Management of adultonset methylmalonic acidemia with. The main cause of this disease is a defect in the conversion of methylmalonyl coa to succinyl coa. Proposed guidelines for the diagnosis and management of. Methylmalonic and propionic acidemia mmapa are inborn errors of metabolism characterized by accumulation of propionic acid andor methylmalonic acid. Frontiers newborn screening for methylmalonic acidemia. It is estimated that the incidence of mma in western populations ranges from 1. Mild clinical features of isolated methylmalonic acidemia. Pathophysiology of lifethreatening acute metabolic decompensations amd in propionic acidemia pa and isolated methylmalonic acidemia mma is insufficiently. Methylmalonic acidemia diagnosis by laboratory methods ncbi.
Methylmalonic acidemia with homocystinuria is an inherited disorder in which the body is unable to properly process protein building blocks amino acids, certain fats lipids, and a waxy fatlike substance called cholesterol. Patients typically present at the age of 1 month to 1 year with neurologic manifestations, such as seizure, encephalopathy, and stroke. Federal register prospective grant of exclusive license. Acidemia, methylmalonic nord national organization for. Subacute bilateral visual loss in methylmalonic acidemia. Methylmalonic and propionic acidemia mmapa are autosomal recessive disorders of propionate catabolism caused by defects in the enzymes methylmalonylcoa mutase mut or propionylcoa carboxylase pcc characterized by accumulation of metabolites of branchedchain amino acid catabolism such as 3hydroxypropionic acid, methylcitric acid andor methylmalonic acid in plasma. Clinical and laboratory study of methylmalonic acidemia the safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Carrier screening to help detect the risk of having a baby with a specific inherited disorder, such as cystic fibrosis. The disorder can result in death if undiagnosed or left untreated. Methylmalonic acidemia is a form of ketotic hyperglycinemia. Traditional diagnosis needs physicians personal level of professional medical knowledge and clinical experience.
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. All structured data from the file and property namespaces is available under the creative commons cc0 license. This leads to a buildup of toxic substances and bouts of serious illness called decompensation events or metabolic crises. Methylmalonic acidemia kansas department of health. We look forward to advancing lb001 and expect to file an investigational new drug ind application in the fourth quarter of 2019. There are few detailed consensus and guidelines on perioperative clinical characteristics of liver transplantation lt in patients with methylmalonic acidemia mma. These disorders are caused by mutations in the methylmalonylcoa mutase apoenzyme or by impaired synthesis of the enzymatic cofactor, 5deoxyadenosylcobalamin 2, 3. Methylmalonic acidemia information mount sinai new york. Variable dietary management of methylmalonic acidemia. Get a printable copy pdf file of the complete article 969k, or click on a page image below to browse page by page.
Signs and symptoms of this condition usually appear in early infancy and include vomiting, dehydration, hypotonia, lethargy, and failure to thrive. The value of liver transplantation for methylmalonic acidemia. Cobalamin c disease cblc, also known as methylmalonic aciduria with homocystinuria, is an inherited disease characterized by hypotonia, lethargy, mental retardation, seizures, vision problems, and bloodrelated problems. This page was last edited on september 2009, at 05.
It was thought that the neurologic abnormalities seen in this disease were exclusively the consequences of these acute crises. Serum vitamin b 12 may be elevated in the cobalamin disorders. Methylmalonic acidemia genetics home reference nih. Links to pubmed are also available for selected references.
Teaching about metabolic diseases in medical school and residency programs is poor. Two types of mma that are non responsive to vitamin b12 and caused by mutations in the mmacoa mutase mut gene are referred to as mut 0 and mut. Newborn screening disorders year added acmg code core conditions organic acid condition fatty acid oxidation disorder amino acid disorder endo disorder hgb disorder other 1 2006 prop propionic acidemia x 2 2006 mut methylmalonic acidemia methylmalonylcoa mutase x 3 2006 cbl a,b methylmalonic acidemia cobalamin disorders x. Each document posted on the site includes a link to the corresponding official pdf file on govinfo. These conditions, at one time designated as idiopathic acidosis of infancy, often result in lifethreatening acidbase disorders.
Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl coa mutase perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl coa mutase ledley, fred d. Hence, the constellation of laboratory findings in mma is the following. Guven a, cebeci n, dursun a, aktekin eh, baumgartner mr, fowler b. Methylmalonic acidemia mma is a rare inherited metabolic disorder caused by deficiency of the enzyme methylmalonylcoa mutase. Newborn screening disorders florida administrative register. Erosive dermatitis resembling the skin lesions of acrodermatitis enteropathica has been described in a number of aminoacidopathies and organic acidemias. Among mma, the cblc type were characterized megaloblastic anemia, growth disorder and neurological symptoms zhang et al.
The patient presented today with methylmalonic acidemia provides us with an opportunity to discuss not only this condi. Methylmalonic acidemia mma, an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonylcoa mutase mut. Methylmalonic acidemia mma is usually caused by a deficiency of the enzyme methylmalonylcoa mutase mcm, a defect in the transport or synthesis of its. Two types of mma that arenon responsive to vitamin b12 and caused by mutations in the mmacoa mutase mut gene are. Neurologic nonmetabolic presentation of propionic acidemia. Methylmalonic acidemia, vitamin b12 responsive the british inherited metabolic disease group bimdg has published on its website guidelines for the emergency management of patients with inherited metabolic disorders. Clustering of mutations in methylmalonyl coa mutase. Methylmalonic acidemia can be caused by an inherited deficiency of methylmalonylcoa mutase, an adenosylcobalaminrequiring enzyme that converts lmethylmalonylcoa to succinylcoa figure 975, or in the metabolic pathway that catalyzes the biosynthesis of adenosylcobalamin from vitamin b 12 figure 978 and table 972. Methylmalonic acidemia and the disease associated with the more proximal defect in the same pathway, propionic acidemia, are the most common clinically significant genetic disorders of organic acid metabolism fenton and rosenberg 1995. Patients are prescribed a protein restricted diet to prevent elevated levels methylmalonyl coa.
Acidemia propionica pdf propionic acidemia is an inherited disorder in which the body is unable to process certain parts of proteins and lipids fats properly. In some, the dermatitis is a manifestation of untreated disease, while in others, including methylmalonic acidemia, skin lesions have been ascribed to nutritional deficiency due to therapeutic amino acid restrictions. Isolated mma is primarily caused by the deficiency of methylmalonylcoa mutase mma mut. Methylmalonic acidemia with homocystinuria genetics home. Refer to the help section for more detailed instructions. Methylmalonic acidemia methylmalonylcoa mutase deficiency propionic acidemia. Source and compound parameters for mma quantification by msms 1 pdf file. Jul 11, 2018 methylmalonic acidemia mma is an autosomal recessive inherited disorder that is characterized by the abnormal accumulation of methylmalonylcoa and methylmalonic acid in body fluids, which is caused by either a defect in methylmalonylcoa mutase mcm, ec 5. Listing a study does not mean it has been evaluated by the u. Methylmalonic acidemia mma is a genetic disorder caused by a deficiency in the methylmalonylcoa mutase mcm enzyme. Methylmalonic acidemia can occur in individuals of all races and ethnicities, with an incidence in the united states of approximately 191,000 and a calculated carrier frequency of 1 in 151. In 14 patients with methylmalonic acidemia we studied the correlations between clinical severity considered in terms of survival and number of acute episodes, daily tolerance to proteins. Methylmalonic acidemia mimicking diabetic ketoacidosis in.
Methylmalonic acidemia mma, an autosomal recessive metabolic disease, is a type of organic acidemia. Methylmalonic acidemia mma is a group of rare approx. Like other mitochondrial enzymopathies, enzyme replacement therapy ert is not available, and although promising, aav gene therapy can be limited by preexisting immunity and has been associated with genotoxicity in mice. Mma due to mut gene mutations usually led to severe phenotype, and around 3540% of cases are due to new. Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant. Methylmalonic acidemia mma is an inherited organic acidemia usually present with recurrent episodes of acute illness. This app is designed to support families and children with mma on protein restricted diets. The central emergency features of the mma are profound metabolic ketoacidosis and hypoglycemia. Methylmalonic acidemia mmaemia is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonylcoa into succinylcoa. The key finding in methylmalonic acidemia is the accumulation of methylmalonic acid in body fluids and tissues. Diagnosis of methylmalonic acidemia using machine learning. Glutaric acidemia type 1 type 2 hyperlysinemia pipecolic acidemia saccharopinuria. Metabolics the nutricia learning center features tools and educational resources for metabolic healthcare professionals.
Methylmalonic acidemia adult metabolic diseases clinic. Propionic acidemia, also known as propionic aciduria or propionylcoa carboxylase deficiency pcc deficiency, is a rare autosomal recessive metabolic disorder, classified as a branchedchain organic acidemia. Methylmalonic acidemia is a disorder in which the body cannot break down certain proteins and fats. There is a 1 in 4, or 25% chance that two carriers of the gene will have a baby with methylmalonic acidemia. It is ok to leave any of these columns blank or to not include the column in the import file.
Mma presents with lethargy, acidosis, hypoglycemia hyperglycemia, ketosis, and recurrent episodes. Methylmalonic acidemia an overview sciencedirect topics. Methylmalonic acidemia is the biochemical hallmark of a group of autosomal recessive genetic metabolic disorders that prevent the body from converting lmethylmalonylcoa into succinylcoa. Mma is a group of disorders in which methymalonylcoa cannot be broken down by methylmalonylcoa mutase mut, an enzyme involved in the breakdown.
Methylmalonic acidemia new england consortium of metabolic. Symptoms of a decompensation event include poor feeding, vomiting, trouble breathing, and lack of energy lethargy. Here are the ones the management for an acute decompensation in children and adults with methylmalonic acidemia due to a. Dec 26, 2017 methylmalonic acidemia is an autosomal recessive disorder of amino acid metabolism, involving a defect in the conversion of methylmalonylcoenzyme a coa to succinylcoa. Understanding acute metabolic decompensation in propionic and. Background patients with propionic acidemia usually present in the neonatal period with lifethreatening ketoacidosis, often complicated by hyperammonemia.
Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. Methylmalonic acidemia mma is a rare genetic metabolic disease, and most of its cases are autosomal recessive. It involves defects in a protein used to change vitamin b. Citations may include links to fulltext content from pubmed central and publisher web sites. Original article insights into the molecular mechanisms of. Methylmalonic acidemia controlled with oral administration. Get a printable copy pdf file of the complete article 1. Methylmalonic acidemia controlled with oral administration of vitamin b12.
Methylmalonic acidemia refers to a group of inherited conditions in which the body cant breakdown certain parts of proteins and fats. Treatment is aimed at reducing the sources of the precursors. Moreover, it could represent an ideal tier2 test for confirmation of methylmalonic acidemia, reducing the number of falsepositive results of routinely applied methods. Isolated methylmalonic acidemiaaciduria is caused by complete or partial deficiency of the enzyme methylmalonylcoa mutase mut 0 enzymatic subtype or mut. Isolated methylmalonic acidemia aciduria mma is a devastating metabolic disorder with poor outcomes despite current medical treatments. Metabolic phenotype of methylmalonic acidemia in mice and. Affected infants can experience vomiting, dehydration, weak muscle tone hypotonia, developmental. With each pregnancy, there is the same 25% chance of having a child with methylmalonic acidemia. Pathophysiology of propionic and methylmalonic acidemias. Perioperative characteristics and management of liver transplantation for isolated methylmalonic acidemiathe largest experience in china. Prevalence of complications occurring in pa and mma. In some families, there may be only one child with. Teach physicians about oa organic acidemia association.
Jci insight fgf21 underlies a hormetic response to. Isolated methylmalonic acidemiaaciduria mma is a devastating metabolic disorder with poor outcomes despite current medical treatments. Manufacture and commercialization of gene therapy products for human gene therapy use to treat andor prevent methylmalonic acidemia mma. Methylmalonic acidemia definition of methylmalonic acidemia.
Propionic acidemia is a very rare genetic form of ketotic hyperglycinemia. Generation of a human ipsc line sdqlchi021a from a. Perspectives on methylmalonic acidemia resulting from molecular cloning of methylmalonyl coa mutase. Methylmalonic acidemia mma is an autosomal recessive hereditary disease wang et al.
The class of methylmalonic acidemia is assigned on the basis of the results of the 14 cpropionate incorporation assay, which indirectly measures the activity of the mut methylmalonylcoenzyme a enzyme. Clustering of mutations in methylmalonyl coa mutase associated with mut methylmalonic acidemia. The disorder presents in the early neonatal period with poor feeding, vomiting, lethargy, and lack of muscle tone. About 1 in 20 000 babies are born with methylmalonic acidemia each year in canada. Methylmalonic acidemia, also called methylmalonic aciduria, is an autosomal recessive metabolic disorder that disrupts normal amino acid metabolism.
Clinical and laboratory study of methylmalonic acidemia. Methylmalonic aciduria is a genetically heterogeneous disorder of methylmalonate and cobalamin cbl. Demographic characteristics and enzymatic and mutation information for the 29 patients studied are listed by age. Isolated methylmalonic aciduria is found in patients with mutations in the mut gene causing partial, mut, or complete, mut0, enzyme deficiency. During the study, 236,368 newborns were screened for mma by tandem mass. Jan 19, 2016 methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and lipids properly.
Identification of a novel deletion in the mmaa gene in two. Propionic and methylmalonic acidemia are recessive disorders of the metabolism of thr,val, ile, met, odd chain fatty acids, and cholesterol classic presentation is with shock, acidosis and hyperammonemia, neutropenia and thrombocytopenia it is diagnosed by urine organic acids methylcitrate or methylmalonic acid, plasma amino acids. Media in category methylmalonic acidemia this category contains only the following file. Patients present either shortly after birth with acute deterioration. Perioperative characteristics and management of liver. Methylmalonic aciduria due to methylmalonylcoa mutase. The effects of methylmalonic acidemia vary from mild to lifethreatening. Treatment attempts with highdose intravenous steroids and coenzyme q10 combined with vitamin e were ineffective. Logicbio therapeutics receives rare pediatric disease. Genetic and genomic systems to study methylmalonic acidemia.
Methylmalonic acidemia mma is an autosomal recessive inherited disorder that is characterized by the abnormal accumulation of methylmalonylcoa and methylmalonic acid in body fluids, which is caused by either a defect in methylmalonylcoa mutase mcm, ec 5. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to lifethreatening. Newborn screening act sheet elevated c3 acylcarnitine. A typical episode is ushered in with ketonuria and vomiting, followed by acidosis, dehydration, and lethargy, leading, in the absence of. Methylmalonic acidemia mma organic acidemia association. Insights into the molecular mechanisms of methylmalonic acidemia using microarray technology lianshu han, shengnan wu, feng han, xuefan gu department of pediatric endocrinology and genetic metabolism, xinhua hospital, shanghai institute for pediatric research, shanghai jiaotong university school of medicine, shanghai 200092, china. For more information on this disorder, choose ketotic hyperglycinemia as your search term in the rare disease database. Individuals affected with this disorder present with lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and hypotonia in the first year of life 2. Pubmed comprises more than 26 million citations for biomedical literature from medline, life science journals, and online books. Understanding acute metabolic decompensation in propionic. Methylmalonic and propionic acidemia mmapa are inborn errors of metabolism characterized by accumulation of propionic acid andor methylmalonic acid due to deficiency of methylmalonylcoa mutase mut or propionylcoa carboxylase pcc. This pdf file can be printed as a 2sided document print and copy all pages, including blank pages.
Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. To define the metabolic adaptations in mma in acute and chronic settings, we studied a mouse model generated by transgenic expression of mut in the muscle. This disorder is due to either a mutant methylmalonylcoa mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. The patients underlying disease was metabolically well controlled by strict diet and carnitine supplementation. Methylmalonic acidemia mut information for health professionals. Most of the patients show acute deterioration, metabolic. Methylmalonic acid quantified in dried blood spots. Toxic damage of both optic nerves due to mma is the most likely mechanism. Methylmalonic acidemia mma is an autosomal recessive metabolic disorder.
Doctors dont usually test newborns for methylmalonic acidemia, but because it may cause the unexplained deaths and serious illnesses of some babies, many states are now thinking of including it among the many diseases for which doctors and midwives screen infants immediately after birth. The united states department of health and human services recommends screening for this condition at birth because early detection and treatment is helpful. Multiple conditions can be included in an import file. Logicbio therapeutics receives rare pediatric disease designation for lb001 for the treatment of methylmalonic acidemia. This document has been published in the federal register.
Methylmalonic aciduria, mma, isolated methylmalonic acidemia methylmalonic acidemia mma is a group of rare approx. Select up to three search categories and corresponding keywords using the fields to the right. Methylmalonic acidemiaaciduria mma is a genetically heterogeneous group of inherited metabolic disorders biochemically characterized by the accumulation of methylmalonic acid. Testing for methylmalonic acidemia is often done as part of a newborn screening exam. The result is a buildup of a substance called methylmalonic acid in the blood. Methylmalonic acidemia mma is an organic acid disorder. Jan 27, 2020 methylmalonic acidemia refers to a group of inherited conditions in which the body cant breakdown certain parts of proteins and fats. Multiple conditions canbe included in an import file. These advances were possible thanks to new pathophysiological insights. Perspectives on methylmalonic acidemia resulting from.
Jun 20, 2019 acidemia propionica pdf propionic acidemia is an inherited disorder in which the body is unable to process certain parts of proteins and lipids fats properly. Leave columns that do not apply to a con dition blank. Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats lipids properly. Methylmalonic acidemia, cobalamin c type, presenting with. Over the last decades, advances in clinical care for patients suffering from propionic acidemia pa and isolated methylmalonic acidemia mma have resulted in improved survival. Plasma total homocysteine will be elevated in the cobalamin c, d and f deficiencies. Pdf isolated methylmalonic acidemiaaciduria is caused by complete or partial deficiency of the enzyme methylmalonylcoa mutase mut 0. Methylmalonic acidemia mma incidence was evaluated based on newborn screening in xuzhou from november 2015 to december 2017, and the clinical, biochemical and molecular characteristics of patients with mma harboring mmachc and mut mutations were summarized. Files are available under licenses specified on their description page. Methylmalonic acidemia methelmalonic acideemeea is genetic disorder that affects how protein is broken down in the body.
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