vitamin-b-12 and Hypertension--Pulmonary

Combined methylmalonic aciduria and homocystinuria, cblC type, (MAHCC) is a rare autosomal recessive metabolic disorder of remethylation caused due to mutations in the MMACHC (metabolism of cobalamin associated C) gene with predominant neurological involvement. Microvascular, renal, and cardiovascular complications are also known to occur. However, the disease presenting primarily with a cardiovascular phenotype without any neurological involvement is a rare entity. We report a case of developmentally normal 23-mo-old female child, who presented with pulmonary arterial hypertension (PAH) and succumbed to cardiac failure. Extensive workup for PAH was inconclusive. Posthumous trio whole-exome sequencing revealed pathogenic compound heterozygous variants in the MMACHC. Diagnosis of MAHCC should be considered as a differential diagnosis for unexplained PAH in children. An elevated plasma homocysteine level can serve as a simple screening modality for this disorder. Accurate diagnosis has paramount therapeutic implications, as management with hydroxocobalamin and betaine may lead to partial or complete remission of PAH in these patients.

Topics: Amino Acid Metabolism, Inborn Errors; Female; Homocystinuria; Humans; Hypertension, Pulmonary; Infant; Mutation; Oxidoreductases; Vitamin B 12; Vitamin B 12 Deficiency

Methylmalonic acidemia (MMA) is an autosomal recessive disorder that can be classified into two types: (1) vitamin B12-responsive and (2) vitamin B12-non-responsive. In MMA cases with long-term survival, renal failure is often a problem, and timing for kidney transplantation for MMA is controversial. We encountered a vitamin B12-non-responsive MMA case for which regular hemodialysis for renal failure was initiated; the patient was 16 years old when she first received regular hemodialysis and 35 years old when she developed pulmonary artery hypertension (PAH). PAH can complicate regular hemodialysis; however, PAH in this case was considered to be a complication of MMA because it was responsive to medical treatment and reversible. In this report, we discuss the role of regular hemodialysis in MMA and the causal relationship between MMA and regular hemodialysis for PAH.

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Female; Humans; Hypertension, Pulmonary; Kidney Failure, Chronic; Renal Insufficiency; Vitamin B 12

Methylmalonic aciduria and homocystinuria, cobalamin C (CblC) disease (OMIM 277400), is the most frequent inborn error of vitamin B12 (cobalamin, Cbl) metabolism and is caused by an inability of the cell to convert Cbl to its active forms (MeCbl and AdoCbl). More than 75 mutations have been identified in the MMACHC gene which is responsible for CblC disease. We present a case with CblC disease and pulmonary arterial hypertension (PAH) as the main symptom. The patient improved dramatically with parenteral hydroxocobalamin treatment. Most cases of CblC disease have a multisystemic disease with failure to thrive, developmental delay, hypotonia, visual impairment, and hematologic manifestations. This patient had isolated pulmonary hypertension and hyperhomocysteinemia which is thought to be an important factor in the pathogenesis of PAH. Genetic analysis identified a novel homozygous mutation (c.484G > T; p.Gly162Trp) in the MMACHC gene.. CblC disease should be considered in the differential diagnosis of pulmonary hypertension.

Topics: Carrier Proteins; DNA; DNA Mutational Analysis; Echocardiography; Female; Humans; Hypertension, Pulmonary; Infant; Metabolism, Inborn Errors; Mutation; Oxidoreductases; Pulmonary Wedge Pressure; Vitamin B 12

This case-control study was conducted to test the hypothesis that fasting homocysteine levels are higher in PPH patients than in healthy controls.. Levels of plasma total homocysteine, serum folate, vitamin B-12, and serum creatinine in 18 consecutive patients with PPH were compared with data from 36 age- and sex-matched controls.. Eight of the 18 patients (44.4%) and three of the 36 controls (8.3%) had elevated plasma total homocysteine (tHcy) levels (> or = 15 mol/l, odds ratio 8.8; 95% CI: 2.0-39.6; P = 0.005). There was an inverse correlation between tHcy levels and creatinine clearance in patients with PPH (P = 0.036).. PPH patients are significantly more likely to have hyperhomocysteinemia, and higher mean plasma total homocysteine levels than in controls. Plasma total homocysteine may be an important factor in the pathogenesis of PPH.

Topics: Adolescent; Adult; Aged; Case-Control Studies; Creatinine; Fasting; Female; Folic Acid; Humans; Hyperhomocysteinemia; Hypertension, Pulmonary; Logistic Models; Male; Middle Aged; Vitamin B 12

An 18-month-old girl presented with macrocytic megaloblastic anaemia followed by haemolytic uraemic syndrome. Metabolic investigations led to the identification of an inborn error of cobalamin metabolism consisting of defective methylcobalamin biosynthesis, probably cobalamin G, since methionine synthase activity was decreased under standard reducing conditions. Despite treatment, pulmonary hypertension progressively developed and responded to oxygen therapy. Renal involvement evolved to terminal failure and haemodialysis, while pulmonary hypertension was controlled by oxygen therapy. Such clinical manifestations have never been reported in association with a defect of methylcobalamin and thus of methionine biosynthesis. A congenital abnormality of cobalamin metabolism was suspected then confirmed in the presence of typical haematological features associated with unusual clinical manifestations such as progressive renal failure and pulmonary hypertension.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Anemia, Megaloblastic; Female; Hemolytic-Uremic Syndrome; Humans; Hypertension, Pulmonary; Infant; Metabolism, Inborn Errors; Methionine; Vitamin B 12