NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction

Manor, Joshua; Calame, Daniel G.; Gijavanekar, Charul; Fisher, Kristen; Hunter, Jill V.; Mizerik, Elizabeth; Bacino, Carlos A.; Scaglia, Fernando; Elsea, Sarah H.

doi:10.1016/j.ymgme.2022.04.003

Cited by 12 publications

(43 citation statements)

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“…We speculate that head trauma in adults, in addition to paediatric head trauma (Case 1 [ 2 ]), fever or illness in children, may precipitate neurometabolic crises associated with pathogenic NAXD variants, although one will be more confident of the former if the precipitant is also identified in future cases. The partial amelioration in the adult patient after B3 treatment, alongside preliminary niacin-based n-of-1 interventions for NAXD and NAXE deficiency cases (reviewed in [ 1 , 11 ]) provide evidence that early intervention may attenuate the severity of the injury or illness. Lastly, our work highlights the importance of considering rapid WGS for adults with likely monogenic disorders in ICU to aid in diagnostic decisions, with these benefits already demonstrated in a paediatric setting [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma

Bergen

Gunanayagam

Bournazos

et al. 2023

IJMS

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We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.

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Section: Discussionmentioning

confidence: 99%

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma

Bergen

Gunanayagam

Bournazos

et al. 2023

IJMS

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“…NAD levels are also reduced in the NAXE knockout heart, which is consistent with our findings of metabolites in the plasma [ 30 ]. The reduced NAD levels are probably the cause of the red, flaky skin of Pellagra disease in patients with NAXE mutation [ 13 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration

Kim

Zhou

Zhang

et al. 2022

Cells

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Accumulating evidence indicates that the APOA1 binding protein (AIBP)—a secreted protein—plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and lipid-associated metabolites α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe−/− heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism.

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“…High‐dose niacin supplementation showed improvement in clinical status and reversal of the metabolic perturbations when assessed 6 months post‐crisis. None of the previously published cases have reported abnormal laboratory findings in ACP, PAA, or UOA analysis, making metabolomic profiling a valuable tool in evaluating these patients (Manor et al., 2022).…”

Section: Disorders Of Vitamin and Cofactor Metabolismmentioning

confidence: 99%

“…Case 6 is a 2‐year‐old male who presented with acute onset ataxia, loss of the ability to walk with hyperreflexia, intermittent esotropia, basal ganglia changes on MRI, and elevated lactate. Metabolic tests including ACP and PAA were normal (Manor et al., 2022). Exome sequencing (Baylor Genetics) identified compound heterozygous likely pathogenic variants NM_144772.3:c.804_807delinsA (p.Lys270del) and NM_144772.3:c.386G>C (p.Arg129Pro) in NAXE.…”

Section: Disorders Of Vitamin and Cofactor Metabolismmentioning

confidence: 99%

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Clinical Untargeted Metabolomics as a Functional Screen to Improve Variant Classification

Gijavanekar

Elsea

2023

Current Protocols

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With the rapid increase in clinical exome and genome sequencing, the number of variants of uncertain significance (VUS) that are reported continues to rise, which poses a significant barrier to interpretation of genetic findings. For metabolic disorders, biochemical testing can help alleviate this burden of variant interpretation by providing functional validation of uncertain genetic findings in many cases. However, a major limitation of traditional biochemical testing is the targeted, narrow range of analytes clinically available, resulting in delays in diagnosis if testing is negative. Untargeted metabolomic screening offers higher diagnostic yield and assays for thousands of metabolites across multiple metabolic pathways in a single test, saving time and resources for patients, families, and physicians. When integrated with exome or genome sequencing, untargeted metabolomic screening improves diagnostic outcomes by providing functional validation of genetic findings, particularly for VUS. Here, we present representative cases across the breadth of metabolic pathways as examples of the utility of metabolomics in genomic variant classification.

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NAXE deficiency: A neurometabolic disorder of NAD(P)HX repair amenable for metabolic correction

Cited by 12 publications

References 50 publications

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma

Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma

AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration

Clinical Untargeted Metabolomics as a Functional Screen to Improve Variant Classification

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