Methylmalonicaciduria results from an autosomal recessive inherited genetic defect in methylmalonic CoA mutase (MCM), an enzyme required for the proper metabolism of some protein components, cholesterol, and fatty acids. As a result of a deficiency in MCM, methylmalonic acid accumulates in the bloodstream and urine, causing a severe metabolic disorder that may lead to death. Treatment consists chiefly of diet modification and the administration of several medications that may counteract this process
The symptoms experienced by an infant with MCM deficiency vary with the type of mutation present. Infants born with the mut0 type MCM deficiency will typically show more severe symptoms that manifest in the first 1-2 weeks of life, while infants with the mut- type MCM deficiency will have slightly milder symptoms that begin later in infancy. Both sets of infants may show poor feeding, vomiting, lethargy, and low muscle tone, as well as a failure to grow at the normal rate. The disorder may first come to medical attention as it escalates into a full scale overwhelming attack, often triggered by intake of large amounts of dietary protein. If the condition has not yet been diagnosed, treatment is often poor, and patients may experience kidney damage, inflammation of the pancreas, or strokes that result in severe paralysis. More severe attacks can lead to seizures, coma, and eventually, death. As a result, newborns and infants with MCM deficiency may die early, even before a diagnosis can be reached. If the infant survives the first attack, similar attacks may occur during an infection or following ingestion of a high-protein diet. Between episodes the patient may appear normal, but often, mild to moderate mental retardation will develop. Some infants with this disorder have characteristic facial features with a broad nose bridge, prominent lower eyelid folds, triangular mouth, and high forehead. Other symptoms of the disorder include frequent infections (especially yeast infections of the skin and mouth), enlarged liver, and low amounts of red blood cells. Often a family history is present for affected siblings or siblings that died very early in life for unclear reasons. A small percentage of people with the MCM deficiency apparently experience no symptoms or complications of the disease. For reasons not yet understood, these patients can tolerate a normal protein intake and accumulate high levels of methylmalonic acid in their body fluids without consequence
When symptoms such as those described above are encountered in a young infant or newborn, a diagnostic search for MCM deficiency should be considered. A routine blood test performed on almost all people who come to the hospital with severe illness will show high levels of acid in the bloodstream. Other clues to possible MCM deficiency include high levels of other substances in the bloodstream that appear with methylmalonicacidemia such as ketones and ammonia, or the presence of abnormally low amounts of glucose or red blood cells. After high levels of acid in the bloodstream are noted, and if methylmalonicacidemia is suspected, samples of the urine and the blood will be taken and tested for the amount of methylmalonic acid. Abnormally high levels of methylmalonic acid suggest that MCM deficiency may be present. Genetic studies can then be performed to determine if any mutation in the MCM gene is present. When the disease is diagnosed in a child, research laboratories can test unaffected siblings to determine if they are carriers of the mutant MCM gene. The same technology can be used to diagnose MCM deficiency before the birth of a child, by analyzing fluid or tissue from the sac surrounding the unborn fetus.
Prognosis depends on early and accurate diagnosis of the disease and the prompt initiation of diet modification and medications. In those infants who escape early diagnosis, the prognosis is poor as severe attacks will lead to complications as extreme as sudden death. In those infants that do survive initial attacks, damage to the developing brain and kidneys may result that leave the child severely incapacitated. The addition of the medications, L-carnitine and metronidazole, to the management of this disorder has changed the prognosis. Scientists point out that although most patients before 1985 died, those after 1985, when these drugs were introduced, survived with improved general health. Thus, if detected early and treated appropriately, the lifestyle of a well-managed patient with MCM deficiency can be relatively normal, without mental retardation or growth delay.
Current research into a cure for MCM deficiency is focusing on the ability of liver transplantation or gene therapy to correct the abnormal MCM gene, however there is no cure for MCM deficiency at this time. The methods of treatment focus on three areas: diet/lifestyle modification, treatment with medications, and support during severe attacks of the disease. Dietary changes include restriction of the amino acids that are converted to methylmalonic acid: methionine, threonine, valine, and isoleucine. As a result, people with MCM deficiency are limited to a low protein diet that provides the minimum natural protein needed for growth. Calcium and multivitamin supplements should also be taken to correct any nutritional deficiencies that result from avoiding high-protein foods. Activity in children with MCM deficiency need not be restricted. People with MCM deficiency may benefit from several medications when taken daily. The antibiotic, metronidazole, kills bacteria that live in the intestine and produce substances that are converted to methylmalonic acid. The supplement, L-carnitine, is often used to reduce some of the toxic effects of high levels of methylmalonic acid. Although most reports state that there is no benefit from vitamin B12 supplementation, a few reports suggest that a trial of vitamin B12 may be reasonable to determine if it will result in improved MCM function. Finally, bicarbonate can be used to counteract low levels of acid that persist in the bloodstream. All of the above medications can be used to aid in treatment of a severe attack of methylmalonicacidemia. In addition, a patient in crisis should be given excessive amounts of intravenous fluids, to help clear methylmalonic acid from the circulation. Special blood filtering machines can be used when levels of methylmalonic acid or ammonia become dangerously high. Stressful situations that may trigger attacks (such as infection) should be treated promptly. Patients with MCM deficiency should be seen regularly by a team of health care specialists including a primary care provider, a dietician, and a biochemical geneticist who is familiar with the management of the disease. Parents should be educated in the signs and symptoms of impending attacks and how to respond appropriately. Close monitoring of amino acid levels, urinary content of methylmalonic acid, and growth progress is necessary to ensure proper balance in the diet and the success of therapy.