Reversible Pulmonary Hypertension in CblC Deficiency (MMACHC c.80 A>G): long-term outcomes of metabolic and PH-targeted therapy

BACKGROUND: Cobalamin C (cblC) deficiency, caused by MMACHC mutations, is a rare metabolic disorder with multisystem involvement. Pulmonary hypertension (PH) is an underrecognized but potentially life-threatening complication. This study aimed to characterize the clinical features and treatment outcomes of PH in children with cblC deficiency, particularly those carrying the MMACHC c.80 A > G variant. METHODS: We retrospectively analyzed 17 pediatric patients with genetically confirmed cblC deficiency who presented with PH as the initial manifestation. Clinical, biochemical, imaging, genetic, and therapeutic data were reviewed. RESULTS: All patients had PH at diagnosis, with 64.7% (11/17) exhibiting moderate-to-severe pulmonary artery systolic pressure (PASP) elevation. Macrocytic anemia and renal dysfunction were common. HRCT revealed centrilobular ground-glass nodules, interlobular septal thickening, and pulmonary hemorrhage. B-type natriuretic peptide (BNP) levels were significantly higher in the moderate-severe group. All patients received metabolic therapy, and 11 received PH-targeted drugs. Glucocorticoids led to rapid clinical improvement in two patients presenting with pulmonary hemorrhage or hypoxemia. PASP normalized in all cases within 18 months. No recurrence occurred during follow-up. CONCLUSION: PH is a serious but reversible complication of cblC deficiency. Early diagnosis and combined metabolic and PH-targeted therapy can reverse vascular remodeling. Screening for cblC should be considered in children with unexplained PH and macrocytic anemia or renal involvement. IMPACT: This study presents the largest cohort to date of pediatric patients with cblC deficiency presenting with pulmonary hypertension (PH) as the initial manifestation. It identifies a potential genotype-phenotype association between the MMACHC c.80 A > G variant and reversible pulmonary vascular disease. The findings highlight the importance of early metabolic and PH-targeted therapy, and support screening for cblC deficiency in children with unexplained PH and macrocytic anemia or renal involvement.