Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia

Vatanavicharn, Nithiwat; Champattanachai, Voraratt; Liammongkolkul, Somporn; Sawangareetrakul, Phannee; Keeratichamroen, Siriporn; Cairns, James R. Ketudat; Srisomsap, Chantragan; Sathienkijkanchai, Achara; Shotelersuk, Vorasuk; Kamolsilp, Mahattana; Wattanasirichaigoon, Duangrurdee; Svasti, Jisnuson; Wasant, Pornswan

doi:10.1016/j.ymgme.2012.05.012

Cited by 27 publications

(28 citation statements)

References 31 publications

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“…2 A review of 14 Thai patients with isolated MMA identified eight patients with RTA and four patients with CKD, indicating that renal involvement was a common complication in MMA. 4 Hence, the decreased excretion of uric acid can result from decreased glomerular filtration due to CKD. Moreover, hyperuricemia may cause interstitial fibrosis and CKD, consequently, could worsen uric acid excretion.…”

Section: Discussionmentioning

confidence: 99%

“…His detailed clinical findings with regard to MMA and genotype have been previously reported. 3,4 His past medical history was complicated by chronic kidney disease (CKD), distal RTA (dRTA), basal ganglia infarction, asthma, and mild mental retardation. He presented with fever, right big toe pain and could not bear weight on his right foot for 3 days.…”

Section: Casementioning

confidence: 99%

“…4 The complications of MMA included CKD and RTA. The patient had intermittent pain and swelling over both big toes approximately twice a month for 1 year.…”

Section: Casementioning

confidence: 99%

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Juvenile gout in methylmalonic acidemia

Charuvanij

Pattaragarn

Wisuthsarewong

et al. 2016

Pediatrics International

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Methylmalonic acidemia (MMA) is an inborn error of metabolism caused by either deficiency of the enzyme methylmalonyl-CoA mutase or a defect in adenosyl-cobalamin synthesis. Chronic kidney disease is its common complication and, in combination with persistent acidosis, leads to hyperuricemia. Symptomatic hyperuricemia or gout, however, has not been reported in MMA. We herein report two pediatric cases of MMA caused by MMAB mutations (cblB defect) with renal tubular acidosis, chronic kidney disease, hyperuricemia, and gout. The clinical findings of gout in these cases included recurrent first metatarsophalangeal arthritis and/or tophi. The patients responded to treatment with colchicine and allopurinol.

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Section: Discussionmentioning

confidence: 99%

Section: Casementioning

confidence: 99%

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Juvenile gout in methylmalonic acidemia

Charuvanij

Pattaragarn

Wisuthsarewong

et al. 2016

Pediatrics International

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“…However, our research subjects were children diagnosed as MMA with homocystinuria. Because the pathogenic mechanisms between isolated methylmalonic academia and methylmalonic academia with homocystinuria are different [4,9], the alarming symptoms may have different predictable values.…”

Section: Discussionmentioning

confidence: 99%

“…Hörster, et al [15] reported that high concentrations of MMA in urine are a known risk factor for the development of chronic kidney disease. Moreover, homocysteine can induce myocardial injury by promotion of endothelial dysfunction, formation of thromboxane A2, enhancement of platelet aggregation, reduction in the protective effect of nitric oxide, and the procoagulant effects [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The disturbance of the tricarboxylic acid cycle and respiratory chain may also be involved in the pathogenesis [18].…”

Section: Discussionmentioning

confidence: 99%

Predictors of survival in children with methymalonic acidemia with homocystinuria in Beijing, China: A prospective cohort study

Song

Wang

et al. 2015

Indian Pediatr

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Objective: (i) To determine whether clinical features and biochemical parameters help to predict survival of methylmalonic acidemia with homocystinuria; (ii) To find the cutoff values of biochemical parameters for predicting survival of methylmalonic acidemia with homocystinuria.Design: A prospective cohort study. Setting:A pediatric tertiary hospital in Beijing; all patients were followed until death or June 2013. Outcome measures: The data of clinical characteristics and pretreatment biochemical parameters were collected. The Cox regression analysis was performed to identify independent risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The best cutoff values for these independent factors were determined by the receiver characteristic curve.Results: Newborn onset (OR=6.856, 95%CI=2.241-20.976, P=0.001), high level of methylmalonic acid in urine (OR=1.022, 95%CI=1.011-1.033, P<0.001), and high level of urea in serum (OR=1.083, 95%CI=1.027-1.141, P=0.003) were independent negative risk factors for survival of patients with methylmalonic acidemia and homocystinuria. The cutoff values of maximum predictive accuracy of methylmalonic acid in urine and urea in serum were respectively 5.41 mmol/mmol creatinine and 7.80 mmol/L by receiver operating characteristic curve analysis. Conclusion:The patients of methylmalonic acidemia with homocystinuria tend to have an adverse outcome if they have newborn onsets. Elevated urea and urinary methylmalonic acid are predictors of adverse outcomes for the patients. They show similar effect for predicting severe adverse prognosis. The combination of methylmalonic acid in urine concentration and urea in serum concentration provided the most accurate predictive tool.

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Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

et al. 2017

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Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations. We biochemically investigated how missense mutations in MMAA in 22 patients lead to disease. About a third confer instability to the recombinant protein in bacterial and human expression systems. All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding. However, all mutations strongly decreased functional association with MUT by reducing GTPase activity stimulation upon incubation with MUT, while nine mutant proteins additionally lost the ability to physically bind MUT. Finally, all mutations interfered with gating the transfer of AdoCbl from MMAB to MUT. This work suggests loss of functional interaction between MMAA and MUT as a disease-causing mechanism that impacts processing and assembly of a cofactor to its destination enzyme.

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Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia

Cited by 27 publications

References 31 publications

Juvenile gout in methylmalonic acidemia

Juvenile gout in methylmalonic acidemia

Predictors of survival in children with methymalonic acidemia with homocystinuria in Beijing, China: A prospective cohort study

Protein destabilization and loss of protein‐protein interaction are fundamental mechanisms in cblA ‐type methylmalonic aciduria

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