CASE OF NAXD DEFICIENCY PRESENTING WITH DEVELOPMENTAL REGRESSION AND PROGRESSIVE ENCEPHALOPATHY

Introduction: Developmental regression in children can indicate underlying neurodegenerative or metabolic diseases, often posing diagnostic and therapeutic challenges. Defects in NAD(P)HX dehydratase (NAXD), an enzyme crucial for maintaining cellular NAD(P)H levels, are implicated in progressive encephalopathy. This case report highlights NAXD deficiency as a rare but critical cause of developmental regression, with a focus on genetic findings and clinical presentation.

Case Presentation: A 9-month-old infant with a history of normal development until 7 months of age presented with rapid developmental regression, including loss of motor skills, social engagement, and speech. Clinical examination revealed hypotonia, hypertonia, exaggerated reflexes, hepatomegaly, and pancytopenia. Genetic testing identified a homozygous mutation in the NAXD gene, confirming the diagnosis. MRI showed brain atrophy and restricted diffusion in the basal ganglia, while MRS indicated metabolic abnormalities. Despite supportive therapy, the child developed seizures, respiratory failure, and multiorgan dysfunction, eventually leading to death.

Discussion: NAXD deficiency leads to toxic accumulation of NAD(P)HX metabolites, impairing mitochondrial function and causing progressive neurological decline. Our case presents atypical features, including the absence of fever-triggered neurological deterioration, which suggests subtle or unnoticed febrile episodes may contribute to symptom exacerbation. The use of whole-exome sequencing (WES) was crucial for diagnosis, aligning with other reports linking NAXD mutations to early-onset encephalopathy and seizures.

Conclusion and Future Directions: This case underscores the importance of early genetic testing in diagnosing rare metabolic disorders like NAXD deficiency. Future research should focus on therapeutic strategies to restore NAD(P)HX balance, including mitochondrial-targeted therapies, and the identification of biomarkers for disease progression. Further studies are needed to optimize clinical management and improve outcomes in affected individuals.