Elsevier

The Journal of Pediatrics

Volume 180, January 2017, Pages 200-205.e8
The Journal of Pediatrics

Original Articles
Comparison of Methods of Initial Ascertainment in 58 Cases of Propionic Acidemia Enrolled in the Inborn Errors of Metabolism Information System Reveals Significant Differences in Time to Evaluation and Symptoms at Presentation

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Objectives

To compare time to evaluation and symptoms at diagnosis of propionic acidemia (PA) by method of ascertainment, and to explore correlations between genotype and biochemical variables.

Study design

Clinical symptoms, genotype, and biochemical findings were analyzed retrospectively in 58 individuals with PA enrolled in the Inborn Errors of Metabolism Information System (IBEM-IS) based on the type of initial ascertainment: abnormal newborn screening (NBS), clinical presentation (symptomatic), or family history.

Results

The average age at initial evaluation and treatment was significantly younger in patients ascertained via abnormal NBS compared with those referred for clinical symptoms. Furthermore, the majority of individuals ascertained because of abnormal NBS were asymptomatic at diagnosis, compared with a minority of clinical presentations. A notable difference in the frequency of metabolic acidosis at initial presentation was observed between those with abnormal NBS (12.5%; 2 of 16) and those with an abnormal clinical presentation (79%; 19 of 24). The frequency of hyperammonemia was similar in the 2 groups.

Conclusion

Our data support the continued value of NBS to identify individuals with PA, who are diagnosed and treated earlier than for other modes of ascertainment. There were no statistically significant correlations between genotype and NBS for C3 acylcarnitines. Although expanded use of NBS has allowed for early diagnosis and treatment, long-term outcomes of individuals with PA, especially with respect to mode of ascertainment, remain unclear and would benefit from a longitudinal study.

Section snippets

Methods

We reviewed available data for 61 patients with PA enrolled in the IBEM-IS. Three patients with no information on initial presentation were excluded. The data review was retrospective and included data entered between June 13, 2007, and November 6, 2015. The abstracted data did not include direct or indirect identifiers. This study was reviewed and granted exempt status by the Institutional Review Board for Clinical Investigations at Duke University and at the University of Wisconsin at Madison.

Results

Data for 58 patients with PA entered into the IBEM-IS were evaluated. The dataset represents a fairly balanced distribution with respect to sex (females, n = 26; males, n = 32). The majority of patients were Caucasian (44 of 58), 3 were Black/African American, 1 was American Indian, and 3 were reported as mixed race. Seven patients lacked information regarding race. Seven individuals were also identified as Amish.

Discussion

We analyzed initial presentations in a cohort of 58 patients with PA enrolled in the IBEM-IS and compared initial symptoms and time to evaluation based on 3 methods of ascertainment reported by the originating center (abnormal NBS, clinical presentation, and family history). The IBEM-IS captures age at initial evaluation by a metabolic specialist and institution of treatment, but not age at presentation. Previous studies have reported that the vast majority of patients with PA present during

References (19)

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    Long term neurologic outcomes may be better with knowledge of the disorder and education for illness care. Prior reports described cardiomyopathy in PA patients as a presenting sign or symptom, lethal complications of acute decompensation, or as chronic complication of the disorder [4–6,11–14]. Of the twenty patients, 5 experienced cardiomyopathy or cardiac related sudden death regardless of the method for diagnosis.

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    Data has shown that the proximal UCD present at ≤2 days in 55% and at <7 days 84% of OTC/CPS patients and have a higher peak ammonia level and a longer average length of stay when compared to patients with distal UCD [7]. This criticism should be considered in light of other current RUSP disorders with “early-onset” presentations such as the distal UCD (e.g., CIT1, ASA) and other “role model” disorders like isolated methylmalonic acidemia and propionic acidemia [20–22]. The improved outcomes of other “early onset” disorders support the potential impact of NBS for the early onset of symptoms in proximal UCD.

  • Propionyl-CoA carboxylase – A review

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    Individuals with classical PA are usually asymptomatic at birth, but present in the first few hours to days of life due to symptoms of metabolic decompensation including poor feeding, vomiting, hyper- or hypotonia, temperature instability, irritability, and lethargy [90–92]. Laboratory abnormalities at presentation may reveal severe, persistent wide anion gap metabolic acidosis with ketosis, hyperlactatemia and hyperammonemia [90,91,93]. Since the clinical presentations of PA individuals are non-specific, mistreatment or inadequate treatment cause deterioration of metabolic decompensation and, if left untreated, lead to death.

  • Dietary practices in propionic acidemia: A European survey

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    In our cohort, 31/38 centres had a median total protein ingested (natural protein plus PFAA) above 120% of WHO/FAO/UNU safe levels of protein intake in at least one age range [6]. Excess PFAA will provide an additional nitrogen load which may contribute to hyperammonaemia, a complication commonly reported in PA [25,26], associated with N-acetylglutamate synthetase inactivation due to accumulation of propionyl CoA [27]. PFAA designed for PA (without valine, methionine, threonine and isoleucine) contain normal to increased amounts of leucine (e.g. 158 mg of leucine per g of protein equivalent from PFAA vs. approximately 100 mg of leucine per 1 g of protein from egg).

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Funding information is available at www.jpeds.com (Appendix 2). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no conflicts of interest.

*

A list of additional members of the Inborn Errors of Metabolism Collaborative is available at www.jpeds.com (Appendix 1).

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