Methylmalonic acid (MMA) is a substance produced in very small amounts and is necessary for human metabolism and energy production. Benefit from the experience of over 60 contributors from around the world lead by Drs. Lawrence F. Eichenfield and Ilona J. Frieden, two of the most important names in the fields of dermatology and pediatrics. Methylmalonic acidemia (MMA) is a group of disorders characterized by the accumulation of methylmalonic acid in the fluids of the affected individual. In California, defects in cobalamin metabolism are more frequent than apoenzyme deficiency, specifically l-methylmalonyl–coenzyme a (CoA) mutase (see Figure 22-4). Maple syrup urine disease: Deficiency of an enzyme called BCKD causes buildup of amino acids in the body. Methylmalonic acidemia is caused by a deficiency in methylmalonyl-CoA mutase, which functions in the conversion of methionine, isoleucine, and valine to succinyl-CoA (see Fig. So far 136 mutations of mutase have been identified. This manual deals specifically with laboratory approaches to diagnosing inborn errors of metabolism. Excess methylmalonic acid is found in the blood of people with methylmalonic acidemia., and other harmful substances to build up in the blood and urine and cause health problems. Here is an extensive update of Pediatric Nephrology, which has become the standard reference text in the field. The propionyl-CoA pathway thus likely functions as an anaplerotic pathway for the citric acid cycle. About. This form is unresponsive to B12 therapy. Have a question? Methionine-, threonine-, valine- and isoleucine-free dietary preparations for the management of methylmalonic acidaemia and proprionic acidaemia. We want to hear from you. The disease has a poor outcome marked by early mortality preceded by a coma. Stephen Cederbaum, Gerard T. Berry, in Avery's Diseases of the Newborn (Ninth Edition), 2012. This is particularly true for gray and white matter disorders, thanks to the superb soft tis sue contrast in MRI which allows gray matter, unmyelinated, and myelinated white matter to be distinguished and their respective disorders ... Methylmalonic Acidemia. Methylmalonic acidemia (MMA) is a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl-coenzyme A mutase characterized by accumulation of methylmalonic acid. A metabolic disorder resulting from an enzyme deficiency and characterized by the presence of excessive amounts of methylmalonic acid in the urine; it can be congenital (genetic causes) or acquired (nutritional causes) because of a severe alimentary deficiency of vitamin B12 . In 2014, guidelines for managment of methylmalonyl-Coenzyme A mutase deficiency (MMC deficiency) were published by professionals across 12 European countries and the United States. New contributors from all over the world-including 70% new to this edition-present the latest challenges in the field and emphasize the adolescent and post-operative outcomes for management. Serum amino acids sometimes demonstrate elevation of glycine. Methylmalonic acidemia (MMA) is a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl–coenzyme A mutase characterized by accumulation of methylmalonic acid. Presents clinical, biochemical, and genetic information concerning those metabolic anomalies grouped under inborn errors of metabolism. About 1/80,000-1/100,000 babies are born with methylmalonic acidemia worldwide. 2. MCM is a It was to remedy this deficiency that this book was conceived. The book opens with a draft etiological classification that goes some way to filling the nosological void. Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMC is converted to succinyl CoA catalysed by a mutase, which requires the coenzyme adenosylcobalamin, and succinyl CoA enters the citric acid cycle. Diagnosis is by urine organic acids that demonstrate large amounts of methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxy propionic acid. Affected newborns are characterized by recurrent vomiting, hepatomegaly, and developmental retardation owing to accumulation of methylmalonic acid. It is only broken down to the 'acid' stage. About 50% is formed from isoleucine, valine, methionine and threonine. The treatment of acute disease consists of protein restriction, empirical therapy with vitamin B12 (1 mg/day intramuscularly), intravenous fluids with 10% glucose and sodium bicarbonate to correct dehydration, electrolyte imbalance and acidosis, high-calorie feeds via a nasogastric tube, and often dialysis. 12-6). The first recognized cases of these disorders were described in 1967. The methionine-, threonine-, valine- and isoleucine-free infant formula XMTVI Analog is suitable for the first year of life. Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency. If you do not want your question posted, please let us know. There are erythema and ulceration in the corners of the mouth and genital areas. In the acute form, drowsiness, coma, and seizures may occur. The methionine-, threonine-, valine- and isoleucine-free drink mix XMTVI Asadon is suitable for infants, children, adolescents and adults; but, unlike other proprietary preparations, it is carbohydrate, fat, vitamin and mineral free, which need to be added to the diet. Treatment with dietary restrictions may be helpful in some cases, and intramuscular hydroxocobalamin is also helpful in some cases.14, Methylmalonic acidemia (MMA): ↑ T2 signal GP ± periventricular white matter (WM), Kearns-Sayre/L-2-hydroxyglutaric aciduria: ↑ T2 GP (> than other deep gray) and peripheral WM, Canavan: ↑ T2 GP (> than other deep gray) and subcortical WM; macrocephaly; ↑ NAA, Neuroferritinopathy: Variable-sized foci ↑ T2 signal GP, putamen, caudate heads with ↓ T2 SN, DN; disease of adults, Guanidinoacetate methyltransferase deficiency (impairs creatine synthesis), Anoxic encephalopathy: ↑ T2 GP (and other deep gray) and cortex, Carbon monoxide poisoning: ↑ T2 GP (± other deep gray, cortex, WM), Cyanide poisoning: ↑ T2 basal ganglia followed by hemorrhagic necrosis, Kernicterus: ↑ T2/T1 globus pallidus in neonate. Children aged 1 year with an assumed weight of 10 kg, on a 3 g amino acid per kg bodyweight diet, and with no other sources of iodine other than their prescribed drinks or gels, have intakes of around 86–120 μg/day of iodine. Methylmalonic acidemia (MMA) is a rare inherited metabolic disorder caused by deficiency of the enzyme methylmalonyl-CoA mutase. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. This deficiency can lead to metabolic crises due to a toxic buildup of acids in the body and progresses into multi-organ disease. Succinyl CoA can also react with glycine to form ALA catalysed by cytosolic ALA synthase. MRI scans typically demonstrate involvement of basal ganglia and white matter, with the globus pallidus being selectively affected (Gao et al., 2009). The patient showed favorable growth and development when kept on a low isoleucine, methionine, threonine and valine diet. MMA can be caused by a series of defects, most of which lead to deficiency of the enzyme . Some patients, but not usually newborn infants with methylmalonic acidemia caused by apoenzyme deficiency, are responsive to pharmacologic therapy with vitamin B12. Plasma amino acids typically show elevation of glycine but may be normal. Treatment includes aggressive management of decompensation events, a low-protein diet, certain medications, antibiotics and, in some cases, liver and kidney transplantation. If the results are rapidly available, the outlook for the neonatal period may be improved. Methylmalonic Acidemia (MMA) is an autosomal recessively inherited organic acid disorder due to deficient activity of mitochondrial B12-dependent methylmalonyl-CoA mutase, an enzyme which limits the conversion of methylmalonyl-CoA to succinyl-CoA. Although some cases of methylmalonic acidemia, especially those caused by a cobalamin F and cobalamin C type of defect, have presented with a dermatitis similar to that seen in acrodermatitis enteropathica,80,81 more commonly the dermatitis begins after the institution of dietary restrictions.82 In either case the appearance is similar and in a primarily periorificial location. Methylmalonic acidemia -mutase deficiency (MUT) . John W. Pelley, in Elsevier's Integrated Review Biochemistry (Second Edition), 2012. Get the latest public health information from CDC: https://www.coronavirus.gov (link is external)
. Some of these genetic changes delete or duplicate a small amount of genetic material in the MMAB gene. This study uses a type of gene therapy to address methylmalonic acidemia (MMA), a rare genetic defect that causes problems with digestion of fats and proteins resulting in a buildup of methylmalonic acid in tissues and blood. Impaired function can result from either a mutation of the l-methylmalonyl-CoA mutase apoenzyme or deficient availability of the adenosyl form of vitamin B12. Skin rashes can result from the metabolic perturbations or the dietary restrictions used to manage these inherited disorders of amino acid metabolism. Methylmalonic acidemia & Kidney Dr. Alaleh Gheissari, Professor of Paediatrics Paediatric Nephrologist 10/22/2021 2. The diagnosis of metabolic diseases is facilitated by this clinical book. . Most mut0 patients have an earlier and more severe The important laboratory findings include metabolic acidosis usually associated with an increased anion gap, ketosis, and hyperammonemia. Most diagnoses are ascertained by expanded newborn screening. An erosive erythema with periorificial accentuation resembling staphylococcal scalded skin syndrome and a periorificial rash resembling acrodermatitis enteropathica have both been described in MMA.14,211 Other symptoms in early-onset disease include lethargy, hypotonia, neutropenia, and thrombocytopenia. They can direct you to research, resources, and services. Methylmalonic acidemia (MMA) is a condition with many different forms, all of which have different causes and treatments. Therefore if there is a clinical concern, testing for an organic aciduria should be performed. You may want to review these resources with a medical professional. The treatment of chronic state centers on the judicious use of a low-protein diet, an amino acid supplement low in the MMA precursors, carnitine to alleviate free carnitine deficiency, and appropriate calories and fluid. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood. The baby is usually well at birth, as with UCDs, but then gradually begins to manifest problems with feeding, vomiting, lethargy, and perhaps seizures. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. Vesicles, Pustules, Bullae, Erosions, and Ulcerations. Due to a genetic defect, the body is unable to properly process certain parts of proteins, leading to the symptoms of the condition. The HPO collects information on symptoms that have been described in medical resources. Other mutations change a single protein building block (amino acid) used to . The cobalamin transport deficiencies are assessed by measuring serum cobalamin levels and absorption by the Schilling test, in addition to DNA testing (Pupavac et al., 2016). One next-generation sequencing panel includes 24 genes associated with elevated methylmalonic acid (Pupavac et al., 2016). The elevation of plasma ammonium may be as high as in severe newborn-onset hyperammonemic syndromes. A diminished color in the processed blood specimen indicates that the infant may have biotinidase deficiency. Clinical manifestations are usually due to the accumulation of toxic substances in the body. Inborn errors of metabolism are a group of inherited genetic disorders characterized by enzyme defects. Copyright © 2021 Elsevier B.V. or its licensors or contributors. For a 25 kg child of 8 years requiring 2 g protein/kg/day and with no source of protein or iodide other than the prescribed preparations, the daily iodide intake is around 137 μg/day of iodine, which is higher than the current recommendation for children (120 μg/day of iodine). The long term effects of methylmalonic acidemia depend on which gene is mutated and the severity of the mutation. This book is a printed edition of the Special Issue "Current Strategies for the Biochemical Diagnosis and Monitoring of Mitochondrial Disease" that was published in JCM They result from deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (encoded by MUT) or by a defect in the synthesis of its cofactor AdoCbl (cblA, cblB . Methylmalonic acidemia is caused by a defect in methylmalonyl-CoA mutase, racemase or one of the enzymes involved in the synthesis of adenosylcobalamin, the essential cofactor of methylmalonyl-CoA mutase (cblA and cblB). When the amino acids and fats are not broken down normally . Propionyl CoA is metabolized by mitochondrial carboxylase and racemase to L-methylmalonyl-CoA. Signs and symptoms of this condition usually appear in early infancy and include vomiting, dehydration, hypotonia, lethargy, and failure to thrive. O’Brien, in Reference Module in Biomedical Sciences, 2014. These resources provide more information about this condition or associated symptoms. Methylmalonic acidemia is an autosomal recessive disease caused by a deficiency in methylmalonyl coenzyme A mutase, an adenosylcobalamin-requiring enzyme that catalyzes the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A in the metabolic pathways of valine, isoleucine, methionine, threonine, and odd-chain fatty acids . It has an autosomal recessive inheritance. Have a question? Propionic acidemia is a rare metabolic disorder affecting from 1/20,000 to 1/250,000 individuals in various regions of the world. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. This test measures the level of MMA in blood or sometimes urine. For most diseases, symptoms will vary from person to person. These recommendations for iodine intake may be exceeded if all daily amino acids are sourced only from proprietary methionine-, threonine-, valine- and isoleucine-free drink or gels; for example a 10-year-old child weighing 32 kg could have iodine intakes of 183–200 μg/day. A baby with MUT is either not making enough methylmalonyl-CoA mutase enzymes or is making non-working methylmalonyl-CoA mutase enzymes, or the enzymes the body is making are not working properly. The 2nd Edition of Metabolic Diseases provides readers with a completely updated description of the Foundations of Clinical Management, Genetics, and Pathology. We want to hear from you. Background. (HPO) . There are different forms of methylmalonic acidemia, each with different causes and treatments. There is a lymphocytic perivascular infiltrate within the dermis, as well as areas of orthokeratosis and parakeratosis, with spongiosis of the epidermis. Online access via www.studentconsult.com - included with your purchase - allows you to conveniently access the book's complete text and illustrations online as well as relevant content from other Student Consult titles. Methylmalonic acidemia can clinically resemble other organic acidemias, necessitating analysis of urine organic acids for diagnosis. Plasma amino acid analysis may reveal elevations of several amino acids, such as glycine and alanine. A volume in the Handbook of Clinical Neurology series, which has an unparalleled reputation as the world's most comprehensive source of information in neurology International list of contributors including the leading workers in the field ... Serum B12 levels must be assessed to ensure that elevated methylmalonic acid and homocysteine levels, if present, are not the result of a nutritional deficiency of cobalamin. It can potentially cause coma and death, particularly if not correctly diagnosed and treated. [ 7 ] Complementation studies revealed the presence of at least 8 different complementation groups (mut0, mut-, cblA, cblB, cblC, cblD [and CblD variant 2], cblF, cblJ) that cause MMA. This section provides resources to help you learn about medical research and ways to get involved. The diagnosis is made by documenting characteristic abnormal levels of plasma amino acids. http://www.ncbi.nlm.nih.gov/books/NBK1231/, http://ghr.nlm.nih.gov/condition/methylmalonic-acidemia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=79284, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180313/, https://www.ncbi.nlm.nih.gov/pubmed/26101005. This is formed from propionyl-CoA which is formed in vivo from the catabolism of odd –chain fatty acids, cholesterol and C-5 ketone bodies. Other potentially toxic metabolites that accumulate include methylcitric acid, malonate and 3-hydroxypropionic acid which could also inhibit the citric acid cycle. Most PA patients present with symptoms in the first few days of life. . It is needed to breakdown certain fats too. About 60 percent of methylmalonic acidemia cases are caused by mutations in the MMUT gene. Biochemical testing for abnormal levels of specific chemicals, Testing for responsiveness to vitamin B12, Aggressive treatment of decompensation events, Vitamin B12 supplementation for the vitamin B12 responsive subtypes, Avoidance of stressors (such as fasting or illness) that can lead to a decompensation event, Liver and kidney transplant in some cases. As with propionic acidemia, some cases are not identified through newborn screening, and some infants will develop clinical symptoms before the newborn screen results are available. The prognosis of MMA is guarded, with many patients remaining severely impaired neurologically in spite of aggressive dietary support. Deficient activity may be due to a defect in the enzyme or reduced amount of B12 (cobalamin) cofactor. The disease is caused by partial deficiency in the activity of the mitochondrial vitamin B12-dependent enzyme methylmalonyl-CoA mutase which is a result of mutations in the MUT gene (6p21). Questions sent to GARD may be posted here if the information could be helpful to others. expand submenu for Find Diseases By Category, expand submenu for Patients, Families and Friends, expand submenu for Healthcare Professionals. Patients who are particularly brittle or who develop renal failure receive either liver, kidney, or combined liver-kidney transplants, but their efficacy at curing the primary disease process has not been proved. Renee Howard, Ilona J. Frieden, in Neonatal Dermatology (Second Edition), 2008, The term methylmalonic acidemia (MMA; see Chapter 17) refers to a group of defects in the metabolism of isoleucine and valine. In methylmalonic acidemia (MMA), the enzyme methylmalonyl-CoA mutase (MUT) fails to break down odd-chain fatty acids and the amino acids isoleucine, valine, methionine, and threonine. Do you know of a review article? Methylmalonic acidemia is a genetic disease that appears in early infancy with a frequency of about 1:50 000 people and can result in respiratory distress, hypotonia, hepatomegaly, mental retardation, chronic kidney disease and pancreatitis. NIH Scientists Develop Breath Test for Methylmalonic Acidemia The clinical features vary from mild involvement to severe neurological impairment, coma and death. The pathway involves the formation of propionyl-CoA and its conversion to methylmalonyl-CoA before the formation of succinyl-CoA.
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