Asd in dsm 54/9/2024 ![]() A recent registry study reported a history of ASD diagnosis among 10 of 48 respondents, the majority ( n = 7) of whom also reported ID. Autism spectrum disorder (ASD) has only recently been assessed in studies of individuals with PA, and while common, it is usually observed in addition to ID. Intellectual disability (ID) is common in this population the largest retrospective case series found that 76% of 40 participants with IQ testing had scores in the range of ID, and a large registry survey reported developmental delays and/or deficits in cognitive, motor, and language skills in more than 70% ( N = 40). One of the long term complications in individuals with PA is the poor cognitive and developmental outcomes. Although a rare metabolic disorder, PA has been recognized since the 1960s and is representative of a group of disorders termed organic acidemias, which are collectively common and difficult to treat inborn errors of metabolism. The estimated birth incidence of PA varies by region, ranging 1:1000–1:500,000 worldwide, and 1:105,000–1:500,000 in the United States. In mild cases, individuals with PA often remain metabolically stable, but may instead experience learning disabilities and autism spectrum disorder, in addition to dilated cardiomyopathy and chronic kidney disease. ![]() In severe forms, the clinical course is often punctuated by ketoacidotic and/or hyperammonemic metabolic crises resulting in acute encephalopathy. Common chronic symptoms include intellectual disability, epilepsy, movement disorders, sensorineural hearing loss, optic nerve atrophy, anemia, neutropenia, thrombocytopenia, cardiomyopathy, and chronic kidney disease. PA carries a significant risk of mortality and age-dependent morbidity. A deficiency of PCC leads to the accumulation of toxic metabolites (e.g., propionylcarnitine and 2-methylcitrate), disruption of mitochondrial metabolism, and dysregulation of signaling pathways. Propionic acidemia (PA) is an autosomal recessive disorder (OMIM #606054) caused by pathogenic variants in PCCA or PCCB which encode the subunits of the mitochondrial localized enzyme propionyl-CoA carboxylase (PCC). 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. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Reduced 1- 13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. 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. 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. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. 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. 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. Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase.
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