The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Abstract

Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

Cortical thickness and its relationship to cognitive performance and metabolic control in adults with phenylketonuria

“…The small number of studies investigating GM in heterogeneous samples of patients with PKU greatly vary. On the one hand, Bodner et al 5 and Pfaendner et al 6 found smaller whole‐brain volume in patients with PKU, whereas Aldridge et al 7 and Hawks et al 8 could not find any differences. On a more regional level, smaller volumes in brain areas of the bilateral parietal and occipital lobes 9 and the motor and premotor cortex 10 were reported in patients with PKU in comparison to healthy controls.…”

Cognitive Functioning in Adults with Phenylketonuria in a Cohort of Spanish Patients

“…Regarding the clinical manifestations of PKU patients, usually some developmental delay, severe cognitive and psychiatric impairments can arise if PKU is left untreated [ 4 ]. Some cognitive domains such as attention [ 5 , 6 ] and psychomotor speed are usually affected even in early treated adults Aitkenhead et al, [ 49 ], as well as in other domains such as language, memory, learning, deficits in fine motor control, processing speed, and attention control [ 7 ]. Some deficits in working memory [ 5 , 8 ] and executive functions such as problem-solving, planning ability, inhibitory control, and mental flexibility have been reported as well in adults after they stopped or relaxed the diet (Pascucci et al, 2009, 2013).…”

Motor control and learning in individuals with early-treated phenylketonuria.

“…For example, Bodner et al (2012) found increased putamen volumes in a sample of individuals with ETPKU as compared to individuals without PKU. Christ et al (2016) and Aldridge et al (2020) reported ETPKU-related decreases in cortical parietal and cerebellar gray matter volumes, respectively.…”

“…These white matter abnormalities have a primary focus near the trigone of the lateral ventricles and may extend anteriorly with increased severity. There is also growing evidence that cortical, subcortical, and cerebellar gray matter structures may be affected as well (Aldridge et al, 2020; Bodner et al, 2012; Christ et al, 2016).…”