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. 2023 Mar 8;13(3):399.
doi: 10.3390/metabo13030399.

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male

Karen L DeBalsi  1 , John H Newman  2 , Laura J Sommerville  1 , John A Phillips 3rd  2 , Rizwan Hamid  2 , Joy Cogan  2 , Joshua P Fessel  3 , Anne M Evans  1 , Undiagnosed Diseases Network; Undiagnosed Diseases Network; Adam D Kennedy  1
Affiliations

A Case Study of Dysfunctional Nicotinamide Metabolism in a 20-Year-Old Male

Karen L DeBalsi et al. Metabolites. .

Abstract

We present a case study of a 20-year-old male with an unknown neurodegenerative disease who was referred to the Undiagnosed Diseases Network Vanderbilt Medical Center site. A previous metabolic panel showed that the patient had a critical deficiency in nicotinamide intermediates that are generated during the biosynthesis of NAD(H). We followed up on these findings by evaluating the patient's ability to metabolize nicotinamide. We performed a global metabolic profiling analysis of plasma samples that were collected: (1) under normal fed conditions (baseline), (2) after the patient had fasted, and (3) after he was challenged with a 500 mg nasogastric tube bolus of nicotinamide following the fast. Our findings showed that the patient's nicotinamide N-methyltransferase (NNMT), a key enzyme in NAD(H) biosynthesis and methionine metabolism, was not functional under normal fed or fasting conditions but was restored in response to the nicotinamide challenge. Altered levels of metabolites situated downstream of NNMT and in neighboring biochemical pathways provided further evidence of a baseline defect in NNMT activity. To date, this is the only report of a critical defect in NNMT activity manifesting in adulthood and leading to neurodegenerative disease. Altogether, this study serves as an important reference in the rare disease literature and also demonstrates the utility of metabolomics as a diagnostic tool for uncharacterized metabolic diseases.

Keywords: NADH deficiency; NADH metabolism; errors of metabolism; nicotinamide; nicotinamide N-methyltransferase; nicotinamide N-methyltransferase deficiency.

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Conflict of interest statement

K.L.D., L.J.S., A.M.E. and A.D.K. are employees of Metabolon. The other authors have no conflicts of interest.

Figures

Figure 1
Figure 1
Timeline of the patient’s history.
Figure 2
Figure 2
Sample collection time points.
Figure 3
Figure 3
NAD(H) biosynthesis pathways.
Figure 4
Figure 4
The Z-scores for the healthy reference population in comparison to the pre-fast, post-fast, and post-treatment Z-scores for the patient for (A) nicotinamide, (B) 1-methylnicotinamide, and (C) nicotinamide riboside. The box represents the 1st and 3rd quartiles, with the median indicated by a line within the box. The whiskers represent the top 97.5th and bottom 2.5th percentiles of the reference range. Individual values within the reference population (N = 866) outside these percentiles are indicated with circles.
Figure 5
Figure 5
(A) The de novo pathway for the NAD+ biosynthesis, along with the Z-scores for the healthy reference population in comparison to the pre-fast, post-fast, and post-treatment Z-scores for the patient for (B) tryptophan, (C) kynurenine, (D) kynurenate, (E) xanthurenate, and (F) quinolinate. The box represents the 1st and 3rd quartiles, with the median indicated by a line within the box. The whiskers represent the top 97.5th and bottom 2.5th percentiles of the reference range. Individual values within the reference population (N = 866) outside these percentiles are indicated with circles.
Figure 6
Figure 6
(A) Methionine metabolic pathway, along with the Z-scores for the healthy reference population in comparison to the pre-fast, post-fast, and post-treatment Z-scores for the patient for (B) methionine, (C) cystathionine, and (D) cysteine. The box represents the 1st and 3rd quartiles, with the median indicated by a line within the box. The whiskers represent the top 97.5th and bottom 2.5th percentiles of the reference range. Individual values within the reference population (N = 866) outside these percentiles are indicated with circles.
Figure 7
Figure 7
(A) Purine metabolic pathway (through inosine), along with the Z-scores for the healthy reference population in comparison to the pre-fast, post-fast, and post-treatment Z-scores for the patient for (B) inosine, (C) hypoxanthine, and (D) xanthine. The box represents the 1st and 3rd quartiles, with the median indicated by a line within the box. The whiskers represent the top 97.5th and bottom 2.5th percentiles of the reference range. Individual values within the reference population (N = 866) outside these percentiles are indicated with circles.
Figure 8
Figure 8
Z-scores for the healthy reference population in comparison to the pre-fast, post-fast, and post-treatment Z-scores for the patient for (A) stearidonate, (B) docohexaenoate, (C) docopentaenoate, (D) linolenate, (E) eicosapentaenoate, (F) cortisol, and (G) cortisone. The box represents the 1st and 3rd quartiles, with the median indicated by a line within the box. The whiskers represent the top 97.5th and bottom 2.5th percentiles of the reference range. Individual values within the reference population (N = 866) outside these percentiles are indicated with circles.
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