Methylmalonic acidemia

Synonyms

2

Overview

 Methylmalonic acidemia (MMA, also called methylmalonic aciduria), first characterized by Oberholzer et al. in 1967, is an autosomal recessive metabolic disorder. It is a classical type of organic acidemia. The result of this condition is the inability to properly digest specific fats and proteins, which in turn leads to a buildup of a toxic level of methylmalonic acid in the blood.

Methylmalonic acidemia stems from several genotypes, all forms of the disorder usually diagnosed in the early neonatal period, presenting progressive encephalopathy, and secondary hyperammonemia. The disorder can result in death if undiagnosed or left untreated. It is estimated that this disorder has a frequency of 1 in 48,000 births, though the high mortality rate in diagnosed cases make exact determination difficult.

Methylmalonic acidemias are found with an equal frequency across ethnic boundaries


Symptoms

Depending on the affected gene(s), this disorder may present symptoms that range from mild to life-threatening.

  • Stroke
  • Progressive encephalopathy
  • Seizure
  • Kidney failure
  • Vomiting
  • Dehydration
  • Failure to thrive and developmental delays
  • Lethargy
  • Repeated Yeast infections
  • Acidosis
  • Heptomegaly
  • Hypotonia
  • Pancreatitis
  • Respiratory distress

Causes

Genetic

The inherited forms of methylmalonic acidemia cause defects in the metabolic pathway where methylmalonyl-coenzyme A (CoA) is converted into succinyl-CoA by the enzyme methylmalonyl-CoA mutase.

Vitamin B12 is also needed for the conversion of methylmalonyl-CoA to Succinyl-CoA. Mutations leading to defects in vitamin B12metabolism or in its transport frequently result in the development of methylmalonic acidemia.

This disorder has 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.

Nutritional

Though not always grouped together with the inherited versions, it should be noted that a severe nutritional deficiency of vitamin B12 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.

Diagnosis

One of, if not the most common form of organic acidemia, Methylmalonic acidemia is not apparent at birth as symptoms usually 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. 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.

Because of the inability to properly breakdown 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 and/or blood panel. The presence of methylmalonic acidemia can also be indicated through the use of a CT scan or ammonia test. Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine.

Prognosis

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, typically the 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 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.

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 effected 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. Though not all forms of methylmalonyl acidemia are responsive to cobalamin, cyanocobalamin supplements are often used in first line treatment for this disorder. 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.

Surgical

A more extreme treatment includes kidney and/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. It must also be noted that there is evidence to suggest that the central nervous system may metabolize methylmalonic-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.