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Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating
Oleg A Shchelochkov1, Cristan A Farmer2, Colby Chlebowski2
1Organic Acid Research Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Insights
Propionic acidemia (PA) is linked to intellectual disability (ID) and autism spectrum disorder (ASD). ID severity correlates with specific metabolic biomarkers and mitochondrial dysfunction, unlike ASD in PA patients.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Propionic acidemia (PA) is an inherited metabolic disorder caused by PCCA or PCCB gene variants.
- PA impairs propionyl-CoA carboxylase activity, leading to neurodevelopmental issues like intellectual disability (ID) and autism spectrum disorder (ASD).
- The specific mechanisms and biomarkers linking PA to these neurodevelopmental outcomes are not well understood.
Purpose of the Study:
- To investigate the associations between neurodevelopmental phenotypes (ID and ASD) and laboratory/biomarker parameters in individuals with PA.
- To identify potential biomarkers for disease severity and central nervous system (CNS) complications in PA.
Main Methods:
- Analysis of data from a subset of PA patients (n=33) in a natural history study.
- Exploration of correlations between neurodevelopmental diagnoses (ID, ASD), cognitive/adaptive scores, and various laboratory parameters.
- Assessment of plasma, serum, and urinary biomarkers, including metabolic and mitochondrial indicators.
Main Results:
- Intellectual disability (ID) was diagnosed in 61% of participants; ASD in 39%.
- More severe ID profiles correlated with higher plasma propionylcarnitine, 2-methylcitrate, erythropoietin, FGF21, GDF15, and reduced 1-13C-propionate oxidation and glutamine levels.
- ASD showed limited associations, primarily with increased serum erythropoietin and decreased plasma glutamine. Plasma glycine was not significantly associated with ID or ASD.
Conclusions:
- Intellectual disability is robustly associated with metabolic parameters and indicators of mitochondrial dysfunction in PA.
- ASD in PA patients appears less directly linked to the measured metabolic biomarkers compared to ID.
- Disease severity and mitochondrial dysfunction are implicated in CNS complications of PA, suggesting potential biomarkers for monitoring and therapeutic targets.
Abstract:
Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.
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