The methylmalonic acidemias are organic acidemias caused by an enzymatic defect in the metabolism of four amino acids (methionine, threonine, isoleucine, and valine). This results in an abnormally high level of acid in the blood (academia) and body tissues. In the acute form, drowsiness, coma, and seizures may occur. Mental retardation is a long-term consequence. The disorder may be caused by a deficiency of one or more of the enzymes methyl malonyl CoA mutase, methylmalonyl racemase, or adenosylcobalamin synthetic enzymes. Excretion of methylmalonate, a product of amino acid metabolism, in the urine is abnormally high and therefore is a marker of the disorder. All known organic acidemias are inherited as autosomal recessive traits.
Methylmalonic acidemia (MMA) is a lethal, severe heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism with a poor prognosis. Methylmalonic acidemia is a disorder in which the body cannot break down certain proteins and fats. The result is a buildup of a substance called methylmalonic acid in the blood. This condition is passed down through families. It is one of several conditions called an “inborn error of metabolism.
Causes
Researchers at the University of Calgary and McGill University in Canada announced in December 2002 that they had identified genes that underlie two severe forms of methylmalonic academia. This discovery should make possible DNA testing for carriers and prenatal diagnosis, which is important because treatment can be started during pregnancy.
All known organic acidemias are inherited as autosomal recessive traits. Human traits including the classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers of a recessive disorder, is 25 percent. On average, 50 percent of their children will be carriers of the disease but will not show symptoms of the disorder, while 25 percent will receive a normal copy of the gene from each parent. These risks are the same for each pregnancy.
Diagnosis
Methylmalonic Acidemias can usually be diagnosed before birth (prenatally) by measuring the concentration of methylmalonic acid in amniotic fluid or the activity of the deficient enzyme in fluid or tissue samples obtained from the fetus or uterus during pregnancy (amniocentesis or chorionic villus sampling [CVS]). During amniocentesis, a sample of the fluid surrounding the developing fetus is removed and analyzed. CVS involves the removal and examination of tissue from a portion of the placenta. The disorder can be identified at birth through expanded newborn screening with tandem mass spectrometry.
In most affected infants, the disorder is diagnosed or confirmed in the first weeks of life, based upon a thorough clinical evaluation, a detailed patient and family history, and a variety of specialized tests. Laboratory studies (assays) are typically conducted on certain white blood cells (leukocytes) or cultured skin cells (fibroblasts) to confirm the deficient activity of the deficient enzyme. Additional laboratory studies may reveal excessive levels of acids and increased accumulations of ketone bodies in bodily tissues and fluids (ketoacidosis), increased levels of glycine in the blood and urine (hyperglycinemia and hyperglycinemia), high levels of ammonia in the blood (hyperammonemia), and/or decreased levels of circulating platelets and white blood cells (thrombocytopenia and neutropenia).
MMA needs to be diagnosed by some laboratory methods. The basic laboratory markers suggestive of MMA include low bicarbonate levels less than 22 mmol/L in infants and less than 17 mmol/L in neonates, ketones in the urine, blood ammonia levels greater than 150 μg/dL in neonates, 70 μg/dL in infants, and 35-50 μg/ dL in older children and adults, blood glucose levels less than 40 mg/mL in infants and less than 60 mg/mL in children, and absolute neutrophil counts less than 1,500/mm3. Also, C3 values greater than 7 μmol/L and C3:C2 ratios greater than 0.2 measured by tandem mass spectroscopy (MS/MS) show suspected disorders of cobalamin or propionate metabolism. Finally, relatively high concentrations of methylmalonic acid and methyl nitrate in urine from patients’ gas chromatography/mass spectrometry (GC/MS) can lead to a definitive diagnosis of the disorder.
Plasma homocysteine can be measured to identify gene types involved in MMA. Patients with very high concentrations of methylmalonic acid in the urine, but normal homocysteine, have mutations in at least one of the MUT (mut-, mut 0), cable, cable, and cable (var 2) subtypes. Patients with abnormally high concentrations of methylmalonic acid in urine and homocysteine in plasma have mutations in at least one of the cblC, cable, or cable (var 1) subtypes. Patients with slightly elevated methylmalonic acid in the urine, but normal homocysteine, have mutations in at least one of the MCEE, SUCLA2, and benign MMA subtypes.
Mutation analysis is not only the gold standard diagnosis of MMA but also can aid in the choice of treatment strategy, B12 responsive or unresponsive. Several studies reported the gene mutation spectrum in Chinese patients with isolated MMA and cblC type MMA
Laboratory findings include an abnormally high amount of methylmalonic acid in the blood and urine. Metabolic acidosis also occurs. Elevated levels of ketone bodies such as acetone in the blood (ketonemia) or the urine (ketonuria) may develop. An elevated level of ammonia in the blood (hyperammonemia) may also be present. Excessive levels of the amino acid, glycine in the blood (hyperglycinemia) and in the urine (hyperglycinemia) are found. The concentration of white blood cells, blood platelets, and red blood cells may be lower than normal. Low blood sugar (hypoglycemia) may also occur.
Tests that may be done to diagnose this condition include:
- Ammonia test
- Blood gases
- Complete blood count
- CT scan or MRI of the brain
- Electrolyte levels
- Genetic testing
- Methylmalonic acid blood test
- Plasma amino acid test
Treatment
The diet of children with Methylmalonic Acidemias must be carefully controlled. Treatment includes a low-protein diet and avoidance of the amino acids isoleucine, valine, threonine, and methionine. To assure a balanced diet, certain medical foods must be fed to affected children. Massive doses of vitamin B12 are indicated in the B12-responsive variants. In the disorders of cobalamin metabolism, administration of intramuscular and/or oral hydroxycobalamin may correct the defect and restore normal metabolism.
Since the long-term neurodevelopmental outcome is strongly influenced by the duration of coma and peak blood ammonia concentrations, therapy must not be delayed and therefore the diagnostic workup and the initial medical treatment should proceed simultaneously: stabilize the patient; stop protein intake; start intravenous glucose; and seek expert metabolic advice. While waiting for the laboratory diagnosis, drugs including L-carnitine, hydroxocobalamin, biotin, sodium phenylbutyrate, l-arginine-Hcl, and N-carbamyl-glutamate should be properly used.
Standard therapy of long-term management includes L-carnitine; antibiotics to reduce intestinal flora; vitamin B12 in responsive MMA patients; low-protein diet; precursor-free amino acid and/ or isoleucine/valine supplementation; vitamin and mineral supplementation; caring for special situations and provision of an emergency regimen in recurrent illnesses (RX). Generally, cable type is almost all B12- responsive, but the type is B12-unresponsive, and other types are partly responsive to B12. B12-responsive cblC type MMA is most common in China.
Genetic counseling is recommended for the families of children with Methylmalonic Acidemias.
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 results of the affected substance in sufferers developing a carnitine deficiency. The carnitine also assists in the removal of acyl-CoA, the buildup of which is common in low-protein diets by converting it into acyl-carnitine which can be excreted in the urine. Though not all forms of methylmalonic acidemia are responsive to cobalamin, cyanocobalamin supplements are often used in first-line treatment for this disorder.[rx] 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, and threonine, methionine, and valine without causing an attack.[rx]
Surgical
A more extreme treatment includes a kidney 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.[rx] There is evidence to suggest that the central nervous system may metabolize methylmalonyl-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.[rx][rx]
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