Reply: Niacin therapy improves outcome and normalizes metabolic abnormalities in an NAXD-deficient patient

We read with great interest the letter by Manor et al.,¹ which presents evidence of a child with biallelic pathogenic NAXD variants who has shown clinical improvement after niacin therapy as it highlights the potential for successful clinical management of this devastating disorder.

The child was first presented to medical attention at the age of 2 years, because of respiratory failure and gait abnormalities, and diagnostic evaluation revealed elevated creatine kinase and a non-specific mitochondrial disorder. Muscle biopsy showed mitochondrial myopathy and fibres deficient for complexes I and IV, which was reported in several previous NAXD cases.² The muscle weakness continued into the teen years, with gradual deterioration, eventually even interfering with moderate physical activities. Repeat testing demonstrated elevated creatine kinase. Elevated creatine kinase was reported in two cases previously.^2,3 As part of a clinical evaluation at the age of 13, a gene panel for 25 genes associated with Duchenne and other syndromic muscular dystrophies was non-diagnostic. Three years later, febrile illness triggered a rapid myoencephalopathic crisis. The patient was confirmed to have an 8 kb microdeletion spanning exons 1–2 of NAXD and a single nucleotide variant (SNV) within exon 1, predicted to affect splicing. Exon 1 contains the mitochondrial propeptide, and a cytosolic isoform is initiated from an alternative start codon in exon 2.⁴ Although not yet confirmed experimentally, the SNV may affect the mitochondrial isoform, but allow expression of the cytosolic isoform, which could explain the ‘milder’ clinical presentation of this individual.

The commonest feature of previously reported NAXD patients is rapid deterioration after an otherwise trivial fever, infection or illness which has been lethal in all cases^2,3,5,6 except one.⁷ The outstanding feature of the patient who did not succumb after illness may be due to the application of high dose vitamin B3 (500 mg/day). This was reported to alleviate the skin manifestations and stabilize neurological symptoms.⁷ Additionally, a similar therapeutic approach may be of benefit to NAXE patients. A single patient with NAXE deficiency was treated with Coenzyme Q10 and niacin (40–80 mg/day) and showed improved clinical outcomes after treatment.⁸ The current report by Manor et al.¹ describes a second NAXD patient who received niacin supplementation (100 mg/day). In this report, reduction of creatine kinase levels towards normal and a significant improvement in the clinical outcome were reported 11 months after intervention. The creatine kinase levels were sustained at lower, though still slightly elevated, levels 17 months post crisis.

The current study from Manor et al.¹ provides interesting preliminary indicators of metabolic perturbations due to NAXD deficiency occurring in a patient at the time of clinical crisis. Plasma metabolomic analysis showed significant depletion of nicotinamide metabolites, as may be expected due to NAD(P)HX repair deficiency, as well as alterations in TCA cycle intermediates and increased branched chain amino acid levels, indicative of mitochondrial dysfunction. Plasma metabolomics also provided evidence of serine metabolism disturbances in the patient, reminiscent of previously described metabolic perturbations in a yeast NAXD knockout model.⁹ Finally, Manor et al.¹ report that the NAXD patient exhibited reduced plasma levels of plasmalogens, phosphatidylcholines, and certain sphingomyelins, which depend on metabolic inputs from many subcellular compartments, including peroxisomes and the endoplasmic reticulum, for their synthesis. Perturbed serine metabolism along with NAD depletion (exacerbated by febrile illness) and energy crisis due to mitochondrial dysfunction may all contribute towards impaired lipid biosynthesis. Excitingly, niacin treatment in the NAXD patient reported by Manor et al.¹ significantly restored the plasma levels of the reported differential metabolites, indicating that brute-force increase in overall NAD levels via niacin treatment can compensate for an absence of NAXD function in mitochondria (and probably other compartments as well).

From the first reports of pathogenic variants in NAXE, nicotinamide therapy was speculated to be of benefit for disorders of the nicotinamide nucleotide repair system.¹⁰ Now, it is exciting to see potential treatments being tested in patients and providing a degree of protection against severe clinical outcomes. The outcomes reported so far for the two treated NAXD patients^1,7 and the single treated NAXE case⁸ support the use of niacin-based therapies for stabilizing the clinical progression. Despite the early success of these preliminary niacin-based n-of-1 interventions, the precise pathways critically impacted by NAD(P)HX repair deficiency remain to be identified and thus it would be of great interest to further probe the transcriptomic, proteomic and cellular consequences of both NAXD and NAXE deficiency in appropriate disease models. A deeper understanding may inform new or more specific compounds as targeted treatments. Additionally, high throughput drug discovery may be used to identify compounds which may be of even greater therapeutic efficacy for this severe and often fatal disorder.

Data availability

Data availability is not applicable to this article as no new data were created or analysed in this study.

Competing interests

The authors report no competing interests.