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. 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(s) 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: +Isolated methylmalonic acidemiasGeneTypeOMIMNamePrevalenceAge of onsetMCEEMethylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency <1:1,000,000Childhood, InfancyMMAAcblAMethylmalonic acidemia, vitamin B12-responsive, cblA type <1:1,000,000ChildhoodMMABcblBMethylmalonic acidemia, vitamin B12-responsive, cblB typeChildhoodMMADHCcblDv2Methylmalonic acidemia, cblD type, variant 2MMUTmut0Methylmalonic acidemia, vitamin B12-unresponsive, mut0 typeInfancy, Neonatalmut-Methylmalonic acidemia, vitamin B12-unresponsive, mut- typeInfancy, 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:
+Further methylmalonic acidemias Gene Type OMIMNamePrevalenceAge of onsetABCD4cblJ Methylmalonic acidemia and homocystinuria, cblJ type <1:1,000,000Infancy, NeonatalACSF3 Combined malonic and methylmalonic aciduria (CMAMMA) 1:30,000All agesALDH6A1 Methylmalonate semialdehyde dehydrogenase deficiency <1:1,000,000Infancy, NeonatalAMN Imerslund-Grasbeck syndrome 2ChildhoodCBLIF Intrinsic factor deficiency <1:1,000,000ChildhoodCD320TcblR Methylmalonic acidemia due to transcobalamin receptor defect <1:1,000,000Infancy, NeonatalCUBN Imerslund-Grasbeck syndrome 1ChildhoodHCFC1cblX Methylmalonic acidemia and homocystinuria, cblX type <1:1,000,000Infancy, Neonatal LMBRD1 cblF Methylmalonic acidemia and homocystinuria, cblF type <1:1,000,000ChildhoodMLYCD Malonic aciduria <1:1,000,000Childhood MMACHC, PRDX1 cblC Methylmalonic acidemia and homocystinuria, cblC type 1:200,000All ages MMADHC cblD Methylmalonic acidemia and homocystinuria, cblD type <1:1,000,000All agesSUCLA2 SUCLA2-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria <1:1,000,000InfancySUCLG1 SUCLG1-related mtDNA depletion syndrome, encephalomyopathic form with methylmalonic aciduriaInfancy, NeonatalTCN2 Transcobalamin-II deficiency <1:1,000,000Infancy, NeonatalZBTB11 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 (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
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 (ACSF3), 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 (mtFAS) 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 B12, 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.
Diagnosis
Newborn Screening Due to the severity and rapidity with which this disorder can cause complications when left undiagnosed, screening for methylmalonic acidemias is often included in the newborn screening exam. 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. 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.
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. 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. The ratio can then also be used to determine whether it is CMAMMA (MA<MMA) or malonic aciduria (MA>MMA).
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. For better comparability and interpretation of patient reports, Fowler et al. have developed a protocol for a standardized vitamin B12 responsiveness test (in vivo):
Metabolically stable and on the same treatment for at least a month. Specify energy and protein intake. Stop vitamin B12 at least one month before. If worsening, discontinue and resume administration of vitamin B12. For baseline, collect urine from 3 different days. Blood plasma concentrations can also be used if the test is sensitive enough. Intramuscular injection of 1 mg hydroxocobalamin on 3 consecutive days. After injection, collect urine or plasma samples on alternate days for 10 days. The urine or plasma samples should be analyzed in the same run by GC-MS. 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.
Molecular genetic testing