Issue: Ir Med J; Vol 112; No. 7; P980
Fatal Propionic Acidemia: A Challenging Diagnosis
A. Fulmali, N. Goggin
1. Department of Paediatrics, NDDH, Barnstaple, UK 2. Department of Paediatrics, UHW, Waterford, Ireland
Dear Sir,
We present a two days old neonate with severe form of propionic acidemia with lethal outcome. Propionic acidemia is an AR disorder, presents in the early neonatal period with progressive encephalopathy and death can occur quickly.
A term neonate admitted to NICU on day 2 with poor feeding, lethargy and dehydration. Parents are non- consanguineous and there was no significant family history. Prenatal care had been excellent. Delivery had been uneventful. No resuscitation required with good APGAR scores. Baby had poor suck, lethargy, hypotonia and had lost about 13% of the birth weight. Initial investigations showed hypoglycemia (2.3mmol/L), uremia (8.3mmol/L), hypernatremia (149 mmol/L), severe metabolic acidosis (pH 7.24, HCO3 9.5, BE -18.9) with high anion gap (41) and ketonuria (4+). Hematologic parameters, inflammatory markers and CSF examination were unremarkable. Baby received initial fluid resuscitation and commenced on IV antibiotics. Generalised seizures became eminent at 70 hours of age. Loading doses of phenobarbitone and phenytoin were given. Hepatomegaly of 4cm was spotted on day 4 of life. Very soon baby became encephalopathic requiring invasive ventilation. At this stage clinical features were concerning for metabolic disorder and hence was transferred to tertiary care centre where further investigations showed high ammonia level (1178 μg/dl) and urinary organic acids were suggestive of propionic acidemia. Specific treatment for hyperammonemia and propionic acidemia was started. MRI brain displayed diffusion abnormality in thalami, basal ganglia and brain stem bilaterally and EEG showed severe encephalopathy. Enzyme analysis of fibroblasts revealed severely depressed levels of Propionyl-CoA Carboxylase. Despite improvement in metabolic parameters baby continued to deteriorate clinically with increasing encephalopathy and respiratory depression and active care was withdrawn after discussion with parents.
Propionic acidemia is the most common organic acidemia with estimated prevalence between 1:35000- 75000/population. It is caused by mutations in PCCA and PCCB genes which encode α and β subunits of PCC, respectively. Prenatal diagnosis is possible with measurement of the abnormal metabolite in amniotic fluid ¹ ² . Recently a group from Spain demonstrated that non-invasive prenatal diagnosis is possible by studying maternal plasma¹. Clinical findings are nonspecific. Neonatal onset propionic acidemia is characterised by poor feeding, vomiting, hypotonia, lethargy, dehydration, and clinical signs of severe ketoacidosis progress rapidly to coma and death. Seizures occur in about 30% of affected infants. It is frequently accompanied by metabolic acidosis with high anion gap, ketonuria, hypoglycaemia, hyperammonemia and cytopenias. Moderate to severe mental retardation and neurologic manifestations indicating extrapyramidal and pyramidal signs are common sequelae in the older survivors. These abnormalities usually occur after metabolic decompensation. Neuroimaging shows destruction of basal ganglia. This phenomena has been referred to in the literature as metabolic stroke3. Delayed diagnosis or treatment of hyperammonemia leads to high mortality. Thus it becomes medical emergency when present 4. Our patient had most of the above mentioned features. But persistent metabolic acidosis, ketonuria alerted us towards organic acidemia. Thus all neonates with severe metabolic acidosis with ketonuria, one should raise suspicion for organic acidemia; investigations and treatment should be started immediately to avoid severe neurological damage and death.
Corresponding Author: Amruta Fulmali Department of Paediatrics, NDDH, Barnstaple, UK Email: [email protected]
References:
1. Bustamante-Aragones A, Pérez-Cerdá C, Pérez B, de Alba MR, Ugarte M, Ramos C. Prenatal diagnosis in maternal plasma of a fetal mutation causing propionic acidemia. Mol Genet Metab. 2008; 95:101-3. 2. Inoue Y, Ohse M, Shinka T, Kehara T. Prenatal diagnosis of propionic acidemia by measuring methylcitric acid in dried amniotic fluid on filter paper using GC/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 870:160-3. 3. Nelsons Textbook of Paediatrics. 20th Ed. Elsevier Saunders. 4. Rafique M. Propionic acidaemia: demographic characteristics and complications. J Pediatr Endocrinol Metab. 2013; 26 (5-6):497-501.