A Newborn Who Has Acidemia and Abnormal Head Ultrasonography

A newborn male infant presents with profound acidemia and abnormal head ultrasonography findings.The delivery, which occurred at home without medical supervision, was vaginally into a toilet in which the baby remained until paramedics arrived at approximately 20 minutes after birth. Upon their arrival, an Apgar score of 9 was assigned. The infant was warmed, dried, and transported to the community hospital. Birthweight was 2,300 g. The infant was admitted initially to the well newborn nursery. However, 6 hours after arrival, the infant exhibited increased respiratory distress.A blood gas drawn from an umbilical venous line revealed:The infant was transported to a neonatal intensive care unit (NICU).On arrival to the NICU, the patient was intubated and placed on mechanical ventilation. An echocardiogram revealed normal cardiac structure and function. The blood lactate level was elevated at 225.2 mg/dL (25 mmol/L). Blood ammonia concentration also was elevated at 518 mmol/L. Ketones were noted in the urine.The patient was given sodium bicarbonate infusions to a total of 40 mEq/kg over the course of 16 hours due to persistent metabolic acidosis, and the infant was transferred to a referral center.On arrival at the referral center, the patient's laboratory data included:Head ultrasonography was performed.Head ultrasonography 1 | Head ultrasonography 2 | Head ultrasonography 3What is seen in the ultrasound images?What further tests may be helpful?Head ultrasonography revealed bilateral subependymal cyst formation.Further laboratory evaluation included measurement of plasma amino acids, urine organic acids, carnitine, and acylcarnitine profile.The patient continued to receive large amounts of sodium bicarbonate by intravenous infusion. The following day, the lactate concentration had decreased to 135.1 mg/dL (15 mmol/L), and the anion gap to 28. Ammonia concentrations rose as high as 207 mmol/L, but most measurements were less than 100 mmol/L.Urine organic acids demonstrated very large elevations of lactate and ketones. Measurement of plasma amino acids documented elevations in alanine, citrulline, and lysine. Carnitine values were low. The acylcarnitine profile demonstrated significant elevation in C2 species consistent with ketosis. Lactate concentrations remained between 135.1 and 180.2 mg/dL (15 and 20 mmol/L) despite continued treatment. A redox panel showed very elevated lactate/pyruvate and beta-hydroxybutyrate/acetoacetate ratios.These findings, along with the results of head ultrasonography were highly suggestive of pyruvate carboxylase deficiency type B, a congenital lactic acidosis.Congenital lactic acidosis is a primary or secondary defect in pyruvate metabolism. Pyruvate is the end-product of glycolysis and is converted into acetyl-coA by the action of the pyruvate dehydrogenase complex for entry into the citric acid cycle. Products of the citric acid cycle are used by the mitochondrial respiratory chain for energy production. Pyruvate also can be converted into oxaloacetate through the action of pyruvate carboxylase, thus beginning the first step of gluconeogenesis. If a defect exists in either gluconeogenesis, the citric acid cycle, the mitochondrial respiratory chain, or the pyruvate dehydrogenase complex, pyruvate accumulates and is diverted into lactate and alanine. The degree of conversion of pyruvate into lactate (L/P ratio) can be a measure of the cell's redox status because the conversion is catalyzed by the presence of the reduced proton carrier NADH. Typically, high L/P ratios suggest elevated NADH levels. This occurs if the citric acid cycle or mitochondrial respiratory chain is not functioning effectively. Although lactate concentrations can be falsely elevated in samples due to improper technique, an elevated alanine value on an amino acid analysis confirms lactic acidemia.Pyruvate carboxylase (PC) deficiency is a rare autosomal recessive disorder seen in about 1 in 250,000 births. There does not appear to be any racial predilection except for the Algonkian Amerindian tribes of Eastern Canada. PC deficiency has been categorized into groups A, B, and C based on the biochemical phenotype. Group A has been described in North America and is characterized primarily by lactic acidemia and psychomotor retardation. Group B has been described in France and the United Kingdom and has a more complex biochemical phenotype that includes elevated lactate, ammonia, citrulline, and lysine concentrations. Because PC converts pyruvate into oxaloacetate, it is responsible for maintaining the pool of citric acid cycle intermediates within the mitochondria. In PC deficiency, this pool is depleted, and an absence of oxaloacetate results in reduction of aspartate. Aspartate is necessary for the urea cycle, and its absence leads to reduced consumption of citrulline. This secondary defect within the urea cycle explains the hyperammonemia and citrullinemia that can be seen in patients with this form of PC deficiency. Group C is a benign condition.The infant in this case most likely has group B PC deficiency. Enzyme assay of skin fibroblasts or DNA analysis is needed to confirm the diagnosis. Unfortunately, no affected child reported to date has survived beyond a few weeks after birth. Although PC is a biotin-dependent enzyme, supplementation with biotin does not alter the poor prognosis.Subependymal cysts (or pseudocysts because they are not lined by ependyma) are found in up to 5.2% of newborns in the first days after birth. Generally, these regress and carry a good prognosis. However, when associated with other abnormalities, the prognosis can be poor. Subependymal cysts are believed to result from a remnant of the germinative zone. Accordingly, they are more common in preterm infants. Multilocular cysts are associated more often with other morbidities such as infection with cytomegalovirus or rubella, hemorrhage, and chromosomal disorders. They have been linked with cocaine use in the mother, but this association was not confirmed in a prospective study (Bats 2002). For children who have pyruvate carboxylase deficiency, prenatal imaging has demonstrated cysts as early as 29 weeks of gestation. Because PC supplies glutamine for neurotransmitter synthesis and membrane lipid moieties needed during the synthesis of myelin, PC deficiency during a critical time of periventricular white matter development results in metabolic injury and subsequent cystic degeneration.JoDee M. Anderson, MD, Department of Pediatrics, UT Southwestern Medical Center; Henry Lee, MD, Department of Pediatrics, Stanford University Medical Center.

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