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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Methylmalonyl-CoA mutase (MUT) enzyme dysfunction causes methylmalonic acidemia, which typically presents in childhood but can cause acute metabolic-intoxication encephalopathy in adults as described at the beginning of this chapter.
Methylmalonic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Methylmalonic acidemia represents a family of disorders of the metabolism of branched-chain amino acids in which the activity of methylmalonyl CoA mutase is defective (Figure 3.1). Patients with the inborn error of metabolism were first reported in 1967 by Oberholzer et al. [1] and by Stokke et al. [2]. In 1968, Rosenberg and colleagues [3] first clearly distinguished these patients from those with propionic acidemia (Chapter 2), in whom the clinical presentation is often virtually identical.
Lysosomal Vitamin B12 Trafficking
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sean Froese, Matthias R. Baumgartner
Vitamin B12 (cobalamin, Cbl) is required as cofactor for two essential human enzymes: cytosolic methionine synthase and mitochondrial methylmalonyl-CoA mutase. In order to reach these destination enzymes in the correct cofactor forms, Cbl must be taken up, modified and transported across the cell (Figure 7.1). Cellular entry of Cbl occurs through receptor mediated endocytosis, by which Cbl bound to the carrier protein transcobalamin is recognized by its nascent receptor CD320 (also known as the transcobalamin receptor, TCblR). Following progressive acidification in the transition from early- to late-endosomes, and finally lysosomes, the engulfed transcobalamin is degraded and Cbl is released. Free Cbl is then exported from the lysosome into the cytosol, where a series of metabolic steps results in the production of methyl-Cbl, the cofactor form for methionine synthase, or in transport into the mitochondria and the conversion to adenosyl-Cbl, the cofactor form for methylmalonyl-CoA mutase. Methionine synthase (E.C. 2.1.1.13), as part of the methionine cycle, is responsible for the production of methionine and ultimately S-adenosylmethionine. Methylmalonyl-CoA mutase (E.C. 5.4.99.2), a component of the propionate catabolic pathway for branched-chain amino acids, odd-chain fatty acids and the side chain of cholesterol, funnels catabolic intermediates into the tricarboxylic acid cycle.
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.
Optic neuropathy in classical methylmalonic acidemia
Published in Ophthalmic Genetics, 2019
Mohammed AlOwain, Ola Ali Khalifa, Zahra Al Sahlawi, Maged H Hussein, Raashda A Sulaiman, Moeen Al-Sayed, Zuhair Rahbeeni, Zuhair Al-Hassnan, Hamad Al-Zaidan, Hachemi Nezzar, Iftetah Al Homoud, Abdelmoneim Eldali, Brian Altonen, Bedour S Handoom, Joyce N Mbekeani
Methylmalonic acidemia (MMA) is a relatively common autosomal recessive-inherited metabolic disorder of branched-chain amino acids (isoleucine, valine, methionine and threonine), odd-chained fatty acids and cholesterol. Biochemically, methylmalonic acidemia (MMA, OMIM 609058) is the hallmark of a group of metabolic disorders that disturbs the conversion of methylmalonyl-CoA into succinyl-CoA. The classical form is a consequence of mutation of the MUT gene on chromosome 6, responsible for production of the mitochondrial, methylmalonyl CoA mutase apoenzyme (MCM, EC 5.4.99.2) (1–3). The resultant enzyme deficiency prevents vitamin B12-dependent conversion of methylmalonyl-CoA to succinyl-CoA, required in the Krebs cycle for energy production and the accumulation of methylmalonic acid in various tissues and body fluids. This metabolic disorder is characterized by intermittent periods of potentially lethal metabolic decompensation (metabolic acidosis and/or hyperammonemia), usually triggered by concurrent infection, dietary indiscretion and stress, followed by periods of relatively good clinical health (4,5). These episodes are defined as metabolic crises. Disorders of intracellular cobalamin metabolism caused by impaired synthesis or transport of the cofactor, adenosyl-cobalamin (cblA, cblB and variant 2 of cblD-MMA) exhibit phenotypically similar clinical features to MMA (1,3,4).
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.