Methylmalonic acidemias

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. 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 metabolism, they are among the classical organic acidemias.
Methylmalonic acidemias have varying diagnoses, treatment requirements, and prognoses, which are determined by the specific genetic mutation causing the inherited form of the disorder.
The first symptoms may begin as early as the first day of life or as late as adulthood. Symptoms can range from mild to life-threatening. Some forms can result in death if undiagnosed or left untreated.
Methylmalonic acidemias are found with an equal frequency across ethnic boundaries.

Signs and symptoms

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

Acidosis
Cardiomyopathy
Coma
Dehydration
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. However, there are also forms that only develop symptoms in adulthood.

Cause

Genetic

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. The exception is methylmalonic acidemia and homocystinuria, cblX type due to variants in HCFC1 gene, which is inherited in an X-linked recessive manner.
The following are the known genotypes responsible for isolated methylmalonic acidemias:

Gene	Type	OMIM	Name	Prevalence	Age of onset
MCEE			Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency	<1:1,000,000	Childhood, Infancy
MMAA	cblA		Methylmalonic acidemia, vitamin B12-responsive, cblA type	<1:1,000,000	Childhood
MMAB	cblB		Methylmalonic acidemia, vitamin B12-responsive, cblB type		Childhood
MMADHC	cblDv2		Methylmalonic acidemia, cblD type, variant 2
MMUT	mut0		Methylmalonic acidemia, vitamin B12-unresponsive, mut0 type		Infancy, Neonatal
MMUT	mut-		Methylmalonic acidemia, vitamin B12-unresponsive, mut- type		Infancy, Neonatal

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:

Gene	Type	OMIM	Name	Prevalence	Age of onset
ABCD4	cblJ		Methylmalonic acidemia and homocystinuria, cblJ type	<1:1,000,000	Infancy, Neonatal
ACSF3			Combined malonic and methylmalonic aciduria	1:30,000	All ages
ALDH6A1			Methylmalonate semialdehyde dehydrogenase deficiency	<1:1,000,000	Infancy, Neonatal
AMN			Imerslund-Grasbeck syndrome 2		Childhood
CBLIF			Intrinsic factor deficiency	<1:1,000,000	Childhood
CD320	TcblR		Methylmalonic acidemia due to transcobalamin receptor defect	<1:1,000,000	Infancy, Neonatal
CUBN			Imerslund-Grasbeck syndrome 1		Childhood
HCFC1	cblX		Methylmalonic acidemia and homocystinuria, cblX type	<1:1,000,000	Infancy, Neonatal
LMBRD1	cblF		Methylmalonic acidemia and homocystinuria, cblF type	<1:1,000,000	Childhood
MLYCD			Malonic aciduria	<1:1,000,000	Childhood
MMACHC, PRDX1	cblC		Methylmalonic acidemia and homocystinuria, cblC type	1:200,000	All ages
MMADHC	cblD		Methylmalonic acidemia and homocystinuria, cblD type	<1:1,000,000	All ages
SUCLA2			SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria	<1:1,000,000	Infancy
SUCLG1			SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria		Infancy, Neonatal
TCN2			Transcobalamin-II deficiency	<1:1,000,000	Infancy, Neonatal
ZBTB11			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. 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.

Pathophysiology

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

essential amino acids: methionine, valine, threonine and isoleucine
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
acyl-CoA synthetase family member 3
methylmalonyl-CoA epimerase
enzymes involved in adenosylcobalamin synthesis

These are briefly introduced below:

Methylmalonyl-CoA mutase

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. 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.

Acyl-CoA synthetase family member 3

CMAMMA is probably the most common form of methylmalonic acidemias based on its allele frequency, but is rarely diagnosed due to slippage through routine newborn screening, wide symptom variety, and, in some cases, symptoms only appearing in adulthood. Pathogenic mutations of the ACSF3 gene lead to a defect of the mitochondrial enzyme acyl-CoA synthetase family member 3, resulting in accumulation of methylmalonic acid and malonic acid. The enzyme's dual role is the conversion of methylmalonic acid into methylmalonyl-CoA and of malonic acid into malonyl-CoA, the latter being required for mitochondrial fatty acid synthesis and mitochondrial protein malonylation. CMAMMA can therefore be defined not only as an organic acidemia but also as a defect of mitochondrial fatty acid synthesis and of protein malonylation.

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 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.

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, the mutase will be unable to function.