P0649 - Infant with Thiamine Deficiency from a Rare Cause

Introduction
Infants who present with lactic acidosis and lethargy undergo evaluation for sepsis, dehydration, hypoglycemia, and cardiac causes. If lactic acidosis persists, mitochondrial disorders and other inborn errors of metabolism should be considered. The work-up for metabolic diseases is extensive, but a detailed history can guide us through the maze of metabolic defects.

Case Report
We present a case of a 9-week-old girl, ex-37-week gestation, admitted to the pediatric intensive care unit with lethargy and symptoms of an upper respiratory tract infection. Physical examination was notable for decreased responsiveness, hypotonia and head lag. Her initial work-up for sepsis, hypoglycemia, and dehydration was unremarkable. Echocardiogram showed suprasystemic pulmonary hypertension with right atrial and ventricular enlargement. Inhaled nitric oxide was initiated through high-flow nasal cannula, but lactic acidosis persisted. Abnormal upper extremity movements were later observed. Head MRI showed a nonacute left middle cerebral artery territory infarct with associated encephalomalacia. MR spectroscopy revealed abnormal glucose and lactate peaks, suspicious for metabolic disease. Upon further inquiry, the patient’s older sister presented at 2-months of age with lethargy, lactic acidosis and shock-like state that required extracorporeal membrane oxygenation (ECMO). After surviving a prolonged hospitalization, the sister underwent a mitochondrial disease evaluation. The sister is currently healthy, developmentally normal, and her work-up for mitochondrial disease was negative. A “mitochondrial cocktail” was initiated for our patient, and over the next few days, her lactic acid levels decreased and inhaled nitric oxide was discontinued. A repeat echocardiogram showed resolution of pulmonary hypertension. Neurologic exam returned to baseline. The mother revealed that she had teenage onset diabetes and deafness with a difficult to treat anemia, but was lost to follow-up without a unifying diagnosis.

Discussion
This clinical case was puzzling because the family history was highly suggestive of an inherited mitochondrial disease, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS). The rapid improvement from the “mitochondrial cocktail” and mother’s history of anemia are unusual for inherited mitochondrial disorders. Mother’s triad of neurosensory hearing loss, diabetes, and megaloblastic anemia is suggestive of thymine-responsive megaloblastic anemia (TRMA). Whole exome sequencing of the mother identified a homozygous mutation in the SLC19A2 gene that encodes for the thiamine transporter (THTR1) protein. This mutation resulted in thiamine-deficient breastmilk leading to profound thiamine deficiency in our patient. Infant thiamine deficiency exists primarily in countries where breastfeeding mothers depend on overly processed rice, stripped of thiamine, as the main source of nutrition. These thiamine deficient infants had increased incidence of pulmonary hypertension and high mortality rates unless treated early with thiamine supplementation.

Conclusion
This case highlights the complexities and intricacies of mitochondrial disorders where extensive family history-taking provided pivotal clues when the clinical scenario initially failed to “add up.”