Methylmalonic acidemias

Template:Cs1 config Template:Infobox medical condition (new) Methylmalonic acidemias, also called methylmalonic acidurias,Template:Refn are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats.<ref name="MedlinePlus">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.<ref>Template:Cite journal</ref>

Methylmalonic acidemias have varying diagnoses, treatment requirements and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder.<ref name="geno">Template:Cite journal</ref>

The first symptoms may begin as early as the first day of life or as late as adulthood.<ref name="Kölker_2015">Template:Cite journal</ref> Symptoms can range from mild to life-threatening.<ref name="MedlinePlus" /> Some forms can result in death if undiagnosed or left untreated.

Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.<ref name="www.genome.gov">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Symptoms and signs

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

• Acidosis<ref name="NORD">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Cardiomyopathy<ref name="Alfares_2011">Template:Cite journal</ref><ref name="Gregg_1998">Template:Cite journal</ref>
• Coma<ref name="Sloan_2011" />
• Dehydration<ref name="MedLinePlus">Template:Cite encyclopedia</ref><ref name="NORD" /><ref name="GHR">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Developmental delays<ref name="MedLinePlus" /><ref name="NORD" /><ref name="GHR" />
• Dysmorphic features<ref name="Alfares_2011" /><ref name="Gregg_1998" />
• Encephalopathy, progressive<ref name="MedLinePlus" />
• Failure to thrive<ref name="MedLinePlus" /><ref name="NORD" /><ref name="GHR" />
• Gastrointestinal disease<ref name="Alfares_2011" /><ref name="Gregg_1998" />
• Hepatomegaly<ref name="NORD" /><ref name="GHR" />
• Hyperammonemia<ref name="NORD" />
• Hyperglycinemia<ref name="NORD" />/ Hyperglycinuria<ref name="NORD" />
• Hypoglycemia<ref name="NORD" />
• Hypotonia<ref name="NORD" /><ref name="GHR" />
• Infections, recurrent <ref name="MedLinePlus" />
• Ketonemia<ref name="NORD" />/ Ketonuria<ref name="NORD" />
• Kidney failure<ref name="MedLinePlus" /><ref name="GHR" />
• Lethargy<ref name="MedLinePlus" /><ref name="NORD" /><ref name="GHR" />
• Low concentrations of red blood cells, white blood cells and blood platelets<ref name="NORD" />
• Memory problems<ref name="Sloan_2011" />
• Pancreatitis<ref name="GHR" />
• Respiratory distress<ref name="NORD" />
• Speech delay<ref name="Sloan_2011" />
• Seizure<ref name="MedLinePlus" /><ref name="NORD" />
• Stroke<ref name="MedLinePlus" />
• Vomiting<ref name="MedLinePlus" /><ref name="NORD" /><ref name="GHR" />

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.<ref name="MedLinePlus" /> Because of this, symptoms typically manifest anytime within the first year of life.<ref name="Saini_2015">Template:Cite journal</ref> However, there are also forms that only develop symptoms in adulthood.<ref name="Kölker_2015" />

Cause

Genetic

Methylmalonic acidemia has an autosomal recessive pattern of inheritance.

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.Template:Citation needed The exception is methylmalonic acidemia and homocystinuria, cblX type due to variants in HCFC1 gene, which is inherited in an X-linked recessive manner.<ref name="Manoli_2016">Template:Cite book</ref>

The following are the known genotypes responsible for isolated methylmalonic acidemias:<ref name="Manoli_2016" />

Isolated methylmalonic acidemias

Gene	Type	OMIM	Name	Prevalence	Age of onset
MCEE		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 251120	Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency	<1:1,000,000<ref name="Orphanet_3">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Childhood, Infancy<ref name="Orphanet_3" />
MMAA	cblA	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 251100	Methylmalonic acidemia, vitamin B12-responsive, cblA type	<1:1,000,000<ref name="Orphanet_2">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Childhood<ref name="Orphanet_2" />
MMAB	cblB	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 251110	Methylmalonic acidemia, vitamin B12-responsive, cblB type		citation	CitationClass=web }}</ref>
MMADHC	cblDv2	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 277410	Methylmalonic acidemia, cblD type, variant 2
MMUT	mut0	{{#ifeq:none|none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 251000	Methylmalonic acidemia, vitamin B12-unresponsive, mut0 type		citation	CitationClass=web }}</ref>
	mut-		Methylmalonic acidemia, vitamin B12-unresponsive, mut- type		citation	CitationClass=web }}</ref>

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.<ref name="www.genome.gov" />

Furthermore, the following genes are also responsible for methylmalonic acidemias:<ref name="Manoli_2016" /><ref name="Mayo Clinic Laboratories">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Other methylmalonic acidemias

Gene	Type	OMIM	Name	Prevalence	Age of onset
ABCD4	cblJ	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 614857	Methylmalonic acidemia and homocystinuria, cblJ type	<1:1,000,000<ref name="Orphanet_8">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy, Neonatal<ref name="Orphanet_8" />
ACSF3		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 614265	Combined malonic and methylmalonic aciduria (CMAMMA)	1:30,000<ref name="Sloan_2011">Template:Cite journal</ref>	citation	CitationClass=web }}</ref>
ALDH6A1		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 614105	Methylmalonate semialdehyde dehydrogenase deficiency	<1:1,000,000<ref name="Orphanet_10">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy, Neonatal<ref name="Orphanet_10" />
AMN		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 618882	Imerslund-Grasbeck syndrome 2		citation	CitationClass=web }}</ref>
CBLIF		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 261000	Intrinsic factor deficiency	<1:1,000,000<ref name="Orphanet_13">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Childhood<ref name="Orphanet_13" />
CD320	TcblR	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 613646	Methylmalonic acidemia due to transcobalamin receptor defect	<1:1,000,000<ref name="Orphanet_7">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy, Neonatal<ref name="Orphanet_7" />
CUBN		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 261100	Imerslund-Grasbeck syndrome 1		Childhood<ref name="Orphanet_11" />
HCFC1	cblX	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 309541	Methylmalonic acidemia and homocystinuria, cblX type	<1:1,000,000<ref name="Orphanet_6">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy, Neonatal<ref name="Orphanet_6" />
LMBRD1<ref>Template:Cite journal</ref>	cblF	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 277380	Methylmalonic acidemia and homocystinuria, cblF type	<1:1,000,000<ref name="Orphanet_5">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Childhood<ref name="Orphanet_5" />
MLYCD		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 248360	Malonic aciduria	<1:1,000,000<ref name="Orphanet">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Childhood<ref name="Orphanet" />
MMACHC, PRDX1	cblC	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 277400	Methylmalonic acidemia and homocystinuria, cblC type	1:200,000<ref>Template:Cite book</ref>	citation	CitationClass=web }}</ref>
MMADHC<ref>Template:Cite journal</ref>	cblD	none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 277410	Methylmalonic acidemia and homocystinuria, cblD type	<1:1,000,000<ref name="Orphanet_4">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	All ages<ref name="Orphanet_4" />
SUCLA2		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 612073	SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria	<1:1,000,000<ref name="Orphanet_12">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy<ref name="Orphanet_12" />
SUCLG1		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 245400	SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria		citation	CitationClass=web }}</ref>
TCN2		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 275350	Transcobalamin-II deficiency	<1:1,000,000<ref name="Orphanet_9">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Infancy, Neonatal<ref name="Orphanet_9" />
ZBTB11		none	{{#switch:none	short = OMIM:	shortlink = OMIM:	plain = Online Mendelian Inheritance in Man:	full	#default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if: | - }} 618383	Autosomal recessive intellectual developmental disorder 69

Nutritional

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.<ref>Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pathophysiology

File:Methylmalonic acidemias in metabolism.svg

Methylmalonic acid metabolism including some methylmalonic acidemias

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

• essential amino acids: methionine, valine, threonine and isoleucine<ref name="Baumgartner_2014">Template:Cite journal</ref>
• propionic acid from intestinal fermentation<ref name="Baumgartner_2014" />
• odd-chain fatty acids<ref name="Baumgartner_2014" />
• cholesterol side chain<ref name="Baumgartner_2014" />

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:<ref name="NORD" /><ref name="GHR" /><ref name="Sloan_2011" />

• 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:

Methylmalonyl-CoA mutase

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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,<ref name="GHR" /> particularly this enzyme converts methylmalonyl-CoA into succinyl-CoA.<ref name="Kumbham_2022">Template:Cite journal</ref> 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.<ref name="GHR" />

Acyl-CoA synthetase family member 3

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}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.<ref name="Sloan_2011" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Sloan_2011" /> 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).<ref>Template:Cite journal</ref><ref name="Wehbe_2019">Template:Cite journal</ref> CMAMMA can therefore be defined not only as an organic acidemia but also as a defect of mitochondrial fatty acid synthesis.<ref name="Wehbe_2019" />

Methylmalonyl-CoA epimerase

Mutations in the MCEE gene, which encodes the methylmalonyl-CoA epimerase protein, also referred to as methylmalonyl racemase, will cause a much more mild 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.<ref name="GHR" /> 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.<ref>{{#ifeq:|none||{{#switch: | short = OMIM: | shortlink = OMIM: | plain = Online Mendelian Inheritance in Man: | full | #default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if:Methylmalonyl-CoA Epimerase Deficiency |Methylmalonyl-CoA Epimerase Deficiency - }} 251120</ref>

Adenosylcobalamin

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.<ref name="GHR" />

Diagnosis

Newborn Screening

Due to the severity and rapidity in which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemia is often included in the newborn screening exam.<ref name="MedLinePlus" /><ref>Template:Cite encyclopedia</ref> 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.<ref name="Manoli_2016" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="Sloan_2011" /><ref name="Manoli_2016" /> The autosomal recessive intellectual development disorder 69 also has normal propionylcarnitine levels.<ref name="Manoli_2016" /> Methylmalonic acidemia and homocystinuria, cblC type, if mild and with late onset, can also slip through.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Routine & biochemical labs

Typically, the parameter methylmalonic acid is only tested if propionylcarnitine was previously elevated.<ref>Template:Cite journal</ref>

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 used as the main diagnostic criteria for diagnosing the disorder. This disorder is typically determined through the use of a urine analysis or blood panel.<ref name="Saini_2015" /> Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.<ref name="NORD" />

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.<ref name="de Sain-van der Velden_2016">Template:Cite journal</ref> The ratio can then also be used to determine whether it is CMAMMA (MA<MMA) or malonic aciduria (MA>MMA).<ref name="de Sain-van der Velden_2016" /><ref name="Alfares_2011" /><ref>Template:Cite journal</ref>

Vitamin B₁₂ responsiveness test

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.<ref name="Fowler_2008">Template:Cite journal</ref> For better comparability and interpretation of patient reports, Fowler et al. have developed a protocol for a standardized vitamin B₁₂ responsiveness test (in vivo):<ref name="Fowler_2008" />

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 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 GCMS.
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.<ref name="Manoli_2016" /><ref name="Fowler_2008" /> It can provide some insights, but it cannot always correctly predict in vivo vitamin B₁₂ responsiveness.<ref name="Manoli_2016" />

Molecular genetic testing

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, easier accessibility and non-invasiveness, molecular genetic tests replace enzyme assays in most cases.<ref name="Manoli_2016" /> 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.<ref name="Manoli_2016" /><ref name="Mayo Clinic Laboratories" /> 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.<ref name="Manoli_2016" />

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.<ref>Template:Cite journal</ref>

Other

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.<ref name="MedLinePlus" />

Differential diagnosis path<ref name="Manoli_2016" />

Methylmalonic acid levels	Homocysteine levels	Differential diagnosis	Next diagnostics	Vitamin B12 response (in vivo)		Differential diagnosis	Next diagnostics
				Methylmalonic acid levels	Homocysteine levels
Very high	Normal	mut0, mut-, cblA, cbIB, cblDv2	Vitamin B12 response (in vivo)	Unresponsive		mut0, mut-, cbIB	Molecular genetic testing, enzyme assay, 14C propionate incorporation, cobalamin complementation studies
				Responsive (reduction of >50% or normal levels)		cbIA, cbIB, cbIDv2, mut-?
High		MCEE, TcbIR, SUCLG1/A2, CMAMMA, MMSDH and other	Vitamin B12 response (in vivo), enzyme assay, molecular genetic testing	Unresponsive		MCEE, CMAMMA, and other
				Responsive (reduction of >50% or normal levels)		TcblR
	High	cblC,cbID, cblF, cblJ, cbIX, TC-II, TcbIR, B12 deficiency syndromes	Vitamin B12 response (in vivo)	High or normal	High or normal	cblC,cbID, cblF, cblJ
				Normal	Normal	TC-II, TcbIR, B12 deficiency syndromes
		False positive, maternal B12 deficiency

Treatment

Dietary

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, 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.<ref name="pmid82069">Template:Cite journal</ref> 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.<ref name="MedLinePlus" /> CblA und cblB versions of methylmalonic acidemia have been found to be cobalamin responsive.Template:Cn

Surgical

A more extreme treatment includes 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.<ref name="MedLinePlus" /> 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 previous to the transplant or prevent further damage to the brain by continued build up.<ref name="OMIM_ 251000" /><ref name="Kumbham_2022" />

mRNA therapeutics

Preclinical proof-of-concept studies in animal models have shown that mRNA therapy is also suitable for rare metabolic diseases, including isolated methylmalonic acidemia.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Small molecular therapeutics

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.<ref>Template:Cite journal</ref><ref name="Armstrong_2021">Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Armstrong_2021" /> 

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.<ref>Template:Cite journal</ref> By allosterically activating pantothenate kinases, BBP-671 is expected to increase the production of CoA from vitamin B₅ and thus normalize metabolic processes.<ref>Template:Cite journal</ref>

Prognosis

Though there are not 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.<ref name="MedLinePlus" />

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 noncobalamin-responsive variants.<ref name="Kumbham_2022" /> Milder variants have a higher frequency of appearance in the population than the more severe ones.<ref name="Saini_2015" /> Even with dietary modification and continued medical care, it may not be possible to prevent neurological damage in those with a nonresponsive acidemia.<ref name="Kumbham_2022" /> Without proper treatment or diagnosis, it is not uncommon for the first acidemic attack to be fatal.<ref name="MedLinePlus" />

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.<ref name="OMIM_ 251000" />

Research

Nosologic history

The first methylmalonic acidemia was characterized by Oberholzer et al. in 1967.<ref>Template:Cite journal</ref><ref name="OMIM_ 251000">{{#ifeq:|none||{{#switch: | short = OMIM: | shortlink = OMIM: | plain = Online Mendelian Inheritance in Man: | full | #default = Online Mendelian Inheritance in Man (OMIM):}}}} {{#if:Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase deficiency |Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase deficiency - }} 251000</ref>

Neurologic effects

That methylmalonic acid can have disastrous effects on the nervous system has been long 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.<ref name=":0" /> These tests have suggested that methylmalonic acid causes decreases in cellular size and increase in the rate of cellular apoptosis in a concentration dependent manner with more extreme effects being seen at higher concentrations.<ref name=":0" /> 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.<ref name=":0">Template:Cite journal</ref>

Mitochondrial dysfunction

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. RecentTemplate:When research has found that in rat models mitochondria of rats affected by the disorder grow to unusual size, dubbed megamitochondria. These megamitochondria also appear to have deformed internal structures and a loss in 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.<ref>Template:Cite journal</ref>

Benign mut phenotype

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.<ref name=":1" /> 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 near completely asymptomatic version of methylmalonic acidemia.<ref name=":1" /> Despite consistently showing elevated methylmalonic acid in the blood and urine, these individuals appeared for the large part developmentally normal.<ref name=":1">Template:Cite journal</ref>

Notable cases

• 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.<ref name="OMIM_ 251000" />

See also

• Isovaleric acidemia
• Propionic acidemia
• Maple syrup urine disease