People with phenylketonuria (PKU) who receive treatment soon after birth still experience significant reductions in the volume of gray matter, which contains mainly nerve cell bodies, in their cerebellum, a recent study has found.
The cerebellum is a brain region typically associated with motor control, and also participates in cognitive and executive functions. Changes in cerebellar gray matter volume may underlie the cognitive and motor impairments seen in PKU patients, despite early treatment.
The study, “The effects of early-treated phenylketonuria on volumetric measures of the cerebellum,” is published in Molecular Genetics and Metabolism Reports.
PKU is an inherited genetic disorder caused by mutations in the PAH gene, which is necessary to break down the amino acid phenylalanine, a building block of proteins.
In the absence of a functional PAH gene, phenylalanine builds up to toxic levels in the brain and other organs, ultimately leading to irreversible intellectual impairments in people with the condition.
While early and lifelong management with a phenylalanine-restricted diet spares patients from more severe impairments, early-treated patients still experience some neurological and cognitive symptoms.
Recent evidence suggests that the cerebellum, a part of the brain associated with movement and coordination, is physically connected to an area in the brain called the prefrontal cortex — which is associated with cognitive abilities, such as thinking and reasoning — that is also affected in PKU.
However, little is known about the impact of an early phenylalanine-restricted diet on the cerebellum.
In this study, funded in part by a research grant from the National PKU Alliance, U.S.-based researchers examined the cerebellar volume and composition in a group of 20 early-treated PKU patients (11 males and nine females; median age 16) and compared them with 20 age-matched individuals without PKU (10 males and 10 females).
The cerebellum is composed of gray matter and white matter. While gray matter consists mainly of nerve cell bodies and the short connections between them, white matter contains nerve fibers that establish long-range connections between nerve cells and muscles.
The researchers measured brain, cerebellar, gray matter, and white matter volumes using magnetic resonance imaging.
Results showed that the total brain volume was similar between early-treated PKU and non-PKU groups, as were the cerebellar and white matter volumes inside the cerebellum.
However, the cerebellar gray matter was significantly smaller in the early-treated PKU group than in the other group. The researchers speculated that reduced gray matter in the cerebellum may play a role in PKU symptoms.
Results also demonstrated that adherence to dietary treatment in PKU patients, as assessed with blood phenylalanine levels, was significantly associated with greater whole brain volume. But treatment adherence did not affect total cerebellar volume, cerebellar white matter volume, or cerebellar gray matter volume.
While changes in white matter are thought to be associated with PKU neurological and cognitive symptoms, findings from this study suggest that gray matter may also play a role. “Although speculative, it is possible that neurocognitive difficulties in [early-treated PKU] may be more closely tied to markers of [gray matter] disruption,” the investigators wrote.
Additional research is now needed to understand exactly how changes in cerebellar gray matter relate to neurocognitive function in PKU patients.
“This research represents just one piece of the puzzle as we strive to understand how elevated phenylalanine levels associated with PKU may affect the brain,” Shawn Christ, PhD, associate professor at the University of Missouri and study leader, wrote in an email to Phenylketonuria News.
“The cerebellum represents a critical brain region for several cognitive skills, in particular motor control and learning,” he said. “The next step in this line of research is to understand better if and how the cerebellar differences that we observed may relate to past reports of motor difficulties in some individuals with PKU.”
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