Diffuse alveolar hemorrhage in a boy with combined methylmalonic acidemia and homocysteinemia

To the Editor, Type cblC caused by the MMACHC gene is the most common subtype of combined methylmalonic academia (MMA) and homocystienemia (HC). Patients with MMACHC mutations develop various clinical manifestations. Here we describe one case with combined MMA and HC who presented diffuse alveolar hemorrhage and mild pulmonary artery hypertension (PAH). The patient was improved with therapy directed at MMA and PAH. A 6‐year‐old Chinese boy developed vomiting after eating left‐ over food. One day after the onset of vomiting, he developed diffuse weakness and presented to the emergency department. He was previously diagnosed at 1 month of age with combined MMA and HC because of developmental delay. Treatment with mecobalamine, levocarnitine, and folic acid was commenced at that time. He had no history of neurology, pulmonology, nephrology, and cardiology involvements. He was previously diagnosed with mild respiratory infections and had a normal chest X‐ray at 4 years of age. He was followed‐up in a local hospital every 6 months and was doing well with normal development. His parents and 12‐year‐old sister were healthy. On physical examination, he looked pale and was weak. His oxygen saturation was 98% on room air. No crackles or wheezing or cardiac murmurs were auscultated. Laboratory investigations showed a white blood cell count of 17.707/mL with 85% neutrophils, hemoglobin (Hb) 106 g/L, platelet 305 × 10/L, C‐reactive protein concentration 16mg/L, blood ammonia 43 μmol/L and an elevated serum homocysteine (Hcy) 155.06 μmol/L. The urinalysis showed 2+ protein and 25 to 30 red blood cells per high power field. Arterial blood gas analysis revealed PaO2 57 and PaCO2 35mmHg. Methylmalonic acid concentrations on admission were 1275 times the reference value. Sputum culture grew normal flora. A chest radiograph revealed mild interstitial infiltrates in the right middle lobe and both lower lobes (Figure 1A). His chest high‐resolution computed tomography (HRCT) showed a small pleural effusion, subpleural reticular shadows, and bilateral ground‐glass opacities mainly in the lower lobes (Figure 1B). Echocardiography and magnetic resonance imaging of the brain were normal. One week after admission he developed exercise intolerance. On re‐evaluation, his Hb concentration had decreased to 68 g/L. His echocardiogram now demonstrated mild PAH with a pulmonary artery pressure of 40mmHg (normal <35mmHg PAH). Also, diffuse alveolar hemorrhage was suspected with the new onset of diffuse lung infiltrates on chest radiograph and decreased Hb. The bronchoalveolar lavage fluid was tawny in color and microscopic examination revealed numerous hemosiderin‐laden macrophages; thus confirming alveolar hemorrhage. Autoimmune antibodies panel and ANCA were negative. The sequence analysis identified homozygous mutations in the MMACHC with c. 440_441del (p.C149His*32) mutation inherited from his father and c.A80G (p.Q27R) mutation from his mother. This patient's underlying metabolic disorder was treated with hydroxycobalamin, betaine, levocarnitine, folate, and vitamin B6. Bosentan was used as a single therapy targeting the PAH. His Hb gradually increased and HRCT on day 14 (Figure 1C) showed significant improvement. His elevated serum Hcy concentration persisted during the admission. His clinical condition gradually improved during this admission. Two months later, he was asymptomatic with normal Hb, echocardiography, and lung X‐ray but still had elevated serum Hcy. Combined MMA and HC have early‐onset and late‐onset phenotypes. Pulmonary involvement is rarely seen but a few cases with