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 (BCAA) 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.
Signs and symptoms
Depending on the affected gene(s) and mutation, the present symptoms can range from mild to life-threatening.
- Acidosis
- Cardiomyopathy
- Coma
- Developmental delays However, there are also forms that only develop symptoms in adulthood.
The following are the known genotypes responsible for isolated methylmalonic acidemias:
|Childhood, Infancy
|Childhood
|-
|MMADHC
|cblDv2
|
|Methylmalonic acidemia, cblD type, variant 2
|
|
|-
| rowspan="2" |MMUT
|mut0
| rowspan="2" |
|Methylmalonic acidemia, vitamin B12-unresponsive, mut0 type
|
|Infancy, Neonatal
|-
|mut-
|Methylmalonic acidemia, vitamin B12-unresponsive, mut- type
|
|Infancy, Neonatal
|}</div>
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.
<div style="overflow:auto">
{| class="wikitable sortable"
|+Further methylmalonic acidemias
! Gene
! Type
! OMIM
!Name
!Prevalence
!Age of onset
|-
|ABCD4
|cblJ
|
|Methylmalonic acidemia and homocystinuria, cblJ type
|data-sort-value="1000001"| <1:1,000,000
|Infancy, Neonatal
|All ages
|-
|ALDH6A1
|
|
|Methylmalonate semialdehyde dehydrogenase deficiency
|data-sort-value="1000001"| <1:1,000,000
|Infancy, Neonatal
|-
|CBLIF
|
|
|Intrinsic factor deficiency
|data-sort-value="1000001"| <1:1,000,000
|Childhood
|Infancy, Neonatal
|Infancy, Neonatal
| cblF
|
|Methylmalonic acidemia and homocystinuria, cblF type
|data-sort-value="1000001"| <1:1,000,000
|Childhood
|Childhood
|All ages
|-
| MMADHC
| cblD
|
|Methylmalonic acidemia and homocystinuria, cblD type
|data-sort-value="1000001"| <1:1,000,000
|All ages
|Infancy
|-
|TCN2
|
|
|Transcobalamin-II deficiency
|data-sort-value="1000001"| <1:1,000,000
|Infancy, Neonatal Methylmalonyl-CoA requires vitamin B<sub>12</sub> to form succinyl-CoA. When the amount of B<sub>12</sub> 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 B<sub>12</sub> deficiency in serum.
Pathophysiology
thumb|Propionate metabolism and mitochondrial fatty acid synthesis pathways with selected types of methylmalonic acidemias highlighted at the affected enzymes or at the cofactor adenosylcobalamin.
In methylmalonic acidemias, the body is unable to break down properly:
- essential amino acids: methionine, valine, threonine and isoleucine
- propionic acid from intestinal fermentation 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. Pathogenic mutations of the ACSF3 gene lead to a defect of the mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3), resulting in accumulation of methylmalonic acid and malonic acid. 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.
Adenosylcobalamin
Also known as vitamin B<sub>12,</sub> 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 B<sub>12</sub> 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. 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.
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.
Routine & biochemical labs
Typically, the parameter methylmalonic acid is only tested if propionylcarnitine was previously elevated.
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. The ratio can then also be used to determine whether it is CMAMMA (MA<MMA) or malonic aciduria (MA>MMA).
Vitamin B<sub>12</sub> responsiveness test
The test is used for further differential diagnosis and to check the effectiveness of treatment with vitamin B<sub>12</sub>, the latter can prevent unnecessary injections (of vitamin B<sub>12</sub>) in children. For better comparability and interpretation of patient reports, Fowler et al. have developed a protocol for a standardized vitamin B<sub>12</sub> responsiveness test (in vivo):
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. 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. 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.
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. 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. By allosterically activating pantothenate kinases, BBP-671 is expected to increase the production of CoA from vitamin B<sub>5</sub> and thus normalize metabolic processes.
Prognosis
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.
Neurologic effects
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.
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. Recent 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. In contrast, fibroblasts from CMAMMA patients show numerous small, fragmented mitochondria with rounded, punctate structures, caused by dysregulated fission in the context of elevated mitochondrial β-oxidation and reactive oxygen species (ROS) production.
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.
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.