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Pulmonary hypertension with diffuse lung lesions in cobalamin C defect

Cobalamin C (cblC) defect is the most common inherited disorder associated with vitamin B12 metabolism, resulting in an impaired synthesis of the cofactors adenosylcobalamin and methylcobalamin for methylmalonyl-coenzyme A mutase and methionine synthase, respectively. The impaired activity of these enzymes results in increased methylmalonic acid (MMA) and homocysteine levels. The clinical symptoms of cblC defect manifest as multisystem conditions, such as hematologic, renal and cardiovascular diseases. Few reports have described the relationship between pulmonary hypertension (PH) and diffuse lung lesions associated with cblC defect. In cases of hypoxia with diffuse lung lesions, respiratory disease is commonly suspected, but PH due to thrombotic microangiopathy (TMA) should be considered as a differential diagnosis. The present study reports the case of a girl with hypotonia and feeding disorder since 1 year of age, resulting in failure to thrive (bodyweight, 7.7 kg; 4.1 SD). She was referred to the present hospital at 2 years of age for further investigation. Screening tests for metabolic disorders indicated methylmalonic acidemia with normal vitamin B12 and increased blood propionylcarnitine and urinary MMA. On receiving oral adenosylcobalamin (21 mg/day), urinary MMA decreased. Three months after referral to the present hospital, she was admitted for tachypnea and severe cyanosis (room air SpO2 at 70%). Laboratory tests indicated increased serum lactate dehydrogenase (619 IU/L), total bilirubin (1.3 mg/dL) and D-dimer (2.0 ng/ mL) with schistocytes. Urine analysis showed hematuria and proteinuria. Mild–moderate PH was suspected based on tricuspid regurgitation (calculated 41 mm Hg pressure drop) on echocardiography. Computed tomography (CT) showed diffuse ground-glass opacification and interlobular septal thickening with no pulmonary thrombotic materials (Fig. 1a). Lung perfusion scintigraphy using technetium-99m macroaggregated albumin (MAA) showed multiple small defects in the peripheral lung field (Fig. 1b,c). Sildenafil was given for PH due to pulmonary vascular resistance of 13.8 Wood units m on cardiac catheterization. We initially suspected interstitial pneumonia with PH and treated the patient with steroid pulse therapy, but the cyanosis and tachypnea did not improve. Subsequently, a detailed assessment for metabolic disease was performed. Plasma total homocysteine was increased to 137 lmol/L (normal, <15 lmol/L), whereas methionine was decreased to 3.8 lmol/L (normal, 18.9–40.5 lmol/L). Therefore, the patient was diagnosed with methylmalonic acidemia with homocystinuria, with subsequent confirmation of a cblC defect in Methylmalonic aciduria and homocystinuria type C protein (MMACHC), detected as a c.80A>G, p.Q27R mutation in exon 1 and a c.440G>A, p.G147D mutation in exon 4. For the cblC defect, the patient was treated with oral trimethylglycine (390 mg/kg/day), which remethylates homocysteine to methionine, in addition to i.m. hydroxocobalamin (1 mg/day), which was substituted for oral adenosylcobalamin. After 1 month, plasma total homocysteine had decreased to 28.6 lmol/L. The hypoxemia and PH gradually improved, and sildenafil was discontinued. At the time of writing, the patient was 8 years old and neither PH nor clinical manifestations associated with cblC defect had recurred. The pathogenesis of PH associated with cblC defect is poorly understood, and the primary cause of PH is certainly associated with pulmonary microangiopathy resulting from homocystinuria and methylmalonic acidemia. The deleterious reaction of homocysteine to pulmonary vasculature is involved in promoting vasoconstriction and endothelial dysfunction and enhancing platelet aggregation. Although homocysteine appears to be associated with pulmonary vascular dysfunction, hyperhomocysteinemia such as cystathionine synthase deficiency has not been reported to cause PH, apart from thromboembolism. Besides hyperhomocysteinemia, other abnormalities appear to be associated with PH in patients with cblC defect. The histopathology of renal diseases in patients with cblC defect has indicated glomerular TMA lesions. Metabolite toxicity, such as methylmalonic acidemia and hyperhomocysteinemia, appears to develop into TMA. Pulmonary TMA may induce microthrombus formation, vasoconstriction, and vascular smooth muscle cell proliferation in the pulmonary vascular bed, thereby progressing to PH and diffuse lung lesions. Given that lung biopsy was not performed in the present case, we could not histopathologically diagnose TMA. Instead, laboratory data and Correspondence: Keiji Nogami, MD PhD, Department of Pediatrics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. Email: roc-noga@naramed-u.ac.jp Received 5 February 2019; revised 8 June 2019; accepted 2 July 2019. doi: 10.1111/ped.13971