A metabolic signature for NADSYN1-dependent congenital NAD deficiency disorder.

Nicotinamide adenine dinucleotide (NAD) is essential for embryonic development. To date, biallelic loss-of-function variants in 3 genes encoding nonredundant enzymes of the NAD de novo synthesis pathway - KYNU, HAAO, and NADSYN1 - have been identified in humans with congenital malformations defined as congenital NAD deficiency disorder (CNDD). Here, we identified 13 further individuals with biallelic NADSYN1 variants predicted to be damaging, and phenotypes ranging from multiple severe malformations to the complete absence of malformation. Enzymatic assessment of variant deleteriousness in vitro revealed protein domain-specific perturbation, complemented by protein structure modeling in silico. We reproduced NADSYN1-dependent CNDD in mice and assessed various maternal NAD precursor supplementation strategies to prevent adverse pregnancy outcomes. While for Nadsyn1+/- mothers, any B3 vitamer was suitable to raise NAD, preventing embryo loss and malformation, Nadsyn1-/- mothers required supplementation with amidated NAD precursors (nicotinamide or nicotinamide mononucleotide) bypassing their metabolic block. The circulatory NAD metabolome in mice and humans before and after NAD precursor supplementation revealed a consistent metabolic signature with utility for patient identification. Our data collectively improve clinical diagnostics of NADSYN1-dependent CNDD, provide guidance for the therapeutic prevention of CNDD, and suggest an ongoing need to maintain NAD levels via amidated NAD precursor supplementation after birth.

Pattern of mental health attendances at a metropolitan university general practice clinic in Sydney before and during the COVID-19 pandemic.

BACKGROUND AND OBJECTIVES: The aim of this study was to describe the pattern of mental health attendances in a university-based general practice clinic during phases of the COVID-19 pandemic. The COVID-19 pandemic has created social and medical disruptions to the Australian community. There is a literature gap pertaining to the ongoing trends that extend beyond the initial 'first wave' of the pandemic in the context of the Australian landscape. METHOD: Retrospective data were obtained from 435 adults attending a community university-based general practice in Sydney, Australia, during four time periods: T1, before the COVID-19 pandemic (1 February - 7 March 2019); T2, during the first COVID-19 lockdown (31 March - 4 May 2020); T3, during the second COVID-19 lockdown (20 August - 23 September 2021); and T4, after the end of the COVID-19 lockdowns (1 February - 7 March 2022). Attendances were identified as mental health Medicare Benefits Schedule codes for face-to-face, televideo and telephone consultations. Patterns of attendances were evaluated using frequency analysis. RESULTS: There was a decline in mental health attendances compared to all attendances at the general practice from T1 (7.5%) to T2 (4.8%). During T4, mental health attendances returned to 7.1% of all consultations at the general practice. Face-to-face attendances decreased by 50% in T2 relative to T1, and this trend was maintained in T3 and T4, whereas the utilisation of telehealth approached that of face-to-face by T4. DISCUSSION: Post-pandemic policies that support the use of telehealth in general practice may help improve mental healthcare delivery and outcomes.

From Microcytosis to Macrodiagnosis.

A 12-year-old Hispanic girl presented with fatigue, lightheadedness, and intermittent headaches. She was depressed and appeared pale to her mother. Her examination was unremarkable except for palpebral conjunctival pallor and was otherwise noncontributory. She had a profound hypoproliferative microcytic anemia with low iron level, low transferrin saturation, and a normal ferritin level. The patient experienced improvement in clinical symptoms following transfusion of packed red blood cells and oral iron therapy. At follow-up 2 months later, she presented with similar symptoms and persistent microcytic anemia with low iron levels. Her ferritin level was increased along with markedly elevated C-reactive protein and erythrocyte sedimentation rate. An oral iron challenge demonstrated lack of absorption, and hepcidin level was also significantly elevated. Thorough gastrointestinal and rheumatologic evaluations were performed to search for a source of inflammation. Key components of the patient's social history supplemented by serology, radiographic, and pathologic findings ultimately cinched an unexpected diagnosis.