Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review

Wang, Chao; Liu, Dong; Cai, Fengying; Zhang, Xinjie; Xu, Xiaowei; Liu, Xiaojun; Zhang, Chunhua; Wang, Dan; Lin, Sheng‐Xiang; Zhang, Yuqin; Shu, Jianbo

doi:10.1016/j.ejmg.2019.103713

Cited by 35 publications

(46 citation statements)

References 21 publications

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“…A total of 62 (14 variants) pathogenic variants were detected in 32 children with cblC, as shown in our previously published data (Wang, Li, et al, 2019) (Table 2). Among them, mutations c.609G > A (p.Trp203Ter), c.658_660delAAG (p.Lys220del), c.482G > A (p.Arg161Gln), and c.80A > G (p.Gln27Arg) were the most common in this study.…”

Section: Resultssupporting

confidence: 73%

“… a From our previously published data (Wang, Li, et al, 2019), this is the result of 64 alleles from 32 patients with cblC. …”

Section: Resultsmentioning

confidence: 96%

“…Those less than 1 year are early onset type, and those older than 4 years are late onset type (Rosenblatt et al, 1997). As one of the few treatable genetic diseases, cblC can achieve obvious therapeutic effect by early supplementation of vitamin B 12 and L‐carnitine, and some clinical phenotypes can be reversed (Wang, Li, et al, 2019; Wang, Zhao, et al, 2019). Therefore, the establishment of a rapid screening method for the pathogenic variants of MMACHC gene has important clinical significance, especially for patients with late onset cblC, which are difficult to detect because of the absence of typical clinical symptoms.…”

Section: Discussionmentioning

confidence: 99%

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Rapid screening of MMACHC gene mutations by high‐resolution melting curve analysis

Wang

Liu

Cai

et al. 2020

Molec Gen & Gen Med

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Background Cobalamin (cbl) C is a treatable rare hereditary disorder of cbl metabolism with autosomal recessive inheritance. It is the most common organic acidemia, manifested as methylmalonic academia combined with homocysteinemia. Early screening and diagnosis are important. The mutation spectrum of the MMACHC gene causing cblC varies among populations. The mutation spectrum in Chinese population is notably different from that in other populations. Methods A PCR followed by high‐resolution melting curve analysis (PCR‐HRM) method covering all coding exons of MMACHC gene was designed to verify 14 pathogenic MMACHC gene variants found in patients with cblC, including all common mutations in Chinese patients with cblC. Result By PCR‐HRM analysis, 14 pathogenic variants of MMACHC showed distinctly different melting curves, which were consistent with Sanger sequencing. The homozygous type of the most common mutation c.609G > A (p.Trp203Ter) can also be analyzed by specially designed PCR‐HRM. Conclusion The established PCR‐HRM method for screening common pathogenic MMACHC variants in Chinese patients with cblC has the advantages of high accuracy, high throughput, low cost, and high speed. It is suitable for the large‐sample screening of suspected children with methylmalonic acidemia and carriers in population.

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Section: Resultssupporting

confidence: 73%

“… a From our previously published data (Wang, Li, et al, 2019), this is the result of 64 alleles from 32 patients with cblC. …”

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Rapid screening of MMACHC gene mutations by high‐resolution melting curve analysis

Wang

Liu

Cai

et al. 2020

Molec Gen & Gen Med

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“…Chinese patients [10,11]. 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.…”

Section: Discussionmentioning

confidence: 84%

“…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: 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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Outcomes of patients with cobalamin C deficiency: A single center experience

et al. 2020

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Biallelic variants in MMACHC results in the combined methylmalonic aciduria and homocystinuria, called cobalamin (cbl) C (cblC) deficiency. We report 26 patients with cblC deficiency with their phenotypes, genotypes, biochemical parameters, and treatment outcomes, who were diagnosed and treated at our center. We divided all cblC patients into two groups: group 1: SX group: identified after manifestations of symptoms (n = 11) and group 2: NB group: identified during the asymptomatic period via newborn screening (NBS) or positive family history of cblC deficiency (n = 15). All patients in the SX group had global developmental delay and/or cognitive dysfunction at the time of the diagnosis and at the last assessment. Seizure, stroke, retinopathy, anemia, cerebral atrophy, and thin corpus callosum in brain magnetic resonance imaging (MRI) were common in patients in the SX group. Global developmental delay and cognitive dysfunction was present in nine patients in the NB group at the last assessment. Retinopathy, anemia, and cerebral atrophy and thin corpus callosum in brain MRI were less frequent. We report favorable outcomes in patients identified in the neonatal period and treated pre‐symptomatically. Identification of cblC deficiency by NBS is crucial to improve neurodevelopmental outcomes.

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Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review

Cited by 35 publications

References 21 publications

Rapid screening of MMACHC gene mutations by high‐resolution melting curve analysis

Rapid screening of MMACHC gene mutations by high‐resolution melting curve analysis

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

Outcomes of patients with cobalamin C deficiency: A single center experience

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