The default mode network in early-treated phenylketonuria : relationships between functional connectivity, structural integrity, and cognition
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[EMBARGOED UNTIL 08/01/2026] Phenylketonuria (PKU) is an autosomal recessive condition characterized by a deficiency in the enzyme phenylalanine hydroxylase (PAH), which is necessary for the metabolism of the amino acid phenylalanine (Phe) into tyrosine. When left untreated, PKU is associated with significant neurological and cognitive sequelae. Individuals who are diagnosed early and begin treatment shortly after birth (i.e., early-treated PKU; ETPKU) avoid the significant impairments associated with untreated PKU. However, neurological and neurocognitive disruptions are still noted in this population. Even with the accumulated evidence for disruptions in WM integrity, functional connectivity, and neurocognition, the relationship between these sequelae is not well understood. Resting state functional magnetic resonance imaging (fMRI), diffusion tensor imaging (DTI), and neurocognitive data from 35 adults with ETPKU and a demographically similar comparison group of 32 adults without PKU was analyzed. White matter abnormalities were evidenced by significant reductions in axial diffusivity (AD) among individuals with PKU across several connections within the default mode network (DMN). Within the ETPKU group, recent Phe levels were significantly correlated with AD. Several significant correlations between AD and the neurocognitive composites were identified, although the mediation model relating Phe levels, structural connectivity, and cognition was not supported. Functional connectivity within the DMN was also reduced in the ETPKU group but showed no relationship with Phe levels. Although functional connectivity significantly correlated with structural connectivity in the non-PKU group, non-significant relationships were found among those with ETPKU. The present findings underscore the importance of metabolic control and provides insight into the possible mechanisms underlying neurological and cognitive changes associated with ETPKU. Additionally, the present work suggests that the relationship between functional and structural connectivity is more complicated than in unaffected populations.
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Ph. D