Organic acid disorders and disorders of fatty acid oxidation
Steve Hannigan in Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
The onset of this condition is usually during the irst few months of life, although some individuals present with symptoms later in childhood. Symptoms may include lethargy, failure to grow and gain weight (failure to thrive), recurrent vomiting, dehydration, respiratory distress, low muscle tone (hypotonia), delay in mental development, its (seizures), low blood sugar levels (hypoglycaemia) and an enlarged liver (hepatomegaly). There will be a build-up of acids in the body (metabolic acidosis), with abnormally high levels of methylmalonic acid in the blood and urine. There are sometimes high levels of the amino acid glycine in the blood and urine (hyperglycinaemia and hyperglycinuria), and also of ketones in the blood and urine (ketonaemia and ketonuria), as well as of ammonia in the blood (hyperammonaemia). There may also be reduced numbers of platelets (thrombocy-topenia) and white blood cells (neutropenia) in the blood. Acute episodes may include drowsiness and seizures, with subsequent developmental delays. If treatment is not undertaken, coma and death may occur.
Propionic acidemia
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
A patient with propionic acidemia was reported in 1961 [1] as having hyperglycinemia, a disorder of amino acid metabolism. Its most prominent feature was recurrent attacks of ketoacidosis. Analysis of the amino acids of blood and urine revealed very large quantities of glycine. Attacks were related to the intake of protein, and it was shown that ketonuria resulted regularly from the administration not of glycine, but of branched-chain amino acids and threonine and methionine [1, 2]. The discovery of a group of patients with hyperglycinemia who had none of these characteristics led us to coin the term “nonketotic hyperglycinemia” (Chapter 22) to distinguish them from the original group that we called “ketotic hyperglycinemia”. The discovery of methylmalonic acidemia in a group of patients who displayed the ketotic hyperglycinemia syndrome [3–5] led initially to the thought that all these patients had methylmalonic acidemia. However, study of our initial patient and his sister, by Rosenberg and colleagues [6], indicated that neither excreted methylmalonic acid, and that they had propionic acidemia as a result of defective activity of propionyl CoA carboxylase (Figure 2.1). This enzyme is the first step in the pathway of propionate metabolism in which propionyl CoA, the product of the metabolism of isoleucine, valine, threonine, and methionine is converted to methylmalonyl CoA then to succinyl CoA and oxidation in the citric acid cycle.
Megaloblastic Anemias
Harold R. Schumacher, William A. Rock, Sanford A. Stass in Handbook of Hematologic Pathology, 2019
Data suggest that measurement of serum methylmalonic acid and homoocysteine are highly sensitive for detecting intracellular vitamin B12 deficiency. Serum methylmalonic acid and homocysteine are elevated in more than 95% of patients with vitamin B12deficiency (Table 4). Normal levels rule out a deficiency with near certainty. Furthermore, elevated levels are more specific for detecting vitamin B12 deficiency states that low serum B12 levels, which can be decreased without evidence of deficiency. One limitation, however, is that elevations in serum methylmalonic acid can also be seen in patients with renal dysfunction. Measurement of these metabolites is available through reference laboratories and can be done to confirm vitamin B12 deficiency when serum vitamin B12 levels are in the low normal range. Serum homocysteine is elevated in patients with folate deficiency; serum methylmalonic acid is normal.
Clinical application of NGS-based SNP haplotyping for PGT-M of methylmalonic acidemia
Published in Systems Biology in Reproductive Medicine, 2022
Bin He, Lin Wang, Qiuhua Wu, Xiaobin Wang, Xingzhe Ji, Wenhao Shi, Juanzi Shi, Rong Qiang, Shuai Zhen
Methylmalonic acidemia (MMA) is a group of autosomal recessive disorders mainly divided into isolated MMA and combined MMA with homocysteinemia (Almási et al. 2019). The methylmalonyl-CoA mutase (MMUT) type MMA is one of the isolated forms caused by a complete or partial deficiency of MMUT due to mutations in the MMUT (NM_000255.4) gene (Ji et al. 2019a). MMUT deficiency causes elevated levels of methylmalonyl-CoA and methylmalonic acid in body fluids and tissues. Delayed diagnosis and treatment results in the accumulation of methylmalonic acid, which damages the central nervous system and causes deep coma, metabolic crisis and death during the newborn period (Tanacan et al. 2019; Han et al. 2020). Patients with MMA, although treated in accordance with guidelines, including dietary protein restriction, carnitine supplementation and the use of drugs to modulate ammonia, may still experience acute metabolic crisis or even have to undergo surgery (Baumgartner et al. 2014; Fraser and Venditti 2016). Furthermore, these treatments can neither block the vertical heredity of pathogenic mutations nor guarantee quality of life.
Vitamin B12 deficiency in type 2 diabetic patients on metformin: a cross-sectional study from South-Western part of Ghana
Published in Alexandria Journal of Medicine, 2019
Maryam Yakubu, Edwin Ferguson Laing, Paul Nsiah, Richard Anthony, Emmanuel Acheampong, Samuel Kojo Asamoah, Enoch Odame Anto, Gabriel Djokoto, Evans Adu Asamoah, Eddie-Williams Owiredu
The estimation of serum methylmalonic acid was based on the competitive binding enzyme immunoassay technique (standardized with an intra-assay %CVs <6.1% and inter-assay %CVs <10.2%) (MyBioSource, Inc. San Diego, CA, USA) according to the manufacturer’s instructions. Briefly, 50 μL of standards, controls, and samples were pipetted into appropriate microtitre wells which were pre-coated with an antibody specific to MMA. Fifty microliters (50 μL) of Detection A working solution was added to each well, mixed thoroughly, covered with an adhesive strip, and incubated at 37°C for 60 min. The incubation mixture was aspirated from the wells followed by five washes with the wash solution (400 μL). Residual water droplets were removed by striking the wells onto absorbent paper. A 100 μL of Detection A working solution was pipetted into each well, mixed gently and incubated at 37°C for 45 min.
ZRSR2 mutation in a child with refractory macrocytic anemia and Down Syndrome
Published in Pediatric Hematology and Oncology, 2019
Meghna Srinath, Emily Coberly, Kimberly Ebersol, Kirstin Binz, Katsiaryna Laziuk, William T. Gunning, Barbara Gruner, Richard Hammer, Bindu Kanathezhath Sathi
Because of the megaloblastic picture, amino acid profiling was done which revealed elevated methylmalonic acid level (0.60 nmol mL−1 (<0.40)) with normal homocysteine. Intramuscular B12 and oral folate therapy was started, in addition to pRBC transfusion when Hb was persistently lower than 7 g dL−1. After 6 months of pRBC therapy, the frequency of transfusions increased with persistent normocytic-to-macrocytic anemia (MCV 83.7–95.3 fL) and low iron and ferritin despite continuous iron therapy. There was evidence of chronic fecal occult blood loss; however, a Meckel’s scan, upper and lower gut endoscopies, capsule studies, and RBC nuclear scan revealed only chronic gastritis with no active bleeding source. Absorption of oral iron was found to be normal and testing for pernicious anemia (anti-Intrinsic factor antibody) was negative. Testing for mutations in methylmalonyl-CoA mutase was negative, and the patient did not exhibit other features or symptoms of methylmalonyl-CoA mutase deficiency.
Related Knowledge Centers
- Coenzyme A
- Dicarboxylic Acid
- Methylation
- Vitamin B12
- Citric Acid Cycle
- Conjugate
- Malonic Acid
- Methylmalonyl-Coa
- Succinyl-Coa
- Methylmalonyl-Coa Mutase