Organic Acid Disorders |
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| Disease Name | Methylmalonic acidemia, Vitamin B-12 non-responsive |
| Alternate name(s) | Methylmalonic aciduria due to methylmalonic CoA mutase deficiency, Complementation group mut0, Methylmalonyl-CoA mutase |
| Acronym | MMA |
| Disease Classification | Organic Acid Disorder |
| Variants | Yes |
| Variant name | Vitamin B12 metabolic defect with methylmalonic acidemia and homocystinuria |
| Symptom onset | Eighty percent of infants become ill during the first week or life and 90% will present by the end of the first month. Infants with the less severe mut- may present later than the first month. A few may remain asymptomatic or present much later in life depending on the residual enzyme activity and the metabolic stressors. |
| Symptoms | Most common signs and symptoms are lethargy, failure to thrive, recurrent vomiting, dehydration which leads to profound metabolic acidosis, respiratory distress, hypotonia and death if not recognized. Complications of acute episodes can include metabolic stroke, extrapyramidal signs, dystonia and bilateral lucencies of globus pallidus. Survivors may have significant neurological damage. Renal failure may appear during childhood. Clinical spectrum is wide, ranging from fatal neonatal disease to asymptomatic individuals. Patients do not have to have clinical crises in order to have neurological or other organ compromise. |
| Natural history without treatment | Variable depending on the enzyme defect and the patient. Some will die as a neonate, others will survive with deficits and a few others will remain asymptomatic. |
| Natural history with treatment | About 60% of patients die within the first year of life and of those that survive, 40% are distinctly developmentally impaired. Age of onset of symptoms can help prognosticate – those with later onset tend to have a more benign course. Liver and liver/kidney transplant are one treatment option. However, liver transplants have significant preoperative risk and there is documentation of neurological problems after transplant despite improved biochemical values. Renal transplants have shown good response with drops in methylmalonic acid levels, normalization of the diet and absence of acute episodes of metabolic decompensation. However, the effect of any type of transplant is limited because the MMA enzyme is in all tissues and the transplants do not affect the levels made in the cerebro-spinal fluid and brain. |
| Treatment | Protein restricted diet, OH-Cbl injections, carnitine supplementation and oral antibiotic therapy to decrease gut production of propionate. Special medical foods (formula) deficient in methionine, threonine, valine, isoleucine, odd chain fatty acids and cholesterol. Liver transplant and liver/kidney transplant. |
| Other | N/A |
| Physical phenotype | Most patients have no obvious dysmorphic features. Some patients, in whom there is known consanguinity, have had associated birth defects, congenital heart defects, hydronephrosis and facial dysmorphisms. |
| Inheritance | Autosomal recessive |
| General population incidence | 1:48,000 |
| Ethnic differences | None known |
| Population | N/A |
| Ethnic incidence | N/A |
| Enzyme location | Liver, kidneys, cerebrospinal fluid, brain |
| Enzyme Function | Catalyzes methylmalonyl-CoA to succinyl-CoA |
| Missing Enzyme | Methylmalonyl-CoA mutase |
| Metabolite changes | Increased methylmalonic acid in blood and urine. |
| Gene | MCM |
| Gene location | 6p12-q21.2 |
| DNA testing available | Sequencing available internationally |
| DNA testing detail | N/A |
| Prenatal testing | Possible via enzyme assay on amniocytes or CVS.. |
| MS/MS Profile | Elevated C3 propionyl carnitine, elevated C4 DC methylmalonyl carnitine. |
| OMIM Link | www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=251000 |
| Genetests Link | www.genetests.org |
| Support Group | Organic Acidemia Association Save Babies through Screening Foundation |
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