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Beijing Da Xue Xue Bao Yi Xue Ban. 2017 Oct 18;49(5):768-777.

[Pulmonary arterial hypertension as leading manifestation of methylmalonic aciduria: clinical characteristics and gene testing in 15 cases].

[Article in Chinese]

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Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Department of Radiology, Peking University First Hospital, Beijing 100034, China.



To deepen our understanding of Methylmalonic aciduria (MMA) associated pulmonary hypertension (PH) by analyzing the characteristics of clinical presentation, pulmonary high resolusion CT(HRCT), treatment response and gene mutation.


This study includes 15 cases of pediatric patients with MMA associated PH diagnosed and treated in Peking University First Hospital pediatric department between May 2012 and May 2016 with symptoms of PH as their leading presentation. Clinical symptoms and signs were recorded, Routine blood laboratory examinations was done including arterial blood gas analysis. Plasma total homocysteine (Hcy) and brain natriuretic peptide(BNP) level were measured. MMA gene mutation was analyzed. Chest HRCT was done in most of the patients. Standard treatment strategy to MMA and PH was given and follow up study was done, and the related literature was reviewed. Statistical analysis was done. The diagnosis of MMA was made by methylmalonic acid level >100 times the normal value in the urine. The diagnosis of PH was made by pulmonary arterial systolic pressure (PASP)>40 mmHg, which was estimated by the measurement of tricuspid regurgitation velocity through Doppler Echocardiography.


(1) Patient characteristics: There were 10 male and 5 female patients diagnosed as MMA associated PH, aged 0.5 to 13.8 years, with an average of (5.0±4.3) years. The age of onset of PH was (3.7±3.5) years, with an early onset type MMA in 5 cases and late-onset type in 10 cases. (2) Clinical presentation: Among the 15 cases of MMA, the first symptoms were associated with PH in 10 cases, so PH and MMA were diagnosed at the same time, and PH was diagnosed 3 to 72 months post MMA presentation in the other 5 cases. The main presentations of PH were techypnea/dyspnea and cyanosis in 11 cases each, weakness and fatigue on exertion in 6 cases, and edema in 4 cases. PH WHO functional classification (WHO FC) was Class II in 4 , Class III in 5 and Class VI in 6 cases, with an average of Class 3.1±0.8. Multi-system involvements were common with the highest frequency in the kidney (14 cases). Macrocytic anemia was present in 8 cases and sub-clinical hypothyroidism in 5 cases, and mild to moderate mental retardation in 4 cases. (3) Laboratory examination: PASP of the 15 patients was from 49 to 135 mmHg, with an average of (90.3±23.9) mmHg. Total blood Hcy level was severely elevated to (121.2±48.2) μmol/L (range: 35.0-221.0 μmol/L), and Hcy >100 μmol/L within 11 cases. Plasma BNP level was also elevated, median 794 ng/L (range: 21.0-4 995.0 ng/L) with 12 cases >300 ng/L. Blood gas analysis showed low arterial blood oxygen saturation between 70% and 94%, with an average of 81.4%±8.4%. (4) Chest HRCT: chest HRCT showed a diffuse ground-glass centrilobular nodular opacities with septal line thickening in the lungs in 9 cases, and with associated mediastinal lymph node enlargement in 1 case, which indicated pulmonary veno-occlusive disease (PVOD), a rare type of pulmonary arterial hypertension (PAH). There was lung infection or edema in 3 cases, and interstitial infiltration and mesh-like feature in other 3 cases, which was inferred to interstitial lung disease. (5) Gene mutation: Genetic testing was done in 10 cases, totally 5 reported disease-causing mutations were found. There were 100% presence of MMACHC c.80A>G mutation in all the 10 patients tested, with the allelic genes of c.609G>A mutation in 6 patients, including a sister and a brother from the same parents. (6) Treatment and follow up: Intramuscular hydroxocobalamin or vitamin B12 was given to all of the patients, together with betaine, levocarnidtine, folinic acid and vitamin B6. According to the severity of PH, single or combined PAH targeted drugs was given to 11 cases. By an average of (20.0±13.5) days of in-hospital treatment in 13 patients (excepting 1 case treated as outpatient), symptoms remarkably resolved, WHO FC reduced to an average of Class 2.4±0.9, PASP dropped to (69.4±21.3) mmHg, and plasma Hcy and BNP level were decreased to (74.9±25.9) μmol/L and (341.6±180.2) ng/L, respectively. The above values all reached statistical significance (P<0.05) compared with each related value before treatment. There were 2 patients who expired during hospitalization despite of treatment. At the end of 3 months' follow up, all of the 13 patients disposed oxygen, and PASP significantly dropped to 38.7±7.9 mmHg, and plasma BNP returned to normal, but plasma Hcy level showed no further decline. At the last follow up of 27.5±19.0 (range: 11-64) months, all the patients' PASP remained normal except for the 13.8-year-old boy with 6 years-long history of MMA and almost 3.6 years' history of PH still having PASP 58 mmHg.


PH is a severe complication of MMA combined type, especially cblC type, it is more often happens in late-onset type of male patients and can be the first and leading manifestations of MMA. Its clinical symptoms are urgent and severe, characterized by tachypnea/dyspnea and cyanosis, and sometimes right heart failure, hypoxemia is usually present, chest HRCT is often indicative of PVOD, lung edema and interstitial lung disease may occur. Rapid diagnosis and targeted treatment of MMA with appropriate anti-PAH medication can reverse PH and save life. MMACHC gene c.80A>G mutation may be the hot point of MMA cblC type associated PH.

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