Question: Is there a new treatment being developed to cure methylmalonic acidemia?
Answer: Methylmalonic acidemia — MMA, an organic acidemia — is an inherited autosomal recessive condition — the patient must get a defective gene from each of their parents — where the patient is unable to break down certain fats and proteins, causing a buildup of methylmalonic acid in their blood. Although MMA actually encompasses a spectrum of disorders, with different mutations causing different specific pathways leading to the buildup of methylmalonic acid, the condition is overall pretty uncommon, affecting about one in every 50,000 to 100,000 babies in the U.S.
Many people are familiar with a blood test that is routinely done from a small sample of blood obtained from the heel of newborns shortly after their birth. The March of Dimes recommends that “30 specific disorders for which effective treatment is available” be tested for — a list of the disorders they recommend be included can be found at https://americanpregnancy.org/labor-and-birth/newborn-testing — but the specific testing which is performed is different from state to state. Two of these 30 disorders are forms of MMA. Note that this screening test is, by itself, not diagnostic. So, if a baby has a positive screening test further testing — typically blood and urine tests — will need to be done to confirm the diagnosis.
Early symptoms in patients with MMA are variable, depending on the specific form of MMA as well as other factors, but usually begin very shortly after birth and may include increased sleeping, weak muscle tone, vomiting, fever, breathing problems, easy bruising and others. These symptoms overlap symptoms of early infection of a newborn, and hence typically raise concern of an early infection, which is overall more common than MMA, and may also occur as a complication of MMA, and so tests for neonatal infection will usually be done.
Once the diagnosis of MMA is made, the initial treatment is aimed at addressing any acute issues, and then adjusting the baby’s diet — for example a low protein, high-calorie diet specially designed for the specifics of the child’s condition — usually with injections of vitamin B12 — forms of MMA may manifest with B12 deficiency due to inability to absorb this nutrient in their gastrointestinal tract — and other treatments. For those who survive to late childhood, a liver and kidney transplant may be required.
The prognosis for MMA patients is very variable, depending on the specific form of the disease as well as other factors, and ranges from mild complications to moderate/severe neurologic handicap to early death — sometimes during the neonatal period and sometimes later in childhood.
There is a gene therapy treatment for patients with MMA presently being developed which offers hope for a cure for some of these patients. Regular readers may remember one of my columns earlier this year on CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, but the gene therapy treatment in this clinical trial uses a different approach. The technique used in this treatment utilizes the natural DNA repair mechanism that already exists in our cells to correct the genetic defects. This treatment delivers a corrected version of the patient’s abnormal gene, called a transgene, via a viral vector to some of the patient’s cells, in a sense ‘tricking’ the natural DNA repair mechanism to use this correct copy as a template to add the correct gene.
When MMA is suspected or diagnosed, the patient should be followed by a clinician with expertise in this rare disorder. Once the specifics of the condition in the patient are understood, a treatment plan can be discussed with the family to determine what is best for the patient. Family counseling is also a very important part of the overall therapy, as it is with many childhood conditions.
Jeff Hersh, Ph.D., M.D., can be reached at DrHersh@juno.com.