). Mean anxiety scores reduced by 40% from 4.43 (SD=2.56) to 2.65 (SD=2.24); (t(27)=5.058, p<0.001). Patients rated the experience on average 4.75/5 and all would recommend use to a friend. VR was described as absorbing and relaxing.Conclusion: VR may improve anxiety and pain and was acceptable in this setting. Larger scale evaluation will generate important data on feasibility and implementation

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications

Background Pathogenic PLOD3 variants cause a connective tissue disorder (CTD) that has been described rarely. We further characterise this CTD and propose a clinical diagnostic label to improve recognition and diagnosis of PLOD3-related disease. Methods Reported PLOD3 phenotypes were compared with known CTDs utilising data from three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant. PLOD3 mRNA expression in the developing embryo was analysed for tissue-specific localisation. Mouse microarray expression data were assessed for phylogenetic gene expression similarities across CTDs with overlapping clinical features. Results Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection. Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB). Human lysyl hydroxylase 3/PLOD3 expression was localised to the developing cochlea, eyes, skin, forelimbs, heart and cartilage, mirroring the clinical phenotype of this disorder. Conclusion These data are consistent with pathogenic variants in PLOD3 resulting in a clinically distinct Stickler-like syndrome with vascular complications and variable features of EDS and EB. Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes

Gene localization for an autosomal dominant familial periodic fever to 12p13.

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses