Rare disease of children, an international study changes therapy

When we talk about rare diseases, we often also talk about a diagnosis that comes very late. But methylmalonic acidemia, a metabolic disease that affects about 2 people out of a hundred thousand, is instead one of those included in the newborn screening program in Italy. A rare disease – which causes the inability to metabolize the proteins ingested with food – with significant damage to the kidneys, up to end-stage renal failure. In addition to a protein-free diet along with some medications so far the therapy is reminiscent of kidney, liver or combined liver-kidney transplantation.

83 patients involved

But an international multi-center study, involving 83 patients, a high number for a rare disease – coordinated by the Bambino Gesù Children’s Hospital, which followed six for the study and also has a dedicated organ transplant program – showed that the most effective therapy is double transplantation, and that transplantation of the kidney alone is not conclusive. A result so important – presented at the tenth congress of the International Pediatric Transplant Association (IPTA) and being published in an international scientific journal – that some of the centers that participated in the study have already decided to change their intervention guidelines. “The conclusions of the study have very important repercussions on the transplant programs of many centers” explains the doctor Luca Dello Strologocoordinator of the international study, first signature of the study and responsible for the follow-up of kidney transplantation of the Hospital of the Holy See.

What is the disease

Methylmalonic acidemia is caused by a congenital defect involving the metabolism of amino acids and vitamin B12. This defect causes the malfunction of a specific enzyme that makes it impossible for the body to metabolize proteins derived from food, causing the accumulation in the blood of a substance called methylmalonic acid. The accumulation of methylmalonic acid is extremely harmful for the patient who goes through acute episodes of neurometabolic decompensation and, in the longer term, end-stage renal failure from the neonatal period.

How it works

To reduce the toxic accumulation of methylmalonic acid, patients must follow a low-protein diet along with certain medications. In severe forms, organ transplantation is increasingly used: liver when there is no renal insufficiency, kidney or combined liver and kidney when renal insufficiency is present. The diagnosis is made with biochemical and genetic analyzes and in Italy methylmalonic acidemia is one of those diseases subject to mandatory neonatal screening.

I study

The results of the international multicenter study coordinated by Dr. Luca Dello Strologo required the collaboration of 19 large centers in Europe (15) and the United States (4), and the involvement of 83 pediatric patients. This is the largest multicentre case history collected and analyzed so far. Of all patients, 26 (31%) had undergone kidney transplantation, 24 (29%) had liver transplant, and 33 (40%) had both kidney and liver transplantation. The data of the whole cohort were statistically compared to each other to verify which therapeutic solution was the most effective.

The results

From the statistical comparison of the data, it emerged that patients undergoing combined kidney and liver transplant or liver only have lower levels of methylmalonic acid in both blood and urine than those transplanted only of the kidney. The frequency of metabolic crises was also reduced in the first two groups. “Although kidney transplantation was used in about 1/3 of cases and despite being indicated as a possible solution, the data unequivocally demonstrate that it is the therapeutic approach that provides the worst results,” adds Dello Strologo. Even the liver transplant has given better results than the kidney transplant alone in terms of effectiveness, but in this case what makes the difference is the precocity of the intervention. The median age of liver-only transplant recipients was in fact significantly lower than that of the other two cohorts: 1.8 years against 11.1 for kidney transplant recipients and 9.5 for kidney / liver transplant recipients.

The transplant programs will be modified

“The data collected led us to conclude that in patients with methylmalonic acidemia and renal insufficiency isolated kidney transplantation is not as effective as the combined one, although this was not yet supported in the literature – continues Dr. Luca Dello Strologo, coordinator of the study – These The results will involve the modification of the transplant programs of the individual centers for the treatment of methylmalonic acidemia. The Child Jesus has already changed his strategy and since then he has no longer transplanted an isolated kidney and other centers are also aligning “.