Orphanet Journal of Rare Diseases | Clinical Features and Nicotinamide Treatment Outcomes in NAD(P)HX Deficiency Disorders

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This study systematically analyzes the clinical features of NAD(P)HX metabolic repair system deficiency and the significant efficacy of nicotinamide treatment, emphasizing that early diagnosis and intervention can substantially improve prognosis, providing critical therapeutic evidence for this rare and lethal mitochondrial disorder.

 

Literature Overview

The article titled 'Deficiency of the NAD(P)HX metabolic repair system: a treatable mitochondrial disease,' published in Orphanet Journal of Rare Diseases, reviews and summarizes the clinical features, efficacy of nicotinamide treatment, and long-term outcomes in patients with NAD(P)HX metabolic repair system deficiency. The study includes 9 patients diagnosed at Beijing Children's Hospital and integrates data from 50 previously reported cases, systematically analyzing the disease's pathogenesis, clinical manifestations, imaging features, genetic basis, and treatment responses. The results indicate that nicotinamide treatment significantly improves survival rates, and early intervention enhances neurological function and reduces mortality. This study provides crucial evidence for early clinical recognition and standardized treatment of this treatable mitochondrial disorder.

Background Knowledge

The NAD(P)HX metabolic repair system is a highly conserved cellular protective mechanism composed of two enzymes, NAXE and NAXD, responsible for clearing the toxic metabolite NAD(P)HX generated by spontaneous hydration, thereby maintaining intracellular NAD(P)H/NAD(P)+ homeostasis. Mutations in the NAXE or NAXD genes lead to the accumulation of toxic metabolites, inhibiting mitochondrial complex I and pyruvate dehydrogenase activity, resulting in severe mitochondrial dysfunction. Deficiencies in these enzymes cause diseases known as PEBEL1 (NAXE deficiency) and PEBEL2 (NAXD deficiency), characterized by fever-induced acute encephalopathy in infancy, ataxia, dystonia, epilepsy, and respiratory failure, often fatal within 1–2 years. Patients with NAXD deficiency more frequently exhibit skin lesions and hematological involvement, and have higher mortality. Despite the high fatality rate, studies have shown that nicotinamide (vitamin B3), as an NAD+ precursor, can bypass the enzymatic defect and replenish the NAD+ pool, thereby improving metabolic and neurological functions. However, due to the rarity of cases, systematic evaluations of treatment dosage, timing, and long-term efficacy have been lacking. This study fills that gap by providing the largest clinical cohort analysis to date, validating the effectiveness and safety of nicotinamide treatment and laying the foundation for standardized therapeutic protocols.

 

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Methods and Experiments

This study is a single-center retrospective cohort study including 9 patients with NAD(P)HX metabolic repair system deficiency diagnosed at Beijing Children's Hospital between January 2016 and January 2025, all confirmed by whole-exome sequencing to carry pathogenic variants in the NAXE or NAXD genes. Clinical data, neuroimaging, laboratory results, and treatment information were collected. All patients initiated nicotinamide treatment immediately after diagnosis, starting at 100 mg/day and titrated up to 500 mg/day based on tolerance. Regular follow-ups assessed growth, neurological function (using mRS scores), laboratory markers, and MRI changes. Additionally, a systematic search of databases such as PubMed and Embase was conducted to include 50 previously reported cases for pooled analysis. Survival analysis was performed using the Kaplan-Meier method, and Cox regression models were used to evaluate prognostic factors.

Key Findings and Insights

• Among the 9 patients, 8 had NAXE deficiency and 1 had NAXD deficiency; 7 received nicotinamide treatment at doses of 180–500 mg/day, with a median follow-up of 3.92 years. All treated patients survived, with 3 attending school normally and no severe adverse events reported
• Integrated data from 59 patients (45 with NAXE deficiency, 14 with NAXD deficiency) showed an overall mortality rate of 66.7%; among the 21 patients treated with nicotinamide, 17 (80.95%) survived, significantly higher than the untreated group (only 2 survived)
• Among untreated patients, 85.45% died within 2 years of disease onset, primarily due to respiratory failure
• Skin lesion incidence was significantly higher in NAXD-deficient patients than in NAXE-deficient patients (57.1% vs 17.8%), and mortality was also higher (85.7% vs 60.5%)
• Nicotinamide treatment was an independent protective factor for survival (HR=33.43, P<0.001); early intervention prevented disease progression and maintained stability even under stress such as fever
• Fibroblast experiments showed that NAXD deficiency significantly increased the NADH/NAD+ ratio, particularly under heat stress (42°C), supporting the theoretical basis for nicotinamide supplementation

Significance and Future Directions

This study is the first to systematically evaluate the long-term efficacy of nicotinamide in NAD(P)HX metabolic repair deficiency, confirming its feasibility and safety as a first-line treatment. It underscores the importance of early genetic diagnosis, especially in cases of unexplained encephalopathy with fever-induced acute deterioration, where this condition should be considered and nicotinamide treatment initiated promptly. Due to the disease's clinical heterogeneity and frequent misdiagnosis as encephalitis or metabolic encephalopathy, promoting whole-exome sequencing and establishing newborn screening programs are of significant public health importance.

Future research should further explore the optimal dosage, therapeutic window, and long-term neurodevelopmental outcomes of nicotinamide. Additionally, the pathogenic differences between NAXD and NAXE deficiencies require deeper investigation, particularly the roles of cytoplasmic and mitochondrial NAXD in skin lesions. Whether other NAD+ precursors such as nicotinamide riboside or mononucleotides offer superior efficacy warrants validation in larger cohorts. This study provides high-quality evidence for developing international treatment guidelines, advancing precision intervention strategies for treatable rare diseases.

 

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Conclusion

NAD(P)HX metabolic repair system deficiency is a group of rare but treatable mitochondrial disorders primarily affecting infants and young children, presenting with fever-induced acute encephalopathy, ataxia, epilepsy, and rapidly progressive neurological deterioration. Without timely treatment, most patients die of respiratory failure within 2 years of onset, with an overall mortality rate as high as 66.7%. Through analysis of data from 59 patients, this study definitively confirms that nicotinamide treatment can significantly increase survival to 80.95%, with good tolerability, making it a key intervention for improving prognosis. Patients with NAXD deficiency more frequently present with skin lesions and have poorer outcomes, suggesting a more complex pathophysiology. The study emphasizes that early recognition and prompt initiation of nicotinamide treatment are crucial, especially during acute episodes or fever-induced stress, effectively preventing disease progression. Given the non-specific clinical presentation and high risk of misdiagnosis, clinical vigilance should be heightened, and early genetic testing should be performed. In the future, efforts should be made to include this disorder in newborn screening programs to enable early diagnosis and treatment, fundamentally improving patient quality of life and long-term outcomes.

 

Chaolong Xu, Hong Jin, Jiuwei Li, Huafang Jiang, and Fang Fang. Deficiency of the NAD(P)HX metabolic repair system: a treatable mitochondrial disease. Orphanet Journal of Rare Diseases.