Severe renal failure and hyperammonemia in a newborn with propionic acidemia: effects of treatment on the clinical course

Abstract

Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, and can progress to coma if not identified and treated appropriately. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Herein, we report a case of 3-day-old neonate with PA presented with acute renal failure and metabolic acidosis was effectively treated by peritoneal dialysis and conventional methods.

• Propionic acidemia
• renal failure
• metabolic acidosis
• hyperammonemia
• neonate

Introduction

Propionic acidemia (PA) is one of the intoxication type organic acidemias which often present with lethargy, poor feeding, and vomiting and can progress to coma if not identified and treated appropriately. PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA.1 Recent studies have identified the genomic mutations in the genes PCCA and PCCB. Testing of urine organic acids in persons who are symptomatic or those detected by newborn screening reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, and propionylglycine, which are normally not observed in the urine. Testing of plasma amino acids reveals elevated glycine. Individuals with PA develop worsening metabolic acidosis in the presence of physiological stress from increased catabolism.2 Herein, we report a case of 3-day-old neonate with PA presented with acute renal failure (ARF) and metabolic acidosis was effectively treated by peritoneal dialysis and conventional methods.

Case report

The patient presented was a full-term female newborn with encephalopathy in the first days of life. Prenatal care had been excellent and labor and delivery had been unremarkable. Her birth weight was 2.9 kg; gestational age was 38 weeks; and the Apgar index was 9 at 1 min and 10 at 5 min. The parents are consanguineous and have a history of neonatal death, characteristics suggestive of the presence of genetic defects. She presented hypoglycemia (blood glucose 21 mg/dL), metabolic acidosis with increased anion gap (pH: 6.9 and HCO3: 4 mmol/L), ketosis, hyperammonemia (serum ammonia: 1187 µg/dL), dehydration (15% weight loss), prerenal failure (blood urea: 160 mg/dL, creatinine level: 1.62), anemia, leukopenia and thrombocytopenia (blood count revealed hemoglobin: 9 g/dL, leucocyte count: 3 × 10⁹/L and platelet: 21 × 10⁹/L) on the third day of life. The brain ultrasonography was normal. Lab tests revealed electrolytes derangements, metabolic acidosis and renal failure. Her clinical condition and family history suggested an inherited metabolic disease. Oral feeding was stopped immediately, and the baby was treated with intravenous infusions of glucose, parenteral lipid, intermittent administration of non-absorbed antibiotics and l-carnitine. The tandem mass spectrometry was abnormal, with the acylcarnitine results consistent with PA (C3 propionyl carnitine level). The laboratory evaluation also showed high levels of 3-hydroxy-propionic, 2-metil-hydroxybutiric and metil-citric acid in urine, confirming the diagnosis of PA. In order to enhance metabolic detoxification of ammonia, a single dose of carglumic acid (100 mg/kg) was administered through a nasogastric tube. As the patient’s metabolic acidosis was unresponsive to continuous high dose intravenous bicarbonate replacement, peritoneal dialysis was started for the treatment of hyperammonemia and intractable metabolic acidosis. The patient got on well day by day.

Discussion

Many patients in a severe metabolic crisis are not only presented with metabolic ketoacidosis but also with hyperammonemia. Delayed diagnosis or treatment of hyperammonemia, irrespective of the etiology, leads to neurologic damage and potentially a fatal outcome, and thus it becomes a medical emergency when present.3,4 Hyperammonemia is common in neonates with branched-chain organic acidemias, primarily due to the inhibition of N-acetylglutamate (NAG) synthetase; NAG is an activator for carbamoylphosphate synthetase I, the first enzyme of the urea cycle. N-Carbamylglutamate, a NAG analogue, has been reported to correct hyperammonemia in neonates with organic acidemias.5,6 Our patient presented with poor feeding, hypoglycemia, acidosis and hyperammonemia. We stopped all sources of protein temporarily and gave non-protein calories. The patient was treated with intravenous glucose, insulin, sodium benzoate, sodium phenylbutyrate, carnitine and carglumic acid. In spite of these measures, the plasma ammonia concentration remained above 1000 µg/dL. After conventional treatment, peritoneal dialysis (PD) was started. Over the following 24 h, the plasma ammonia fell from 1187 μg/dL to 267 μg/dL and metabolic acidosis was corrected. Despite stopping PD, the ammonia level dropped to normal levels for a neonate. Reversal of catabolism is the mainstay of most interventions in acutely ill individuals with PA. This corrects acidosis more effectively than buffers; however, sometimes dialysis is required. This is particularly important in patients with ammonia >500 µg/dL, extreme acidosis/electrolyte imbalance, coma, dilated pupils, poor neurological finding, deterioration, failure to improve.2

Neonatal-onset PA, the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. The differential diagnosis includes all causes of acidosis including renal tubular acidosis and inherited metabolic disorders of lactate and pyruvate metabolism and oxidative phosphorylation. Disorders of the Krebs cycle can also cause neurologic symptoms, usually accompanied by metabolic acidosis with elevations of specific organic acids in urine. Non-genetic conditions, such as shock and sepsis, also cause acidosis. It is also important to distinguish the underlying cause of high plasma ammonia levels in a neonate. In urea cycle defects, the high ammonia level is the primary metabolic abnormality and is due to an enzymatic block in ammonia metabolism within the urea cycle. Secondary hyperammonemia can be due to metabolic defects such as organic acid disorders and fatty acid oxidation disorders, drugs or other metabolites that may interfere with urea cycle function, or severe liver disease.7,8 Laboratory studies can help distinguish the underlying primary defect and cause of hyperammonemia and guide appropriate treatment.

ARF is a common condition seen in neonatal intensive care units. It is broadly classified into prerenal, intrinsic renal and post renal failure. Renal replacement therapy can correct the metabolic disturbances that accompany suspected or confirmed inborn errors of metabolism. The initial treatment mainly relies on correction of hypotension, acidosis, and hypoxemia, in order to reduce renal vasoconstriction and improve renal perfusion. If necessary, the main renal replacement therapy is usually peritoneal dialysis even if skilled medical and nursing personnel are available in some neonatal intensive care units to perform hemofiltration and hemodiafiltration safely. The complexity and invasiveness of the procedure is probably responsible for high rate of complications and mortality. If appropriate, catheter selection and technique in the placement should be done, PD might improve outcome as in the presented case.2–5 Now she is alive and on regular outpatient clinic visits for PA. PD, although invasive, is an effective therapy in neonates with the diagnosis of PA and as an emergency tool, PD has been also used in the treatment of metabolic crisis resulting from organic acidemias.2

Declaration of interest

The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.