Riboflavin therapy in complex I deficiency: Two new cases of leukoencephalopathy and a systematic literature review.

OBJECTIVE

Complex I (CI) deficiency, the most common biochemical defect in pediatric mitochondrial diseases, presents with diverse phenotypes, including cardiomyopathy, myopathy, Leigh syndrome, and mitochondrial leukoencephalopathy (ML). No curative therapies exist. Riboflavin, a precursor of CI cofactors FMN and FAD, is a potential treatment, but evidence is heterogeneous and formal guidelines are lacking.

METHODS

We retrospectively analyzed two patients with genetically confirmed CI deficiency due to NDUFS1 and NDUFV2 variants, treated with high-dose riboflavin with long-term clinical, biochemical, neurophysiological and MRI follow-up (>16 years). A systematic literature review of riboflavin-responsive CI deficiency was also performed.

RESULTS

Both patients presented with early acute psychomotor regression and extensive cavitating white matter lesions. Riboflavin (up to 10 mg/kg/day) was associated with rapid, near-complete neurological recovery, normalization of lactate and evoked potentials, and MRI improvement, stable in time. Our review identified 43 additional riboflavin-responsive CI cases, including cardiomyopathy (n = 16, largely due to ACAD9 variants), myopathy (n = 12, all ACAD9 variants), ML (n = 8, predominantly NDUFV1/NDUFV2 variants), Leigh syndrome (n = 5), MELAS-like presentations (n = 1), and optic atrophy (n = 1).

INTERPRETATION: Riboflavin may provide durable benefit across several CI-deficiency phenotypes. Beyond established efficacy in ACAD9-related cardiomyopathy, available evidence supports consideration of therapeutic trials in other phenotypes. Our two cases, supported by long-term follow-up and consistent instrumental data, provide further evidence supporting a potential benefit of riboflavin in ML, complementing eight earlier reports limited by short follow-up and sparse imaging. Variants affecting N-module subunits (NDUFV1, NDUFV2, NDUFS1), depending directly on FMN/FAD, may represent particularly suitable candidates for treatment. Prospective studies are warranted.