Proteinuria as a presenting sign of combined methylmalonic acidemia and homocysteinemia: case report

Abstract

Background Disorders of the metabolism and absorption of vitamin B12 can lead to decrease in activity of methionine synthetase and methylmalonate coenzyme A mutase (MMUT), which results in increased levels of methylmalonic acid and homocysteine in blood and urine. Often, combined methylmalonic acidemia (MMA) and homocysteinemia is misdiagnosed due to a lack of specific symptoms. The clinical manifestations are diverse, but proteinuria as the initial presentation is rare. Case presentation Two cases of MMA with homocysteinemia in children are reported. Proteinuria were a primary presenting symptom, followed by anemia and neurologic symptoms (frequent convulsions and unstable walking, respectively). Screening of amino acids and acyl carnitine in serum showed that the propionyl carnitine:acetylcarnitine ratio increased. Profiling of urinary organic acids by gas chromatography–mass spectrometry revealed high levels of methylmalonic acid. Homocysteine content in blood was increased. Comprehensive genetic analyses of peripheral blood-derived DNA demonstrated heterozygous variants of methylmalonic aciduria type C and homocystinuria (MMACHC) and amnionless (AMN) genes in our two patients, respectively. After active treatment, the clinical manifestations in Case 1 were relieved and urinary protein ceased to be observed; Case 2 had persistent proteinuria and was lost to follow-up. Conclusions Analyses of the organic acids in blood and urine suggested MMA combined with homocysteinemia. In such diseases, reports of renal damage are uncommon and proteinuria as the initial presentation is rare. Molecular analysis indicated two different genetic causes. Although the pathologic mechanisms were related to vitamin B12, the severity and prognosis of renal lesions were different. Therefore, gene detection provides new insights into inherited metabolic diseases.

Case Report: A Rare Case of Thrombotic Microangiopathy Induced by Remethylation Disorders

“…The three most common mutations are c.271dupA, c.394C > T, and c.331C > T, However, in Chinese patients, the c.609G > A mutation accounts for 85% of the identified alleles in MMACHC mutation ( 1 ). In this case, heterozygous mutations of MMACHC (c.1A > G and c.80A > G) were found, which have been reported before ( 3 ), although the mutations are uncommon in Chinese patients.…”

“…cblC defect usually occurs during the 1st year of life, and late-onset is applicable to children older than 4 years. There is great variability in the clinical presentation of cblC defect, and more common in the blood and nervous system ( 3 ). In this study, we focus on the TMA, which is a rarely late-onset manifestation in cblC defect.…”

Prominent renal complications associated with MMACHC pathogenic variant c.80A > G in Chinese children with cobalamin C deficiency

“…However, although TMA was the only kidney histologic pattern in our series, thrombocytopenia and serum markers of hemolysis with increased LDH, indirect bilirubin, and reticulocyte count were not prominent, and the preschool age of onset was most common. In the five reported Chinese cases with genetically proven child- and adolescence-onset cblC-associated renal disease ( Table 2 ), a similar phenomenon was observed ( 10 – 14 ). MMACHC genotypes may not explain the reasons for these differences.…”

“…Variant c.80A > G accounts for 5.95%–9.09% in all the Chinese cblC deficiency patients ( 17 , 18 ), whereas in this study all seven patients carried variant c.80A > G, accounting for 57.14% (8/14) of all the mutant alleles. In addition, among five reported Chinese cases with child- and adolescence-onset cblC-associated renal disease and genetic diagnosis ( 10 – 14 ), all of them had MMACHC heterozygous variant c.80A > G ( Table 2 ). In contrast, the most frequent damaged allele in Caucasian patients with cblC defect and renal TMA was c.271dupA ( 5 , 6 ).…”

Case report: A late-onset cobalamin C defect first presenting as a depression in a teenager

“…These complications include encephalopathy, hydrocephalus ( Zhang et al, 2019 ), optic neuropathy and retinopathy ( Alowain et al, 2019 ), pulmonary hypertension, late-onset diffuse lung disease, cardiorespiratory disease ( Liu et al, 2017 ; Zhang et al, 2020 ), proteinuria, renal thrombotic microangiopathy, and kidney function decline ( Chen et al, 2020 ; Liu et al, 2017 ). Thereby, the late-onset cblC patients should be treated perpetually with hydroxocobalamin supplement and routine metabolic monitoring.…”