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.