methylmalonic acidemias

Depending on the affected gene(s) and mutation, the present symptoms can range from mild to life-threatening.

• Acidosis{{Cite web |title=Acidemia, Methylmalonic |url=https://rarediseases.org/rare-diseases/acidemia-methylmalonic/ |access-date=2015-10-29 |publisher=NORD (National Organization for Rare Disorders)}}
• Cardiomyopathy{{Cite journal |vauthors=Alfares A, Nunez LD, Al-Thihli K, Mitchell J, Melançon S, Anastasio N, Ha KC, Majewski J, Rosenblatt DS, Braverman N |date=September 2011 |title=Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype |journal=Journal of Medical Genetics |volume=48 |issue=9 |pages=602–605 |doi=10.1136/jmedgenet-2011-100230 |pmid=21785126 |doi-access=free}}{{Cite journal |vauthors=Gregg AR, Warman AW, Thorburn DR, O'Brien WE |date=June 1998 |title=Combined malonic and methylmalonic aciduria with normal malonyl-coenzyme A decarboxylase activity: a case supporting multiple aetiologies |journal=Journal of Inherited Metabolic Disease |volume=21 |issue=4 |pages=382–390 |doi=10.1023/A:1005302607897 |pmid=9700595}}
• Coma
• Dehydration{{Cite encyclopedia |title=Methylmalonic acidemia |encyclopedia=MedlinePlus Medical Encyclopedia |publisher=US National Library of Medicine |url=https://medlineplus.gov/ency/article/001162.htm |access-date=2024-05-01}}{{Cite web |date=2015-10-26 |title=Methylmalonic acidemia |url=https://medlineplus.gov/genetics/condition/methylmalonic-acidemia/ |access-date=2015-11-02 |website=Genetics Home Reference |publisher=US National Library of Medecine}}
• Developmental delays
• Dysmorphic features
• Encephalopathy, progressive
• Failure to thrive
• Gastrointestinal disease
• Hepatomegaly
• Hyperammonemia
• Hyperglycinemia/ Hyperglycinuria
• Hypoglycemia
• Hypotonia
• Infections, recurrent
• Ketonemia/ Ketonuria
• Kidney failure
• Lethargy
• Low concentrations of red blood cells, white blood cells and blood platelets
• Memory problems
• Pancreatitis
• Respiratory distress
• Speech delay
• Seizure
• Stroke
• Vomiting

As a rule, methylmalonic acidemias are not apparent at birth as symptoms do not present themselves until proteins are added to the infant's diet. Because of this, symptoms typically manifest anytime within the first year of life.{{Cite journal |vauthors=Saini N, Malhotra A, Chhabra S, Chhabra S |date=March 2015 |title=Methylmalonic acidemia mimicking diabetic ketoacidosis and septic shock in infants |journal=Indian Journal of Critical Care Medicine |volume=19 |issue=3 |pages=183–185 |doi=10.4103/0972-5229.152776 |pmc=4366921 |pmid=25810618 |doi-access=free}} However, there are also forms that only develop symptoms in adulthood.

Methylmalonic acidemia has an autosomal recessive pattern of [[inheritance.|152x152px|border|right]]

Methylmalonic acidemias have an autosomal recessive inheritance pattern, which means the defective gene is located on an autosome, and two copies of the gene—one from each parent—must be inherited to be affected by the disorder. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.{{citation needed|date=October 2021}} The exception is methylmalonic acidemia and homocystinuria, cblX type due to variants in HCFC1 gene, which is inherited in an X-linked recessive manner.{{Cite book |title=GeneReviews® [Internet] |vauthors=Manoli I, Sloan JL, Venditti CP |date=2016 |publisher=University of Washington |veditors=Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A |chapter=Isolated Methylmalonic Acidemia |pmid=20301409 |id=NBK1231 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1231/}}

The following are the known genotypes responsible for isolated methylmalonic acidemias:

The mut type can further be divided into mut0 and mut- subtypes, with mut0 characterized by a complete lack of methylmalonyl-CoA mutase and more severe symptoms and mut- characterized by a decreased amount of mutase activity.

Furthermore, the following genes are also responsible for methylmalonic acidemias:{{Cite web |title=Methylmalonic Aciduria Gene Panel, Varies |url=https://www.mayocliniclabs.com/test-catalog/overview/608021 |access-date=2024-05-26 |website=Mayo Clinic Laboratories}}

Though not always grouped together with the inherited versions, a severe nutritional vitamin B₁₂ deficiency can also result in syndrome with identical symptoms and treatments as the genetic methylmalonic acidemias.{{Cite journal |vauthors=Higginbottom MC, Sweetman L, Nyhan WL |date=August 1978 |title=A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian |journal=The New England Journal of Medicine |volume=299 |issue=7 |pages=317–323 |doi=10.1056/NEJM197808172990701 |pmid=683264}} Methylmalonyl-CoA requires vitamin B₁₂ to form succinyl-CoA. When the amount of B₁₂ is insufficient for the conversion of cofactor methylmalonyl-CoA into succinyl-CoA, the buildup of unused methylmalonyl-CoA eventually leads to methylmalonic acidemia. This diagnosis is often used as an indicator of vitamin B₁₂ deficiency in serum.{{Cite web |date=31 January 2000 |title=Vitamin B₁₂ deficiency - The methylmalonic aciduria connection |url=http://www.biology.arizona.edu/biochemistry/problem_sets/b12/04t.html |archive-url=https://web.archive.org/web/20180615083350/http://www.biology.arizona.edu/biochemistry/problem_sets/b12/04t.html |archive-date=15 June 2018 |website=The Biology Project |publisher=Department of Biochemistry and Molecular Biophysics, The University of Arizona}}

File:Methylmalonic acidemias in metabolism.svg

In methylmalonic acidemias, the body is unable to break down properly:

• essential amino acids: methionine, valine, threonine and isoleucine{{Cite journal |vauthors=Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A |date=September 2014 |title=Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia |journal=Orphanet Journal of Rare Diseases |volume=9 |issue=1 |pages=130 |doi=10.1186/s13023-014-0130-8 |pmc=4180313 |pmid=25205257 |doi-access=free}}
• propionic acid from intestinal fermentation
• odd-chain fatty acids
• cholesterol side chain

As a result, methylmalonic acid builds up in liquids and tissues. Those afflicted with this disorder are either lacking functional copies or adequate levels of one or more of the following enzymes:

• methylmalonyl-CoA mutase (MUT)
• acyl-CoA synthetase family member 3 (ACSF3)
• methylmalonyl-CoA epimerase (MCEE)
• enzymes involved in adenosylcobalamin synthesis

These are briefly introduced below:

{{Main|Methylmalonyl-CoA mutase deficiency}}

It is estimated that as many as 60% of isolated methylmalonic acidemia cases are the result of a mutated MMUT gene, which encodes the protein methylmalonyl-CoA mutase. This enzyme is responsible for the digestion of potentially toxic derivatives of the breakdown of the above-mentioned amino acids and fats, primarily cholesterol, particularly this enzyme converts methylmalonyl-CoA into succinyl-CoA.{{Cite journal |vauthors=Kumbham P, Mandava P, Zweifler RM, Kent TA, Nelson Jr SL, Gerstein BY |date=19 September 2022 |title=Methylmalonic Acidemia |url=https://emedicine.medscape.com/article/1161799-overview |journal=EMedicine |veditors=Talavera F, Kirshner HS, Lutsep HL}} Without this enzyme, the body has no means to neutralize or remove methylmalonic acid and related compounds. The action of this enzyme can also be crippled by mutations in the MMAA, MMAB, and MMADHC genes, each of which encodes a protein required for normal functioning of methylmalonyl-CoA mutase.

{{Main|Combined malonic and methylmalonic aciduria}}CMAMMA is probably the most common form of methylmalonic acidemias, but is rarely diagnosed due to slippage through routine newborn screening, wide symptom variety, and, in some cases, symptoms only appearing in adulthood.{{Cite web |title=NHGRI researchers serve up mysterious disease diagnosis - three ways |url=https://www.genome.gov/27545060/2011-news-feature-nhgri-researchers-serve-up-mysterious-disease-diagnosis--three-ways |access-date=2024-04-28 |website=National Human Genome Research Institute}} Mutations of the ACSF3 gene leads to a deficiency of the mitochondrial enzyme acyl-CoA synthetase family member 3, resulting in increased levels of methylmalonic acid and malonic acid. Since the enzyme's task is both the conversion of methylmalonic acid into methylmalonyl-CoA, so that it can be fed into the citric acid cycle, and the conversion of malonic acid into malonyl-CoA, which is the first step in mitochondrial fatty acid synthesis (mtFAS).{{Cite journal |vauthors=Gabriel MC, Rice SM, Sloan JL, Mossayebi MH, Venditti CP, Al-Kouatly HB |date=April 2021 |title=Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria |journal=Molecular Genetics & Genomic Medicine |volume=9 |issue=4 |pages=e1621 |doi=10.1002/mgg3.1621 |pmc=8123733 |pmid=33625768}}{{Cite journal |vauthors=Wehbe Z, Behringer S, Alatibi K, Watkins D, Rosenblatt D, Spiekerkoetter U, Tucci S |date=November 2019 |title=The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1864 |issue=11 |pages=1629–1643 |doi=10.1016/j.bbalip.2019.07.012 |pmid=31376476}} CMAMMA can therefore be defined not only as an organic acidemia but also as a defect of mitochondrial fatty acid synthesis.

Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much milder form of the disorder than the related methylmalonyl-CoA mutase variant. Like the mutase, the epimerase also functions in breaking down the same substances, but to a significantly lesser extent than the mutase does. The phenotypic differences caused by a deficiency of the epimerase as opposed to the mutase are so mild that there is debate within the medical community as to whether or not this genetic deficiency can be considered a disorder or clinical syndrome.{{OMIM|251120|Methylmalonyl-CoA Epimerase Deficiency}}

Also known as vitamin B_12, this form of cobalamin is a required cofactor of methylmalonyl-CoA mutase. Even with a functional version of the enzyme at physiologically normal levels, if B₁₂ cannot be converted to this active form (due to defects in the Adenosylcobalamin synthesis system or cobalamin transporters), the mutase will be unable to function.

Due to the severity and rapidity with which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemia is often included in the newborn screening exam.{{Cite encyclopedia |title=Newborn screening tests |encyclopedia=MedlinePlus Medical Encyclopedia |publisher=Division of Neonatology, Medical University of South Carolina |url=https://medlineplus.gov/ency/article/007257.htm |access-date=April 26, 2016 |vauthors=Lee KG}} For this purpose, a dried blood spot test for the parameter propionylcarnitine (C3) is carried out at the age of 24–48 hours in order to detect isolated methylmalonic acidemias.{{Cite web |title=Newborn Screening Process |url=https://newbornscreening.hrsa.gov/newborn-screening-process |access-date=2024-05-11 |website=Health Resources and Services Administration (HRSA)}}

Due to normal propionylcarnitine levels and asymptomatic symptoms at the time of testing, the probably most common form of methylmalonic acidemias, CMAMMA, slips through the newborn screening. The autosomal recessive intellectual development disorder 69 also has normal propionylcarnitine levels. Methylmalonic acidemia and homocystinuria, cblC type, if mild and with late onset, can also slip through.{{Cite web |date=2023-09-15 |title=Organic acidurias - I |url=https://www.simd.org/MBG-CCSS/2023-09-15/Manoli_MMA_Cbl_MBG_CCSS_09_15_2023_Final.pdf |website=Society for Inherited Metabolic Disorders |vauthors=Manoli I}}

Typically, the parameter methylmalonic acid is only tested if propionylcarnitine was previously elevated.{{Cite journal |vauthors=Held PK, Singh E, Scott Schwoerer J |date=February 2022 |title=Screening for Methylmalonic and Propionic Acidemia: Clinical Outcomes and Follow-Up Recommendations |journal=International Journal of Neonatal Screening |volume=8 |issue=1 |pages=13 |doi=10.3390/ijns8010013 |pmc=8883915 |pmid=35225935 |doi-access=free}}

Because of the inability to properly break down amino acids completely, the byproduct of protein digestion, the compound methylmalonic acid, is found in a disproportionate concentration in the blood and urine of those afflicted. These abnormal levels are the main diagnostic criterion for diagnosing the disorder. This disorder is typically determined through the use of a urine analysis or blood panel. Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.

With the inclusion of the parameter malonic acid, CMAMMA can be quickly differentiated from classic methylmalonic acidemia by calculating the ratio of malonic acid to methylmalonic acid, but only with values from the blood plasma and not from the urine.{{Cite journal |vauthors=de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, van Gassen KL, van Hasselt PM |date=2016 |title=A New Approach for Fast Metabolic Diagnostics in CMAMMA |journal=JIMD Reports |publisher=Springer Berlin Heidelberg |volume=30 |pages=15–22 |doi=10.1007/8904_2016_531 |isbn=978-3-662-53680-3 |pmc=5110436 |pmid=26915364 |veditors=Morava E, Baumgartner M, Patterson M, Rahman S |place=Berlin, Heidelberg}} The ratio can then also be used to determine whether it is CMAMMA (MAmalonic aciduria (MA>MMA).{{Cite journal |vauthors=de Wit MC, de Coo IF, Verbeek E, Schot R, Schoonderwoerd GC, Duran M, de Klerk JB, Huijmans JG, Lequin MH, Verheijen FW, Mancini GM |date=February 2006 |title=Brain abnormalities in a case of malonyl-CoA decarboxylase deficiency |journal=Molecular Genetics and Metabolism |volume=87 |issue=2 |pages=102–106 |doi=10.1016/j.ymgme.2005.09.009 |pmid=16275149}}

The test is used for further differential diagnosis and to check the effectiveness of treatment with vitamin B₁₂, the latter can prevent unnecessary injections (of vitamin B₁₂) in children.{{Cite journal |vauthors=Fowler B, Leonard JV, Baumgartner MR |date=June 2008 |title=Causes of and diagnostic approach to methylmalonic acidurias |url=http://doc.rero.ch/record/316232/files/10545_2008_Article_839.pdf |journal=Journal of Inherited Metabolic Disease |volume=31 |issue=3 |pages=350–360 |doi=10.1007/s10545-008-0839-4 |pmid=18563633}} For better comparability and interpretation of patient reports, Fowler et al. have developed a protocol for a standardized vitamin B₁₂ responsiveness test (in vivo):

1. Metabolically stable and on the same treatment for at least a month. Specify energy and protein intake.
2. Stop vitamin B₁₂ at least one month before. If worsening, discontinue and resume administration of vitamin B₁₂.
3. For baseline, collect urine from 3 different days. Blood plasma concentrations can also be used if the test is sensitive enough.
4. Intramuscular injection of 1 mg hydroxocobalamin on 3 consecutive days.
5. After injection, collect urine or plasma samples on alternate days for 10 days.
6. The urine or plasma samples should be analyzed in the same run by GC-MS.
7. If the mean urine or plasma concentration of methylmalonic acid decreases by more than 50%, it is vitamin B₁₂ responsive.

Furthermore, vitamin B₁₂ responsiveness can also be tested in vitro. It can provide some insights, but it cannot always correctly predict in vivo vitamin B₁₂ responsiveness.

The final diagnosis is confirmed by molecular genetic testing if biallelic pathogenic variants are found in the affected gene(s). Due to their high sensitivity, accessibility, and non-invasiveness, molecular genetic tests have replaced enzyme assays in most cases. There are specific multigene panels for methylmalonic acidemia, but the particular genes tested may vary from laboratory to laboratory and can be customized by the clinician to the individual phenotype. The molecular genetic methods used in these panels range from sequence analysis, deletion/duplication analysis and other non-sequencing based tests, but in the vast majority of cases the diagnosis is made by sequence analysis.

Furthermore, molecular genetic tests are necessary to check suspected diagnoses and correct misdiagnoses that may have been caused by misleading symptoms and results of the vitamin B₁₂ responsiveness test.{{Cite journal |vauthors=Brennerová K, Škopková M, Ostrožlíková M, Šaligová J, Staník J, Bzdúch V, Gašperíková D |date=December 2021 |title=Genetic testing is necessary for correct diagnosis and treatment in patients with isolated methylmalonic aciduria: a case report |journal=BMC Pediatrics |volume=21 |issue=1 |pages=578 |doi=10.1186/s12887-021-03067-3 |pmc=8675494 |pmid=34915869 |doi-access=free}}

The presence of methylmalonic acidemia can also be suspected through the use of a CT or MRI scan, however, these tests are by no means specific and require clinical and metabolic/correlation.

Treatment for all forms of this condition primarily relies on a low-protein diet, and depending on what variant of the disorder the individual suffers from, various dietary supplements. All variants respond to the levo isomer of carnitine as the improper breakdown of the affected substances results in sufferers developing a carnitine deficiency. The carnitine also assists in the removal of acyl-CoA, a buildup of which is common in low-protein diets, by converting it into acyl-carnitine, which can be excreted in urine. Some forms of methylmalonyl acidemia are responsive to cobalamin, although cyanocobalamin supplements could prove detrimental to some forms.{{Cite journal |vauthors=Linnell JC, Matthews DM, England JM |date=November 1978 |title=Therapeutic misuse of cyanocobalamin |journal=Lancet |volume=2 |issue=8098 |pages=1053–1054 |doi=10.1016/s0140-6736(78)92379-6 |pmid=82069 |s2cid=29703726}} If the individual proves responsive to both cobalamin and carnitine supplements, then it may be possible for them to ingest substances that include small amounts of the problematic amino acids isoleucine, threonine, methionine, and valine without causing an attack. CblA und cblB versions of methylmalonic acidemia are cobalamin-responsive.{{cn|date=October 2024}}

A more extreme treatment includes a kidney or liver transplant from a donor without the condition. The foreign organs will produce a functional version of the defective enzymes and digest the methylmalonic acid, however all of the disadvantages of organ transplantation are of course applicable in this situation. There is evidence to suggest that the central nervous system may metabolize methylmalonyl-CoA in a system isolated from the rest of the body. If this is the case, transplantation may not reverse the neurological effects of methylmalonic acid before the transplant or prevent further damage to the brain by continued buildup.

Preclinical proof-of-concept studies in animal models have shown that mRNA therapy is also suitable for rare metabolic diseases, including isolated methylmalonic acidemia.{{Cite journal |vauthors=An D, Schneller JL, Frassetto A, Liang S, Zhu X, Park JS, Theisen M, Hong SJ, Zhou J, Rajendran R, Levy B, Howell R, Besin G, Presnyak V, Sabnis S, Murphy-Benenato KE, Kumarasinghe ES, Salerno T, Mihai C, Lukacs CM, Chandler RJ, Guey LT, Venditti CP, Martini PG |date=December 2017 |title=Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia |journal=Cell Reports |volume=21 |issue=12 |pages=3548–3558 |doi=10.1016/j.celrep.2017.11.081 |pmc=9667413 |pmid=29262333}}{{Cite journal |vauthors=Martini PG, Guey LT |date=October 2019 |title=A New Era for Rare Genetic Diseases: Messenger RNA Therapy |journal=Human Gene Therapy |volume=30 |issue=10 |pages=1180–1189 |doi=10.1089/hum.2019.090 |pmid=31179759}} In this context, the mut methylmalonic acidemia therapy candidate mRNA-3705 from the biotechnology company Moderna, which is currently in phase 1/2, is worth mentioning.{{Cite web |title=A Clinical Trial of a Methylmalonic Acidemia (MMA) Due to MUT Deficiency Treatment for Children and Adults |url=https://trials.modernatx.com/study/?id=mRNA-3705-P101 |access-date=2024-01-04}}

The investigational small molecular therapeutic HST5040 from HemoShear Therapeutics for methylmalonic aciduria and propionic aciduria, which is currently in phase 2, should be mentioned here.{{Cite journal |date=3 January 2024 |title=Study of HST5040 in Subjects With Propionic or Methylmalonic Acidemia (HERO) |url=https://clinicaltrials.gov/study/NCT04732429 |access-date=2024-05-24 |website=ClinicalTrials.gov}}{{Cite journal |vauthors=Armstrong AJ, Collado MS, Henke BR, Olson MW, Hoang SA, Hamilton CA, Pourtaheri TD, Chapman KA, Summar MM, Johns BA, Wamhoff BR, Reardon JE, Figler RA |date=May 2021 |title=A novel small molecule approach for the treatment of propionic and methylmalonic acidemias |journal=Molecular Genetics and Metabolism |volume=133 |issue=1 |pages=71–82 |doi=10.1016/j.ymgme.2021.03.001 |pmc=9109253 |pmid=33741272}} Taken daily orally or by gastric tube, it is designed to prevent toxic accumulation of propionyl-CoA and methylmalonyl-CoA or their derivatives by shunting CoA away from the propionyl-CoA pathway, leading to normal or near-normal levels of these metabolites and potentially improving metabolic state and energy-producing pathways.{{Cite web |title=HST5040 Overview |url=https://hemoshear.com/ht-admin/resources/hemoshear-factsheet.pdf |access-date=2024-05-26 |website=HemoShera}} 

Another small molecule therapeutic in development is BBP-671 from BridgeBio Pharma for pantothenate kinase-associated neurodegeneration (PKAN), propionic and methylmalonic acidemia, which is currently in phase 1.{{Cite journal |date=20 December 2023 |title=A First in Human, Dose Escalation Study to Evaluate the Safety and Tolerability of BBP-671 in Healthy Volunteers and Patients With Propionic Acidemia or Methylmalonic Acidemia |url=https://clinicaltrials.gov/study/NCT04836494 |access-date=2024-05-26 |website=ClinicalTrials.gov}} By allosterically activating pantothenate kinases, BBP-671 is expected to increase the production of CoA from vitamin B₅ and thus normalize metabolic processes.{{Cite journal |vauthors=Subramanian C, Frank MW, Sukhun R, Henry CE, Wade A, Harden ME, Rao S, Tangallapally R, Yun MK, White SW, Lee RE, Sinha U, Rock CO, Jackowski S |date=January 2024 |title=Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=388 |issue=1 |pages=171–180 |doi=10.1124/jpet.123.001919 |pmid=37875310|doi-access=free }}

Though there are no distinct stages of the disease, methylmalonic acidemia is a progressive condition; the symptoms of this disorder are compounded as the concentration of methylmalonic acid increases. If the triggering proteins and fats are not removed from the diet, this buildup can lead to irreparable kidney or liver damage and eventually death.

The prognosis will vary depending on the severity of the condition and the individual's response to treatment. Prognosis is typically better for those with cobalamin-responsive variants and not promising in those suffering from non-cobalamin-responsive variants. Milder variants have a higher frequency of appearance in the population than the more severe ones. Even with dietary modification and continued medical care, it may not be possible to prevent neurological damage in those with a nonresponsive acidemia. Without proper treatment or diagnosis, it is not uncommon for the first acidemic attack to be fatal.

Despite these challenges, since it was first identified in 1967, treatment and understanding of the condition has improved to the point where it is not unheard of for even those with unresponsive forms of methylmalonic acidemia to be able to reach adulthood and even carry and deliver children safely.

The first methylmalonic acidemia was characterized by Oberholzer et al. in 1967.{{Cite journal |vauthors=Oberholzer VG, Levin B, Burgess EA, Young WF |date=October 1967 |title=Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis |journal=Archives of Disease in Childhood |volume=42 |issue=225 |pages=492–504 |doi=10.1136/adc.42.225.492 |pmc=2019805 |pmid=6061291}}{{OMIM|251000|Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase deficiency}}

That methylmalonic acid can have disastrous effects on the nervous system has long been reported; however, the mechanism by which this occurs has never been determined. Published in 2015, research performed on the effects of methylmalonic acid on neurons isolated from fetal rats in an in vitro setting using a control group of neurons treated with an alternate acid of similar pH. These tests have suggested that methylmalonic acid causes decreases in cellular size and an increase in the rate of cellular apoptosis in a concentration-dependent manner, with more extreme effects being seen at higher concentrations. Furthermore, micro-array analysis of these treated neurons have also suggested that on an epigenetic-level methylmalonic acid alters the transcription rate of 564 genes, notably including those involved in the apoptosis, p53, and MAPK signaling pathways.{{Cite journal |vauthors=Han L, Wu S, Han F, Gu X |date=Jun 15, 2015 |title=Insights into the molecular mechanisms of methylmalonic acidemia using microarray technology |journal=International Journal of Clinical and Experimental Medicine |volume=8 |issue=6 |pages=8866–8879 |pmc=4538064 |pmid=26309541}}

As the conversion of methylmalonyl-CoA to succinyl-CoA takes place inside the mitochondria, mitochondrial dysfunction as a result of diminished electron transport chain function has long been suspected as a feature in methylmalonic acidemias. Recent{{When|date=December 2015}} research has found that in rat models, mitochondria of rats affected by the disorder grow to an unusual size, dubbed megamitochondria. These megamitochondria also appear to have deformed internal structures and a loss of electron richness in their matrix. These megamitochondria also showed signs of decreased respiratory chain function, particularly in respiratory complex IV, which only functioned at about 50% efficiency. Similar changes were identified in the mitochondria of a liver sample removed during transplant from a 5-year-old boy suffering from methylmalonic acidemia mut type.{{Cite journal |vauthors=Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP |date=April 2009 |title=Mitochondrial dysfunction in mut methylmalonic acidemia |journal=FASEB Journal |volume=23 |issue=4 |pages=1252–1261 |doi=10.1096/fj.08-121848 |pmc=2660647 |pmid=19088183 |doi-access=free}}

Case studies in several patients presenting nonresponsive mut0 methylmalonic acidemia with a specific mutation designated p.P86L have suggested the possibility of further subdivision in mut type methylmalonic acidemia might exist. Though currently unclear if this is due to the specific mutation or early detection and treatment, despite complete nonresponse to cobalamin supplements, these individuals appeared to develop a largely benign and nearly completely asymptomatic version of methylmalonic acidemia. Despite consistently showing elevated methylmalonic acid in the blood and urine, these individuals appeared, for the most part, developmentally normal.{{Cite journal |vauthors=Underhill HR, Hahn SH, Hale SL, Merritt JL |date=December 2013 |title=Asymptomatic methylmalonic acidemia in a homozygous MUT mutation (p.P86L) |journal=Pediatrics International |volume=55 |issue=6 |pages=e156–e158 |doi=10.1111/ped.12195 |pmid=24330302 |s2cid=27495325}}

• Ryan Stallings, a St. Louis infant, was mistakenly diagnosed with ethylene glycol poisoning instead of methylmalonic acidemia in 1989, leading to a wrongful murder conviction and life sentence for his mother, Patricia Stallings.

• Isovaleric acidemia
• Propionic acidemia
• Maple syrup urine disease

{{Reflist|group=note}}

{{Reflist}}

{{Medical resources

| DiseasesDB = 29509

| ICD10 = {{ICD10|E|71|1|e|70}}

| ICD9 = {{ICD9|270.3}}

| ICDO =

| OMIM = 251000

| OMIM_mult = {{OMIM|251100||none}} {{OMIM|251110||none}} {{OMIM|277380||none}} {{OMIM|277400||none}} {{OMIM|277410||none}} {{OMIM|606169||none}}

| MedlinePlus = 001162

| eMedicineSubj = neuro

| eMedicineTopic = 576

| MeshID =

| ICD10CM = {{ICD10CM|E71.120}}

}}

{{Amino acid metabolic pathology}}

{{Metabolic disorders of vitamins, coenzymes, and cofactors}}

Category:Autosomal recessive disorders

Category:Amino acid metabolism disorders

Category:Rare diseases

Category:Vitamin, coenzyme, and cofactor metabolism disorders