A 1-month-old term boy born at home with a prior history of Escherichia (E.) coli meningitis is hospitalized for poor feeding, hypotonia, encephalopathy, and hepatomegaly. Laboratory evaluation is significant for pancytopenia, severe metabolic acidosis, and hyperammonemia with elevated serum propionylcarnitine (C3) level and low urine methylmalonic acid level on tandem mass spectrometry. Urine reducing substances and blood, urine, and cerebrospinal fluid cultures are negative. A brain magnetic resonance imaging (MRI) demonstrates the following findings in Figure 1.
Figure 1. Axial diffusion-weighted brain MRI findings in the bilateral globi pallidi (red arrowhead), thalami (orange arrow), and bilateral pericentral cortex (red arrow) of a neonate with an abnormal neurologic exam. Image from: Arumugam S, Rangasamy R, Sukumar K, Ramalingam R. A male infant with encephalopathy, cataract, and immune dysfunction. Neoreviews. 2022;23(8):e579–581. 10.1542/neo.23-8-e5751
Which of the following interventions will most likely improve this infant’s survival?
- Granulocyte colony-stimulating factor
- Low galactose diet
- Low protein diet with carnitine supplementation
- Therapeutic hypothermia
Answer: D. Low protein diet with carnitine supplementation
The infant in this case presents with classic features consistent with propionic acidemia (PA). PA is an autosomal recessive organic acid disorder that is caused by a deficiency of propionyl CoA carboxylase (PCC).2,3 This enzyme is involved in the catabolism of specific amino acids (valine, isoleucine, threonine, and methionine), cholesterol, and fatty acids.2,3 A deficiency of PCC results in a buildup of toxic metabolites that can clinically manifest as vomiting, poor feeding, growth failure, temperature instability, abnormal neurologic symptoms (hypotonia, encephalopathy, and seizures) and even death, especially if untreated in the neonatal period.2,3 Although the majority of individuals with PA are symptomatic within a few weeks of age, a small percentage exhibit a late-onset presentation of symptoms outside of the neonatal period.2,3 Hallmark laboratory findings of PA include severe high anion gap metabolic acidosis, hyperammonemia, pancytopenia, and ketonuria.2,3
A preliminary diagnosis of PA involves use of tandem mass spectrometry to detect an elevated C3 level on statewide newborn metabolic screening and/or serum acylcarnitine profile along with an increased amounts of certain urine organic acids.2,3 Diagnosis can be confirmed with a molecular genetic analysis that identifies specific gene mutations in PCCA and PCCB genes and/or and enzymatic studies assessing PCC activity.2,3 Timely diagnosis and treatment focused on avoiding catabolism and following a protein-limited diet with carnitine supplementation to limit toxic metabolite accumulation and promote propionic acid clearance have proven to improve survival (Option D).2,4
Individuals with PA can present with stroke-like infarctions of the basal ganglia as seen in Figure 1.1 Specifically, hyperintense lesions in the putamen and caudate nucleus (Figure 1), as well as abnormal myelination and cortical and white matter atrophy in chronic and untreated disease, can be seen on T2-weighted or diffusion-weighted brain MRI.3,5 These neuroimaging findings can help elucidate a possible metabolic diagnosis in a patient with a constellation of nonspecific signs and symptoms. Of note, early MRI imaging during the neonatal period may not necessarily detect basal ganglia pathology.3,5 Despite having stroke-like features on neuroimaging, the management of these infarctions do not consist of anticoagulation (Option A) since the etiology is not due to thrombi but rather due to metabolic dysfunction associated with toxic metabolite accumulation.3,5
Recent animal experiments and small ongoing clinical trials have suggested the use of therapeutic hypothermia (Option E) during an acute metabolic crisis to improve survival and neurodevelopmental outcomes in patients with hyperammonemic encephalopathy due to inborn errors of metabolism.6,7 However, experience using this type of neuroprotective intervention is in its infancy, and evidence promoting routine use of therapeutic hypothermia is lacking in this population.6,7 Thus, further evaluation for the efficacy of therapeutic hypothermia in patients with organic acidemia is required prior to incorporating it as a standard of patient care.6,7
Along with neurologic complications, several case reports suggest that patients with PA may have immune defects given the frequent recurrent infections and sepsis-associated mortality in the setting of bone marrow suppression and humoral immune dysfunction.3 Although neutropenia is commonly present at diagnosis, it can improve without intervention.3 Additionally, the routine use of granulocyte colony stimulating factor (Option B) is not advised, because there is no experience nor evidence demonstrating improved survival or prognosis.3
The clinical presentation of PA can also mimic other conditions such as galactosemia. Like the infant in this case, patients with galactosemia can manifest with poor feeding, failure to thrive, encephalopathy, hepatomegaly, E. coli sepsis, and abnormal brain imaging.8 Individuals with congenital galactosemia benefit from a low galactose diet (Option C).8 However, the absence of urine reducing substances in this case points against galactosemia.8 Additionally, the elevated serum C3 level and low urine methylmalonic acid noted on tandem mass spectrometry strongly support a diagnosis of an organic acid disorder such as PA.2
Did you know?
- PA is associated with a high risk of mortality that has declined with the introduction of newborn metabolic screening, prompt medical management, and patient monitoring from 41–90% in the 1980s to 7–12% in the 2010s.9 However, early diagnosis and treatment of PA has not altered the high rates of significant neurodevelopment impairment and immunologic, hematologic, and cardiac complications.4,10
- Approximately 25% of patients with PA demonstrate features of cardiomyopathy and long QT syndrome and consequently are at risk for progressive heart failure, sudden cardiac arrest, and/or death.2 However, cardiac symptoms may not occur with the first metabolic crisis nor does the incidence of cardiomyopathy appear to correlate with severity of PA.11 Therefore, individuals with PA are strongly recommended to undergo echocardiogram screening at diagnosis, yearly, and if symptomatic.7
List clinical features and diagnostic tests that can help distinguish PA from other organic acid disorders such as methylmalonic aciduria.
To learn more about this and review organic acidemias, read the following article: Guilder L, Kronick J. Organic acidemias. Pediatr Rev. 2022;43(3):e123–e13412
What organic disorder is associated with an odor of sweaty feet? What organic disorder is associated with an odor of burnt sugar?
To learn more about this and review organic acidemias, read the following article: Guilder L and Kronick J. Organic acidemias. Pediatr Rev. 2022;43(3):e123–e13412
NeoQuest August Authors
Neena Jube-Desai, MD, MBA, University of Maryland Medical Center
Shanmukha Mukthapuram, MD, Cincinnati Children’s Hospital Medical Center
- Arumugam S, Rangasamy R, Sukumar K, Ramalingam R. A male infant with encephalopathy, cataract, and immune dysfunction. Neoreviews. 2022;23(8):e579–581. 10.1542/neo.23-8-e575
- Forny P, Hörster F, Ballhausen D, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. J Inherit Metab Dis. 2021;44(3):566–592
- Sutton VR, Chapman KA, Gropman AL, et al. Chronic management and health supervision of individuals with propionic acidemia. Mol Genet Metab. 2012;105(1):26–33
- Grünert SC, Müllerleile S, de Silva L, et al. Propionic acidemia: neonatal versus selective metabolic screening. J Inherit Metab Dis. 2012;35(1):41–49
- Reddy N, Calloni SF, Vernon HJ, et al. Neuroimaging findings of organic acidemias and aminoacidopathies. Radiographics. 2018;38(3):912–931
- Lichter-Konecki U, Nadkarni V, Moudgil A, et al. Feasibility of adjunct therapeutic hypothermia treatment for hyperammonemia and encephalopathy due to urea cycle disorders and organic acidemias. Mol Genet Metab. 2013;109(4):354–359
- Ninković D, Mustapić Ž, Bartoniček D, et al. The therapeutic hypothermia in treatment of hyperammonemic encephalopathy due to urea cycle disorders and organic acidemias. Klin Padiatr. 2019;231(2):74–79
- Grady N, Millard D. Congenital galactosemia. Neoreviews. 2017;18(4)e228–e233
- Shchelochkov OA, Carrillo N, Venditti C. Propionic acidemia. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds.GeneReviews®. Seattle (WA): University of Washington, Seattle; May 17, 2012
- Grünert SC, Müllerleile S, De Silva L, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013;8:6
- Romano S, Valayannopoulos V, Touati G, et al. Cardiomyopathies in propionic aciduria are reversible after liver transplantation. J Pediatr. 2010;156(1):128–134
- Guilder L, Kronick J. Organic acidemias. Pediatr Rev. 2022;43(3):e123–e134