NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses.

Physical stress, including high temperatures, may damage the central metabolic nicotinamide nucleotide cofactors [NAD(P)H], generating toxic derivatives [NAD(P)HX]. The highly conserved enzyme NAD(P)HX dehydratase (NAXD) is essential for intracellular repair of NAD(P)HX. Here we present a series of infants and children who suffered episodes of febrile illness-induced neurodegeneration or cardiac failure and early death. Whole-exome or whole-genome sequencing identified recessive NAXD variants in each case. Variants were predicted to be potentially deleterious through in silico analysis. Reverse-transcription PCR confirmed altered splicing in one case. Subject fibroblasts showed highly elevated concentrations of the damaged cofactors S-NADHX, R-NADHX and cyclic NADHX. NADHX accumulation was abrogated by lentiviral transduction of subject cells with wild-type NAXD. Subject fibroblasts and muscle biopsies showed impaired mitochondrial function, higher sensitivity to metabolic stress in media containing galactose and azide, but not glucose, and decreased mitochondrial reactive oxygen species production. Recombinant NAXD protein harbouring two missense variants leading to the amino acid changes p.(Gly63Ser) and p.(Arg608Cys) were thermolabile and showed a decrease in Vmax and increase in KM for the ATP-dependent NADHX dehydratase activity. This is the first study to identify pathogenic variants in NAXD and to link deficient NADHX repair with mitochondrial dysfunction. The results show that NAXD deficiency can be classified as a metabolite repair disorder in which accumulation of damaged metabolites likely triggers devastating effects in tissues such as the brain and the heart, eventually leading to early childhood death.

Locus and allelic heterogeneity and phenotypic variability in Waardenburg syndrome.

Waardenburg syndrome (WS) is a disorder of neural crest cell migration characterized by auditory and pigmentary abnormalities. We investigated a cohort of 14 families (16 subjects) either by targeted sequencing or whole-exome sequencing. Thirteen of these families were clinically diagnosed with WS and one family with isolated non-syndromic hearing loss (NSHL). Intra-familial phenotypic variability and non-penetrance were observed in families diagnosed with WS1, WS2 and WS4 with pathogenic variants in PAX3, MITF and EDNRB, respectively. We observed gonosomal mosaicism for a variant in PAX3 in an asymptomatic father of two affected siblings. For the first time, we report a biallelic pathogenic variant in MITF in a subject with WS2 and a biallelic variant in EDNRB was noted in a subject with WS2. An individual with isolated NSHL carried a pathogenic variant in MITF. Blended phenotype of NSHL and albinism was observed in a subject clinically diagnosed to have WS2. A phenocopy of WS1 was observed in a subject with a reported pathogenic variant in GJB2, known to cause isolated NSHL. These novel and infrequently reported observations exemplify the allelic and genetic heterogeneity and show phenotypic diversity of WS.

There is Only a Modest Increase in Neonatal Respiratory Morbidity Following Early Term Elective Cesarean in a South Indian Population.

OBJECTIVES: Elective cesarean deliveries (ECD) are still performed prior to 39 weeks. This study aimed to identify risk of neonatal respiratory morbidity (NRM) following ECD near term, in a South Indian population. Specifically, study aimed to measure the additional healthcare burden due to large number of ECDs performed prior to 39 weeks, in this local population. METHODS: We analyzed NRM among 1329 deliveries (584 ECD and 745 spontaneous vaginal delivery, SVD) in a tertiary hospital over 2 years. Neonates were grouped into: A: 35+0-36+6 weeks, B: 37+0-38+6 weeks, and C: ≥39 weeks. NRM was compared between ECD versus SVD. RESULTS: Majority (433/584) of ECDs were performed between 37+0 and 38+6 weeks. Overall, 32% received steroid prophylaxis. Of 1329 newborns, 18/584 (3.82%) in ECD and 6/745 (0.8%) in SVD group developed NRM (p value of 0.004, OR 3.9, CI 1.54-9.93). Need of respiratory support among ECD was 4.28% compared to 0.53% in SVD (p < 0.001, OR 8.28; CI 2.86-23.94). However, comparing neonates born by ECD between groups B Vs C; there was only a modest increase in NRM (2.07 vs 0.9%; p 0.48, OR 2.3 with CI 0.29-18.4) and in need of respiratory support (2.54 vs 0.9%; p 0.47, OR 2.84; CI 0.36-22.2). CONCLUSION: NRM following early term ECD continues to be a healthcare burden in India. Interestingly in this South Indian population, early term ECDs caused only modest increase in NRM, and this ethnic variation requires further evaluation to determine ideal time for ECD in local population.