Real-world Evidence Supports Conditional Use of IV Formula in Hospitalized Infants With MSUD

Hospitalized infants with the rare metabolic disorder maple syrup urine disease (MSUD), who are intolerant to oral or enteral administration of branched-chain amino acid-free formula, may benefit from an intravenous formulation.

Although both the oral or enteral formulation and the intravenous (IV) formulation of branched-chain amino acids (BCAA) were effective in treating hospitalized patients with maple syrup urine disease (MSUD), the IV formula yielded a shorter time to episode resolution, according to a recent study.

The retrospective observational study, published in JMID Reports, highlighted some of the cases where the IV formulation may be necessary and used real-world data to show heterogeneity in treatment approaches for patients facing a MSUD-related decompensation episode.

“The particular strength of this study is that it is the largest cohort study in MSUD yet conducted, building on a previous analysis, to provide greater insight into the optimal management of decompensation episodes and offers further confirmation of the clinical efficacy, safety, and utility of the IV BCAA-free treatment for use in emergency settings,” wrote the investigators.

MSUD is a rare autosomal metabolic disease characterized by an inability to break down BCAAs, such as valine, isoleucine, and leucine. MSUD is usually diagnosed during infancy and is estimated to affect 1 in 185,000 to 491,000 births.

The clinical phenotype of MSUD can vary in severity, often causing feeding difficulties shortly after birth. If left untreated, the condition could result in seizures, coma, impairments in energy homeostasis, development delays, irreversible neurological damage, and death.

MSUD is typically managed by a protein-restricted diet with BCAA-free formula supplements. Early diagnoses and treatment can generally lead to a good prognosis. However, patients who adhere to dietary restrictions can still have metabolic decompensations, which can occur at any age.

Patients who experience metabolic decompensations require urgent treatments to normalize leucine levels and avoid permanent brain damage and death. Decompensation episodes are treated by providing a higher concentration of BCAA-free formula than administered at home. There is currently no drug specifically targeted to treat metabolic decompensation.

Although there are some published management recommendations, real-world evidence on MSUD decompensation episodes is limited. Oral or enteral BCAA-free formulations may be difficult or impossible to administer, suggesting that IV formulations may provide an additional avenue to provide care.

The investigators extrapolated data from medical records on patients with MSUD hospitalized for decompensation episodes from 4 rare disease reference centers in France and 1 in Germany. Hospitalizations occurred between January 1, 2010 and December 31, 2016.

Patients were included based on their diagnosis, whether they were under surveillance during hospitalization, had a fully documented medical history, and experienced at least 1 decompensation episode requiring more than 24 hours of hospitalization with a plasma leucine level of over 381 μmol/L at admission.

Data was available for 55 patients (51% male) and 129 episodes, of which 126 episodes for 54 patients were included in the analysis.

Administration of BCAA-free formula intravenously was required for patients with gastric intolerance (33%), refusal to undergo nasogastric tubing (31%), “emergency” (14%), coma (8%), and as prophylaxis prior to a scheduled surgery (6%).

The mean time that it took to achieve episode resolution was shorter in the IV group, amounting to 7.4 days, compared with 9.2 days for the oral and enteral formula group.

Additionally, normalization of leucine levels at discharge was achieved in approximately 80% in both administration groups, taking roughly 2.9 days in the oral or enteral group and 4 days in the IV group.

The investigators said that “this apparent but albeit not significant difference may have resulted from the ‘time to episode resolution’ variable encompassing both leucine normalization and/or the resolution of clinical signs and symptoms as determined by the attending physician, which may have biased these findings.”

In the pediatric subgroup, there were no significant differences between administration groups for any outcome.

Analysis of the adult subgroup revealed a shorter mean time to episode resolution (7.7 days) for the IV group compared with the oral or enteral formula group (15.8 days; P = .008). Also, duration of hospitalization in this subgroup lasted for a mean of 4.6 days in the IV group and 6 days in the oral/enteral group.

Seven adverse events were recorded in 2 patients, of which only 2, nausea and vomiting, were considered treatment related and all eventually resolved.

The investigators identified several study limitations, including that the retrospective design, inclusion of episodes involving hemodialysis and hemofiltration, subjective and heterogeneous definition of “episode resolution”, the different methodologies for measuring leucine levels may all have contributed to some form of bias.

“Considering that excessive leucine levels are a clinical emergency condition, IV administration of BCAA-free formula may be a particularly useful alternative in emergency settings, if the patient is not able to receive or cannot tolerate oral treatment or enteral tubing,” wrote the investigators.


de Lonlay P, Posset R, Mütze U, et al. Real-world management of maple syrup urine disease (MSUD) metabolic decompensations with branched chain amino acid-free formulas in France and Germany: A retrospective observational study. JMID Rep. March 6, 2021;59(1):110-119. doi: 10.1002/jmd2.12207

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