Methylmalonic acidemia (MMA), also called methylmalonic aciduria, is an autosomal recessive metabolic disorder. It is a classical type of organic acidemia. 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. Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult. Methylmalonic acidemias are found with an equal frequency across ethnic boundaries. Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening. Stroke Progressive encephalopathy Seizure Kidney failure ...
A methylmalonic acid blood test is typically used to screen for vitamin B12 deficiency. With Request A Test, ordering your Methylmalonic Acid testing couldnt be easier or more convenient. Order your lab tests, give your sample, get results.
An 8 wk old male Yorkshire terrier was presented with a 2 wk history of recurrent hypoglycemia, lethargy, and seizures. Investigations revealed a marked increase in blood ammonia, low serum cobalamin, and increased levels of urinary methylmalonic acid (MMA) excretion. No liver vascular abnormality was detected. The patient was diagnosed with methylmalonic aciduria due to cobalamin malabsorption. The patient responded well to parenteral cobalamin administration, and the urinary MMA levels normalized rapidly following instigation of treatment. Due to the suspected hereditary nature of selective cobalamin deficiency, one sibling of this dog was screened and found to be normal. This is the first reported case of MMA secondary to hypocobalaminemia in Yorkshire terriers, and the second report of this disease in a dog in the United Kingdom. Given the fact that clinical signs of MMA are similar to those seen in dogs with portosystemic shunts and that Yorkshire terriers are predisposed to liver vascular ...
A malonic acid derivative which is a vital intermediate in the metabolism of fat and protein. Abnormalities in methylmalonic acid metabolism lead to methylmalonic aciduria. This metabolic disease is attributed to a block in the enzymatic conversion of methylmalonyl CoA to succinyl CoA. [PubChem]
Get a methylmalonic acid urine test near you at a lab. The urine methylmalonate test checks urine MMA levels with fast results at a reasonable cost - Accesa Labs
The aims of this study were to document the levels of cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) in serum and their relations to symptoms, clinical findings, and other factors in order to improve the possibilities of detecting early deficiency of vitamin B12 or folate, and to study the effects of cobalamin and folic acid treatment over a three-year period.. The study population consisted of a 20% random sample of persons 70 years or older living in Älvkarleby in mid-Sweden. They were invited to a survey and 224 (88.4%) persons responded. Data were obtained by questionnaire, laboratory investigations and physical examination for the period 1993 - 1999.. In a multivariate analysis performed at baseline, serum MMA and tHcy were significantly and independently correlated to age, serum cobalamin, and creatinine levels, and tHcy also to sex and serum folate. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin or mean red cell ...
Methylmalonic acidemia (MMA), one of the most common inborn errors of organic acid metabolism, is heterogeneous in etiology and clinical manifestations. Affected patients with cblA, cblB and mut classes of MMA are medically fragile and can suffer from complications such as metabolic stroke or infarction of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis, and developmental delay. The frequency of these complications and their precipitants remain undefined. Furthermore, current treatment protocol outcomes have continued to demonstrate substantial morbidity and mortality in the patient population. Rarely, solid organ transplantation (liver, and/or kidney) has been used to treat patients. Disordered intracellular metabolism of vitamin B12 produces another group of disorders that feature methylmalonic acidemia as well as (hyper)homocysteinemia. These conditions are named after the corresponding cellular complementation class cobalamin C (cblC), D and F and ...
... are often mentioned when B12 (and homocysteine) is discussed. Some claim that MMA tests is a gold standard for measuring B12 deficiency. Just like homocysteine, MMA is a controversial topic. Here are some links to information about MMA and MMA tests.
Definition of methylmalonic acid. Provided by Stedmans medical dictionary and Drugs.com. Includes medical terms and definitions.
Vitamin B12 (cobalamin) deficiency is a common disorder with potential irreversible haematological and neurological consequences.. - Currently used diagnostic tests such as the evaluation of serum vitamin B12 and the Schilling test are insufficient, e.g. the positive predictive value of a low serum vitamin B12 level for actual vitamin B12 deficiency (i.e. tissue deficiency) is low.. - Insufficient availability of vitamin B12 will lead to the accumulation of methylmalonic acid and homocysteine in the body. Nearly all patients with vitamin B12 deficiency also have substantially increased levels of methylmalonic acid and homocysteine.. - New tests of serum methylmalonic acid and homocysteine are highly sensitive for vitamin B12 deficiency and may obviate the need for the somewhat cumbersome Schilling test.. Ned Tijdschr Geneeskd. 2005;149:2789-94 ...
Treatment with the anti-diabetic drug metformin is followed by a decline in plasma cobalamin, but it is unsettled whether this denotes an impaired cobalamin status. This study has explored changes in the markers of cobalamin status in women with Polycystic Ovary Syndrome treated with metformin (1.5-2.5 g per day) (n = 29) or placebo (n = 23) for six months. Serum samples were collected before and after two, four, and six months of treatment. We found serum cobalamin to decline and reach significant lower levels after six months of treatment (p = 0.003). Despite the decline in serum cobalamin, we observed no reductions in the physiological active part of cobalamin bound to transcobalamin (holotranscobalamin), or increase in the metabolic marker of cobalamin status, methylmalonic acid. Instead, the non-functional part of circulating cobalamin bound to haptocorrin declined (p = 0.0009). Our results have two implications: The data questions whether metformin treatment induces an impaired cobalamin status
Methylmalonic acidemia (MMA) is a heterogeneous disorder of propionate metabolism. MMA is caused by deficiency of the mitochondrial enzyme, methylmalonyl-CoA mutase-apoenzyme activity (MUT) or defective in adenosylcobalamin (coenzyme) synthesis.1 The most patients with cblA and half patients with cblB forms of MMA are responsive to vitamin B12.2,3 Clinical manifestation of MMA may be acute or chronic. The acute form of the disease occurs during infancy and even as early as the second day of life with poor feeding, vomiting, dehydration, weight loss, temperature instability, lethargy, hypotonia, seizure and progressing to coma. Laboratory findings include: metabolic acidosis, ketosis, hypoglycemia, hyperlactatemia, hyperammonemia, pancytopenia.4. Definitive diagnosis of isolated MMA is based on analysis of organic acids in plasma and/or urine; however genetic testing diagnosis in some condition is accessible to confirm the diagnosis of isolated MMA. Below, we describe the presentation and ...
During fetal life and infancy, an adequate cobalamin status is important for normal growth and central nervous system development. A metabolic profile consistent with impaired cobalamin status is prevalent in breast-fed infants. Whether this profile reflects immature organ systems or cobalamin deficiency has not been clarified.. Low levels of cobalamin, elevated levels of total homocysteine (tHcy), cystathionine and/or methylmalonic acid (MMA) in the blood are measures of impaired cobalamin status.. The purpose of this randomized, controlled study is to determine if cobalamin supplementation may influence the metabolic profile related to cobalamin status in infants.. Six weeks old infants will be randomly assigned to receive either an intramuscular injection with 400 µg cobalamin or no intervention. Concentrations of cobalamin and folate in serum, and total homocysteine (tHcy), methylmalonic acid (MMA) and cystathionine in plasma will be determined at inclusion and at the age of 4 months. A ...
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). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of
Oberholzer et al and Stokke et al reported the first patients with methylmalonic acidemia (MMA). Clinical and genetic heterogeneity became evident very early when some patients responded to pharmacological doses of cobalamin (vitamin B-12) and others did not.
A collection of disease information resources and questions answered by our Genetic and Rare Diseases Information Specialists for Methylmalonic acidemia
Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We randomly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin (normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 mmol/L). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37.2 mmol/L in the oral ...
Vitamin B12 is an essential cofactor that is integral to methylation processes important in reactions related to DNA and cell metabolism, thus a deficiency may lead to disruption of DNA and cell metabolism and thus have serious clinical consequences.1 Intracellular conversion of vitamin B12 to two active coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine, respectively.2 3 Methylmalonic acid is converted into succinyl-CoA, of which vitamin B12 is a cofactor for the reaction. Homocysteine is biosynthesised from methionine then resynthesised into methionine or converted into amino acid cysteine. Vitamin B12 (also referred to as cobalamin) deficiency is relatively common, with important and variable clinical consequences. This review presents a concise summary of the most up to date evidence on how to diagnose and manage vitamin B12 deficiency. ...
This test measures the amount of a substance called methymalonic acid (MMA) in your blood. Higher levels may mean you have a vitamin B12 deficiency.
HCMM : Second-tier assay of newborn screening specimens when abnormal propionyl carnitine or methionine concentrations are identified in a primary newborn screen
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology. ...
Common causes include poor absorption from the stomach or intestines, decreased intake, and increased requirements.[1] Decreased absorption may be due to pernicious anemia, surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications, and some genetic disorders.[1] Decreased intake may occur in vegetarians or people who are malnourished.[1][7] Increased requirements occur in people with HIV/AIDS, and in those with rapid red blood cell breakdown.[1] Diagnosis is typically based on blood levels of vitamin B12.[2] Elevated methylmalonic acid levels may also indicate a deficiency.[2] A type of anemia known as megaloblastic anemia is often but not always present.[2]. Treatment consists of using vitamin B12 by mouth or by injection; initially in high daily doses, followed by less frequent lower doses as the condition improves.[3] If a reversible cause is found, that cause should be addressed if possible.[8] If no reversible cause is found - or when ...
OBJECTIVES: To investigate the relationship between markers of vitamin B(12) status and brain volume loss per year over a 5-year period in an elderly population. METHODS: A prospective study of 107 community-dwelling volunteers aged 61 to 87 years without cognitive impairment at enrollment. Volunteers were assessed yearly by clinical examination, MRI scans, and cognitive tests. Blood was collected at baseline for measurement of plasma vitamin B(12), transcobalamin (TC), holotranscobalamin (holoTC), methylmalonic acid (MMA), total homocysteine (tHcy), and serum folate. RESULTS: The decrease in brain volume was greater among those with lower vitamin B(12) and holoTC levels and higher plasma tHcy and MMA levels at baseline. Linear regression analysis showed that associations with vitamin B(12) and holoTC remained significant after adjustment for age, sex, creatinine, education, initial brain volume, cognitive test scores, systolic blood pressure, ApoE epsilon4 status, tHcy, and folate. Using the upper (for
Coβ-4-ethylphenyl-cob(III) alamin (EtPhCbl) is an organometallic analogue of vitamin B12 (CNCbl) which binds to transcobalamin (TC), a plasma protein that facilitates the cellular uptake of cobalamin (Cbl). In vitro assays with key enzymes do not convert EtPhCbl to the active coenzyme forms of Cbl suggesting that administration of EtPhCbl may cause cellular Cbl deficiency. Here, we investigate the in vivo effect of EtPhCbl in mice and its ability, if any, to induce Cbl deficiency. We show that EtPhCbl binds to mouse TC and we examined mice that received 3.5 nmol/24h EtPhCbl (n=6), 3.5 nmol/24h CNCbl (n=7) or NaCl (control group) (n=5) through osmotic mini-pumps for four weeks. We analyzed plasma, urine, liver, spleen, submaxillary glands and spinal cord for Cbl and markers of Cbl deficiency including methylmalonic acid (MMA) and homocysteine (tHcy). Plasma MMA (mean±SEM) was elevated in animals treated with EtPhCbl (1.01±0.12 µmol/L) compared to controls (0.30±0.02 µmol/L) and CNCbl ...
Obviously its all quite restrictive and thats a problem for school trips and things. Youve got to notify local hospitals in advance and normally get GOSH to fax my regimes and things through so I can get treatment quickly if needed. I cant go on school trips abroad - it would be too difficult for the school.. "Also, I take packed lunches to school, and when we go to restaurants, Mum has to phone ahead to explain. When we go on holiday, we have to take a load of food with us, so I cant stay in a hotel. It does restrict the type of holiday we go on.. "My family cope really well. They couldnt do anything better to adapt, theyre incredible. But MMA really isnt as bad as you might read on the internet.. "Ive been to the British Grand Prix. Id always said to Mum and Dad that I really wanted to see a Formula 1™ race, and when we came to GOSH someone showed us a poster. We filled out an application form and I got selected. I was over the moon. We went on a garage tour and I met drivers ...
Detecting disorders of Vitamin B12 and/or folic acid by determining the levels of holotranscobalamin II (A); homocysteine (B); methylmalonic acid (C) and optionally cystathionine (D).
This study was designed to assess whether symptoms, functional measures, and reported disabilities were associated with vitamin B12 (B12) deficiency when defined in three ways. Participants, aged 60 or more years of age, in 1999-2002 National Health and Nutrition Examination Surveys (NHANES) were categorized in relation to three previously used definitions of B12 deficiency: (1) serum B12 < 148 pmol/L; (2) serum B12 < 200 pmol/L and serum homocysteine > 20 μmol/L; and (3) serum B12 < 258 pmol/L or serum methylmalonic acid > 0.21 μmol/L. Functional measures of peripheral neuropathy, balance, cognitive function, gait speed, along with self-reported disability (including activities of daily living) were examined with standardized instruments by trained NHANES interviewers and technicians. Individuals identified as B12 deficient by definition 2 were more likely to manifest peripheral neuropathy OR (odds) (95% confidence intervals), p value: 9.70 (2.24, 42.07), 0.004 and report greater
Other B-complex vitamins like folate, vitamin B6, and vitamin B2 are also essential for the One-carbon pathway.. 2. Vitamin B12 acts as a coenzyme in another important reaction that is needed for myelin synthesis and stabilization. Another biochemical reaction, the conversion of methylmelonyl-CoA into succinyl CoA, also requires the coenzyme cobalamin. If this reaction does not occur, methylmalonyl-CoA gets converted to methylmalonic acid (MMA), which is a myelin destabilizer. Excess MMA leads to the synthesis of abnormal fatty acids instead of myelin. These abnormal fatty acids are incorporated into neuronal lipids leading to the formation of a fragile myelin sheath. Subsequently, abnormal myelination or demyelination occurs. The result is severe central and peripheral nervous system dysfunction.. Vitamin B12 deficiency causes various neuropsychiatric problems ranging from neuropathy to dementia in the elderly. Vitamin B12 deficiency is found to cause neurological and psychiatric problems in ...
In a study of adults aged 20 and over, researchers at Tufts University showed that homocysteine and methylmalonic acid are at much higher levels in individuals who have a combination of vitamin B12 deficiency and high blood ...
Dx: low B12, high methylmalonic acid, Schillings test (radioactive B12, binds to IF before it can be absorbed), hypersegmented PMNs on peripheral ...
A blood B12 level measurement is a very unreliable test for vegans, particularly for vegans using any form of algae. Algae and some other plant foods contain B12-analogues (false B12) that can imitate true B12 in blood tests while actually interfering with B12 metabolism. Blood counts are also unreliable as high folate intakes suppress the anaemia symptoms of B12 deficiency that can be detected by blood counts. Blood homocysteine testing is more reliable, with levels less than 10 micromol/litre being desirable. The most specific test for B12 status is methylmalonic acid (MMA) testing. If this is in the normal range in blood (,370 nmol/L) or urine (less than 4 mcg /mg creatinine) then your body has enough B12. Many doctors still rely on blood B12 levels and blood counts. These are not adequate, especially in vegans ...
This application note describes a simple, effective protocol for the extraction of methylmalonic acid (MMA) from serum using ISOLUTE® SAX strong anion exchange solid phase extraction plates, demonstrating high, reproducible analyte recoveries with low protein and phospholipid content in the extracts. Very clean extracts are possible due to the purely anion exchange retention mechanism available using this silica based sorbent. This minimizes the co-extraction of endogenous interferences through hydrophobic (or non-polar) retention. The method can be easily automated using the Biotage Extrahera. Details of the automated procedure and data comparing manual and automated method performance are included ...
Complete information for MMAA gene (Protein Coding), Methylmalonic Aciduria (Cobalamin Deficiency) CblA Type, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Among the defects in cobalamin metabolism, two complimentary groups, Cbl A and B, affect synthesis of adenosyl cobalamin. Two other groups, Cbl E and G, affect the synthesis of methyl cobalamin, which is an essential cofactor for methionine synthase, and defects result in hyperhomocysteinemia. Also, defects in Cbl C, D, and F affect synthesis of both adenosyl cobalamin and methyl cobalamin, and will therefore result in both methylmalonic acidemia and hyperhomocysteinemia ...
Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with ...
A recent case report by Traber et al in the Journal of Neuroopthalmology (August 25, 2011 Epub) describes an adult patient with methylmalonic acidemia (MMA) and sudden onset of bilateral vision loss with optic atrophy. This may not be commonly though of as a frequent adult complication of MMA. However, this sudden onset of vision loss has been described before in adults […]. ...
RAS-like GTPase Transport Protein: This protein from M. tuberculosis is a member of the Ras super family of proteins. Ras is involved in signal transduction and activating mutations in human Ras are associated with many types of cancer. While originally annotated as an arginine/ornithine transport system ATPase, we show that the protein is most likely a GTPase based on the compound (GDP) bound to the structure. The structure of the GTPase domain of the protein is similar to that of human Ras and several amino acids that line the GTP binding pocket are conserved. Ras-like GTPases use the organic chemical GTP (guanosine-5-triphosphate) as a regulator of function. During the signal transduction reaction, GTP is converted to GDP (guanosine diphosphate). GDP is shown in the figure bound to the active site of the M. tuberculosisRAS-like GTPase crystal structure. Our structure is related in sequence and structure to the methylmalonic acidemia type A protein (PDB ID 2WWW), a protein which is responsible for a
The baby seems normal at birth, but as he or she starts to eat the vomiting begins. Other symptoms might include dehydration, panting, lethargy, failure to thrive and then it gets really bad: seizures, encephalopathy and stroke. If the disease isnt picked up by a newborn screening test - usually a heel stick that produces a drop of blood for testing up to 40 disorders - terrified parents present their deteriorating baby for answers. If doctors fail to act fast, the baby may die. Speedy diagnosis is critical. Too much ammonia in the blood, a product of protein breakdown, provides a key clue. The child likely has been stricken with an inborn error of metabolism, a recessive genetic disorder that interferes with the normal digestion of food. Among the most common are the methylmalonic acidemias (MMA), affecting between one in 50,000 and 80,000 babies born in the United States. Babies that survive - and some do not - often suffer brain damage or at least cognitive impairment. Among MMA patients who ...
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Ive been tagged by these 2 hot and lovely mommas, Umma and Cecile. I also thought this tag is fun and cute so, I took a picture using my cellphone (side-view effect, hehehe). Well, it took me a few hours to post this because I need to get my daughter to school. But here it is ...
The GPR roundtable meeting is aimed at scientists, engineers and georadar/GPR users with the aim of constructively discussing and analyzing new knowledge and insights. The goal of the workshop is to spread knowledge about GPR technology and its use, as well as, to provide a unique possibility to participants to exchange ideas about the advances in their work and discuss their results. Results are presented in German and English More: Georadar Rundtisch Gespräch (GPR Roundtable meeting) …. ...
Here is an article that took me a very long time to put together last year, which I posted on transients.info (October), that I thought would be worth...
TY - JOUR. T1 - Early-onset combined methylmalonic aciduria and homocystinuria. T2 - Neuroradiologic findings. AU - Rossi, A.. AU - Cerone, R.. AU - Biancheri, R.. AU - Gatti, R.. AU - Schiaffino, M. C.. AU - Fonda, C.. AU - Zammarchi, E.. AU - Tortori-Donati, P.. PY - 2001. Y1 - 2001. N2 - BACKGROUND AND PURPOSE: Combined methylmalonic aciduria and homocystinuria (MMA-HC) is caused by impaired hepatic conversion of dietary cobalamin to methylcobalamin and adenosylcobalamin, resulting in decreased activity of methylmalonyl-CoA mutase and methionine synthase. Patients with the early-onset variety present within 12 months of age with severe neurologic, hematologic, and gastrointestinal abnormalities. We describe the neuroradiologic features of early-onset MMA-HC and discuss related pathophysiological mechanisms. METHODS: Twelve infants with hypotonia, failure to thrive, poor feeding, and hematologic abnormalities were diagnosed with MMA-HC on the basis of a typical plasmatic and urinary metabolic ...
In any vitamin B12 deficiency there is an increase in levels of methylmalonic acid, which is the main characteristic of B12 deficiency, which differentiates it from folic acid deficiency. Vegetarians should analyze what levels of methylmalonic acid present to determine possible subclinical B12 deficits.. The increase in methylmalonic acid is due to the lack of activity of the methylmalonyl-CoA mutase enzyme, which requires cobalamin (vitamin B12) as the coenzyme to produce Succinyl-CoA (which will subsequently be used to form erythrocytes).. Therefore, methylmalonic acid accumulates because Succinyl-CoA can not be formed, because of the decreased activity of the enzyme methylmalonyl-CoA mutase, which uses B12 as cofactor. This leads to decreased synthesis of the heme group (no red blood cells can be formed) and decreased gluconeogenesis.. The explanatory scheme of the reaction is as follows:. ...
Medical definition of methylmalonic acid: a structural isomer of succinic acid present in minute amounts in healthy human urine but excreted in large…
Methylmalonic acidemia (MMA) is an autosomal recessive disorder resulting in failure to process various amino acids and lipids. The classical form results in methylmalonyl CoA mutase deficiency, preventing the Vit B12-dependent conversion of methylmalonyl CoA to succinyl CoA, required in Krebs cycle. Patients typically present in early infancy with lethargy, vomiting, dehydration and failure to thrive. Long-term complications include renal failure (CRF), encephalopathy and pancreatitis. 4 cases of optic atrophy (OA) have been reported in classical MMA on appropriate dietary restrictions. The exact etiology is unknown but likely is multi-factorial. With improved survival of patients offered advanced treatment, OA needs to be identified so that prophylactic/therapeutic intervention, when available, can be incorporated into management protocols. The purpose of this observational study is to identify and determine the prevalence of OA in a small cohort of patients with classical MMA.. ...
Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations. We biochemically investigated how missense mutations in MMAA in 22 patients lead to disease. About a third confer instability to the recombinant protein in bacterial and human expression systems. All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding. However, all mutations strongly decreased functional association with MUT by ...
Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations. We biochemically investigated how missense mutations in MMAA in 22 patients lead to disease. About a third confer instability to the recombinant protein in bacterial and human expression systems. All 15 purified mutant proteins demonstrated wild-type like intrinsic GTPase activity and only one (p.Asp292Val), where the mutation is in the GTP binding domain, revealed decreased GTP binding. However, all mutations strongly decreased functional association with MUT by reducing
Pathophysiology of life-threatening acute metabolic decompensations (AMD) in propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is insufficiently understood. Here, we study the metabolomes of PA and MMA patients over time, to improve insight in which biochemical processes are at play during AMD. Longitudinal data from clinical chemistry analyses and metabolic assays over the life-course of 11 PA and 13 MMA patients were studied retrospectively. Direct-infusion high-resolution mass spectrometry was performed on 234 and 154 remnant dried blood spot and plasma samples of PA and MMA patients, respectively. In addition, a systematic literature search was performed on reported biomarkers. All results were integrated in an assessment of biochemical processes at play during AMD. We confirmed many of the metabolite alterations reported in literature, including increases of plasma valine and isoleucine during AMD in PA patients. We revealed that plasma leucine and phenylalanine, and urinary pyruvic
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