P3C338: The Sweet Deceit of a Screen

Introduction: Maple syrup urine disease (MSUD) is a rare autosomal recessive genetic disorder caused by decreased activity of branched-chain alpha-ketoacid dehydrogenase. This enzyme is required to break down branched-chain amino acids (BCAAs) including leucine, isoleucine, and valine. In the absence of this enzyme, toxic amounts of BCAAs accumulate in our bodies. In particular, elevated plasma leucine causes fatigue, abdominal symptoms, and acute neurologic dysfunction. Children with untreated MSUD develop diffuse subcortical gray matter edema and are at risk of death secondary to central transtentorial herniation. All national newborn screening (NBS) tests for this disease. Once diagnosed, this disease can be managed with dietary restrictions and lifelong monitoring of BCAA blood levels.

Case Description: We describe a case of a 15-day-old full-term male with a normal NBS who presented to our pediatric intensive care unit intubated with a chief complaint of altered mental status. He initially presented with poor weight gain and lethargy at an outside ED. His labs were remarkable for a metabolic acidosis with pH 7.09, HCO3 16, base deficit 16, anion gap 20, and ammonia level 74. CT head was concerning for diffuse hypoxic-ischemic injury and cerebral edema. Due to a high concern for metabolic crisis, amino acids were prioritized during the work-up of altered mental status. MRI brain revealed restricted diffusion, diffuse cerebral edema, and cerebellar herniation. EEG showed comb-like theta frequency sharp activity, an unusual finding that can be a particular hallmark of MSUD.

Given the risk of intracranial herniation and brain death, a multidisciplinary decision was made to reduce amino acid metabolites with dialysis without a confirmed diagnosis of MSUD. Send-out amino acid labs returned a few days later and were consistent with MSUD (leucine 2912, isoleucine 404, and valine 521). Neurologic examination improved greatly after dialysis and the patient was successfully extubated on hospital day 5.

Discussion: Despite a normal first NBS, on further genetic testing this infant was found to have MSUD Type II with mutation in the DBT gene - which is responsible for the enzyme complex that breaks down BCAAs. When our geneticist further reviewed the NBS values, it showed an elevated Leu:Ala ratio with a Collaborative Laboratory Reports score of 207 indicating possible MSUD. Unfortunately, this screen was still reported as normal. MSUD can present as classic, intermediate, or intermittent with severity based on the variance of residual enzyme activity. This case highlights the importance of keeping a low threshold for workup for this genetic disorder in an infant who presents with altered mental status during the first week of life despite falsely reassuring NBS results.

Conclusion: NBS is a great tool to evaluate for treatable metabolic illnesses. If clinically warranted, normal results should still be verified given the increased mortality of untreated illness.