Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients

Liu, Jinrong; Peng, Yun; Zhou, Nan; Liu, Xiaorong; Meng, Qun; Xu, Hui; Zhao, Shunying

doi:10.1186/s13023-017-0610-8

Cited by 33 publications

(23 citation statements)

References 19 publications

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“…MMA type CblC has been previously reported to be associated PAH, while ILD was rarely reported previously. Our colleagues first reported four MMA patients who were associated with ILD previously [27] and two of them were included in this cohort. A characteristic HRCT pattern of diffuse poorly defined centrilobular nodules coexisting with PAH were found in five out of the seven patients, which may be suggestive for the diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Tang

Liu

et al. 2020

Orphanet J Rare Dis

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Background: Childhood interstitial lung diseases (ILD) (chILD) refer to a rare heterogeneous group of disorders. Global collaborations have been working on the etiologies and classification scheme of chILD. With the development of medical technologies, some new diseases were identified to be associated with chILD and its etiologic spectrum is expanding. The aim of this study is to describe the etiologic spectrum of chILD in children older than 2 years of age and summarize the approaches to diagnosis of chILD. Methods: We made a retrospective analysis of children older than 2 years of age with chILD who referred to Beijing Children's Hospital from 21 provinces all over China from 2013 to 2018. After excluding pulmonary infection, congenital heart disease, bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiectasis, 133 patients were included and categorized by etiology. Clinical manifestations, high-resolution computed tomography, laboratory data, genetic data and pathologic findings were all collected and reviewed. Results: Systemic disease associated ILD were the most common causes, accounting for 49.6% of the patients, followed by alveolar structure disorder-associated ILD (27%), exposure related ILD (13.5%), and disorders masquerading as ILD (3.8%). In systemic disease associated ILD, in addition to common etiologies such as vasculitis (10.5%) and connective tissue diseases (9.0%), primary immunodeficiency diseases (PID) associated ILD (9.8%), interstitial pneumonia with autoimmune features (6.8%), and metabolic diseases (6.8%) were not rarely found. Some newly reported etiologies such as STING-associated vasculopathy with onset in infancy, COPA syndrome and STAT3 mutation were included in PID associated ILD. Genetic tests contributed to 15% of the diagnoses which mainly distributed in PID associated ILD, metabolic diseases and surfactant dysfunction disorders, and contributed to the final diagnoses more than lung biopsies (13.5%) and biopsies of rashes or other tissues (12%). Conclusions: This study first demonstrated an etiologic spectrum of chILD in Chinese children older than 2 years of age and summarized the approaches to diagnosis. The etiologic spectrum of chILD is expanding with more genetic etiologies being recognized.

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Section: Discussionmentioning

confidence: 99%

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Tang

Liu

et al. 2020

Orphanet J Rare Dis

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“…The majority of MMA onset from different neurological damage, [ 15 – 17 ] but some of them may first onset with unusual presentations, such as mimicking diabetic ketoacidosis, [ 18 ] late-onset diffuse lung disease, [ 19 ] and Juvenile gout. [ 20 ] For this girl, although the brain CT and MRI scan were suggesting the existence of brain atrophy, there were no clinical manifestations such as vomiting, lethargy, convulsions, movement disorders, and mental retardation.…”

Section: Discussionmentioning

confidence: 99%

Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia

et al. 2017

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Rationale:Methylmalonic acidemia (MMA) is a common organic acidemia, mainly due to methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (VitB12) metabolic disorders. Cobalamin C (CblC) type is the most frequent inborn error of cobalamin metabolism; it can develop symptoms in childhood and often combine multisystem damage, which leads to methylmalonic acid, propionic acid, methyl citrate, and other metabolites abnormal accumulation, causing nerve, liver, kidney, bone marrow, and other organ damage.Patient concerns:A 4-year-old girl presented with paleness, fatigue, severe normochromic anemia, and acute kidney injury.Diagnosis:Based on severe normochromic anemia and acute kidney injury, renal biopsy showed membranous proliferative glomerular lesions and thrombotic microvascular disease, supporting the diagnosis of aHUS. Although the serum vitamin B12 was normal, further investigation found the concentration of urinary methylmalonic acid and serum homocysteine increased obviously, genetic analysis revealed a heterozygous MMACHC mutation (exonl: c. 80A >G, c. 609G >A). The final diagnosis was aHUS induced by inherited methylmalonic acidemia (MMACHC heterozygous mutation exonl: c. 80A >G, c. 609G >A).Interventions:The patient was treated with a 1mg vitamin B12 intramuscular injection daily for 4 days after which the dose was then adjusted to a 1mg intramuscular injection twice a week. At the same time, the girl was given levocarnitine, betaine, folic acid, along with supportive treatment.Outcomes:After treated by vitamin B12 for 10 days, the patient condition significantly improved, Follow-up results showed complete recovery of hemoglobin and renal function.Lessons:Although the majority of MMA onset from neurological damage, our case illustrates that partial CblC-type MMA can onset with severe metabolic aHUS. On the basis of chronic thrombotic microangiopathy (TMA)-induced renal damage, it can be complicated by acute hemolytic lesions. MMA should be considered in those patients with unclear microangiopathic hemolytic anemia accompany significant megaloblastic degeneration in bone marrow. We should pay attention to the causes and adopt a reasonable treatment strategy.

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“…The allele frequency of the c.80A>G variant is 9.09% in the Chinese population with CblC deficiency [12]. Our previous published study, 3 CblC deficiency patients with DLD also had c.80A>G mutation [8], which suggested DLD might be highly associated with c.80A>G mutation. The c.609G>A mutation is a hot spot mutation (43.64%) in Chinese patients with CblC deficiency [10][11][12], which often lead to early-onset cblC disease [12].…”

Section: Discussionmentioning

confidence: 80%

“…Both microangiopathy and thromboembolism can be the underlying mechanisms for PAH in cobalamin deficiency (combined MMA and homocysteinemia) [3][4][5][6][7]. Only a few patients had diffuse lung disease (DLD) in cobalamin C deficiency (CblC deficiency) [8].…”

Section: Introductionmentioning

confidence: 99%

Cobalamin C deficiency presenting with diffuse alveolar hemorrhage and pulmonary microangiopathy: a case series of four patients

Liu

Tang

Zhou

et al. 2019

Preprint

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Background: The clinical manifestations of combined methylmalonic acidemia (MMA) and homocysteinemia (cobalamin deficiency) vary, but typically include neurologic, developmental and hematologic abnormalities. Only a few patients had diffuse lung disease (DLD). We analyse the clinical features of cobalamin C deficiency (CblC deficiency) who developed late-onset DLD mainly diffuse alveolar hemorrhage (DAH) to strengthen an understanding of it.Results: This study describes 4 patients aged 4-years-2-months to 7-years-6-months with CblC deficiency who developed late-onset DLD. Of these, the first 3 patients presented predominantly with DAH, and the last patient with pulmonary microangiopathy confirmed by lung biopsy. All patients accompanied by pulmonary arterial hypertension (PAH), and 2 accompanied by moderate megaloblastic anemia. Diffuse ground-glass opacification and poorly defined ground-glass centrilobular nodules were seen on high-resolution computed tomography (HRCT) in 1 patient and 3 patients respectively. All patients were suspected of having idiopathic pulmonary hemosiderosis (IPH) or interstitial lung disease (ILD) at other hospitals. The last 2 patients received treatment with high dose corticosteroid before admission, but the symptoms didn’t improve. Moreover, all patients carried compound heterozygous mutations (c.80A>G, c.609G>A) and improved significantly after being treated for CblC deficiency and PAH.Conclusions: CblC deficiency should be considered in the differential diagnosis of DAH especially with PAH, and pulmonary microangiopathy be the main reason of DLD in these patients.

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Combined methylmalonic acidemia and homocysteinemia presenting predominantly with late-onset diffuse lung disease: a case series of four patients

Cited by 33 publications

References 19 publications

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age

Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia

Cobalamin C deficiency presenting with diffuse alveolar hemorrhage and pulmonary microangiopathy: a case series of four patients

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