White matter pathology in phenylketonuria☆
Introduction
Phenylketonuria (PKU1; OMIM 261600 and 261630) is an inborn error of metabolism associated with diffuse brain pathology. The consequences are usually severe when this metabolic condition is left untreated; however, white matter pathology is common even in early diagnosed and treated individuals. PKU appears to principally affect cortical and subcortical white matter, although there is emerging evidence that this condition also influences cortical development, in particular dendritic growth and dendritic spine density [1]. Little is known about the cortical changes related to early-treated PKU in humans as dendritic abnormalities are not easily detectable with current neuroimaging paradigms. However, some recent studies have reported volumetric reductions in gray matter structures including the motor cortex, thalamus, and hippocampus [2], [3]. In contrast, considerable human research has examined how PKU impacts white matter development, and this literature will be the focus of this review.
Section snippets
Histopathology
While human histopathology studies are limited to small numbers of selective samples of different ages, these studies can provide important insights into the specific neuropathology associated with PKU. The brains of untreated PKU patients generally show impaired myelination, reflected by pallor of the white matter on myelin stains [1], [4]. Astrocystic gliosis is usually present in these affected white matter tracts [5]. In animal models of PKU, studies have demonstrated that oligodendrocytes
Structural MRI
Probably the first report of white matter abnormality in treated PKU patients using conventional MRI was in 1989 [11]. This case report described two young adults displaying neurological deterioration (years after diet discontinuation) who on T2 weighted images exhibited increased signal intensity in periventricular white matter.
This report was followed by a series of studies published in the early 1990s, which investigated neuroanatomical changes in treated PKU patients using structural MRI.
Regression of white matter abnormalities
The regression in MRI-defined white matter abnormalities observed in a patient by Thompson et al. [12] has also been described by others [17], [28], [29]. Bick et al. [17] noted less severe white matter pathology in two of three patients who returned to a strict low-Phe diet in just 3 months, however, these improvements diminished for both patients when treatment was again discontinued. In this study, the improvement in MRI changes appeared related to the maintenance of good metabolic control.
Metabolic control
Evidence that the severity of white matter pathology can be reduced with a return to a strict low-Phe diet and good metabolic control (i.e., blood Phe < 400 μmol/L) implies that the evolution of this lesion is linked to poor metabolic control. While most studies have found that the severity of abnormalities is related to blood Phe levels [15], [17], [18], [22], [23], [24], [25], [27], [31], this is not a universal finding [13], [16]. The approach for determining the role of metabolic control in
Neurophysiological evidence of white matter alteration
White matter integrity can be reliably explored by neurophysiological techniques, which are useful in detecting a possible impairment of nervous potential generation and conduction—a frequent finding in demyelinating diseases. Lou et al. [21] found normal visual evoked potentials (VEP) in 14 PKU subjects with a wide spectrum of white matter involvement. Cleary et al. [18] recorded VEP and somatosensory evoked potentials (SEP), central motor conducting time, and peripheral motor nerve conduction
Advanced MRI sequences
Conventional MRI studies have clearly demonstrated that periventricular white matter pathology is common in early-treated PKU patients, and the severity of pathology is strongly associated with metabolic control. The changes in MRI have been described as elevated water content, edema, and immature or vacuolated myelin [16], [18], [24]. However, more advanced MRI sequences are necessary to fully understand the etiology of these white matter abnormalities, such as MRS and diffusion tensor imaging
Functional consequences of PKU-related white matter pathology
Cognitive and motor functions are dependent on both the structural integrity of specific brain regions as well as the tracts connecting these brain structures. The smooth flow of neural impulses is necessary for the brain to operate efficiently so that information can be transmitted throughout the brain and integrated across multiple regions [54]. The speed of neural transmission is largely dependent on the structural properties of the connecting fiber tracts, such as axonal diameter and
Conclusions
PKU is associated with diffuse white matter pathology in both treated and untreated patients. In untreated patients this is likely to reflect hypomyelination (lack of myelin formation) while in early-treated patients this pathology is likely to reflect intramyelinic edema. Research demonstrates that this pathology is associated with metabolic control, and as such can be reversed with adherence to a strict low-Phe diet for at least 2 months. There is some debate relating to the functional
References (91)
- et al.
Maternal phenylketonuria: magnetic resonance imaging of the brain in offspring
J. Pediatr.
(1996) - et al.
Neurological deterioration in young adults with phenylketonuria
Lancet
(1990) - et al.
Magnetic resonance imaging of the brain in phenylketonuria
Lancet
(1994) - et al.
Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change
J. Pediatr.
(1995) - et al.
Kinetics of phenylalanine transport at the human blood–brain barrier investigated in vivo
Brain Res.
(1997) - et al.
Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations
Neuropsychologia
(2002) - et al.
Age-related working memory impairments in children with prefrontal dysfunction associated with phenylketonuria
J. Int. Neuropsychol. Soc.
(2002) The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain
Brain Res.
(1972)The neuropathology of phenylketonuria: human and animal studies
Eur. J. Pediatr.
(2000)- et al.
Global and regional volume changes in the brains of patients with phenylketonuria
Neurology
(2006)
MR imaging-based volumetry in patients with early-treated phenylketonuria
AJNR Am. J. Neuroradiol.
Pathophysiology of phenylketonuria
Ment. Retard. Dev. Disabil. Res. Rev.
Neuropathology of phenylketonuria
J. Neuropathol. Exp. Neurol.
Evidence for central nervous system glial cell plasticity in phenylketonuria
J. Neuropathol. Exp. Neurol.
Turnover of the fast components of myelin and myelin proteins in experimental hyperphenylalaninaemia. Relevance to termination of dietary treatment in human phenylketonuria
J. Inherit. Metab. Dis.
Myelin turnover in hyperphenylalaninaemia. A re-evaluation with the HPH-5 mouse
J. Inherit. Metab. Dis.
Neuropathology of a 4-month-old infant born to a woman with phenylketonuria
Dev. Med. Child Neurol.
Neurological deterioration in adult phenylketonuria
J. Inherit. Metab. Dis.
Phenylketonuria: MR imaging of the brain with clinical correlation
Radiology
Different degrees of white matter abnormalities in untreated phenylketonurics: findings in magnetic resonance imaging
J. Inherit. Metab. Dis.
Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities
Dev. Med. Child Neurol.
Disturbed myelination in patients with treated hyperphenylalaninaemia: evaluation with magnetic resonance imaging
Eur. J. Pediatr.
White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings
Eur. J. Pediatr.
The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study
J. Inherit. Metab. Dis.
Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients
J. Inherit. Metab. Dis.
An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninemia
J. Inherit. Metab. Dis.
Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment
Radiology
MR imaging of phenylketonuria
AJNR Am. J. Neuroradiol.
Brain MRI changes in phenylketonuria. Associations with dietary status
Brain
Neuroradiological (MRI) abnormalities in phenylketonuric subjects: clinical and biochemical correlations
Neuropediatrics
Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia
J. Inherit. Metab. Dis.
Progression of cerebral white matter abnormalities in early treated patients with phenylketonuria during adolescence
Neuropediatrics
Complete reversal of moderate/severe brain MRI abnormalities in a patient with classical phenylketonuria
J. Inherit. Metab. Dis.
Neuropsychological and neuroradiological (MRI) variations during phenylalanine load: protective effect of valine, leucine, and isoleucine supplementation
J. Child Neurol.
Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?
Dev. Neuropsychol.
Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria
J. Inherit. Metab. Dis.
Blood–brain barrier phenylalanine transport and individual vulnerability in phenylketonuria
J. Cereb. Blood Flow Metab.
In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy
Pediatr. Res.
The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy
Pediatr. Res.
In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment
Neuropediatrics
Variability of blood–brain ratios of phenylalanine in typical patients with phenylketonuria
J. Cereb. Blood Flow Metab.
Blood–brain phenylalanine relationships in persons with phenylketonuria
Pediatrics
Individual blood–brain barrier phenylalanine transport determines clinical outcome in phenylketonuria
Ann. Neurol.
Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria
Pediatrics
Brain phenylalanine concentration in the management of adults with phenylketonuria
J. Inherit. Metab. Dis.
Cited by (145)
Maximal dietary responsiveness after tetrahydrobiopterin (BH4) in 19 phenylalanine hydroxylase deficiency patients: What super-responders can expect
2024, Molecular Genetics and Metabolism ReportsCerebral blood flow and white matter alterations in adults with phenylketonuria
2024, NeuroImage: ClinicalNeuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria
2023, Journal of PediatricsNeuroimaging in early-treated phenylketonuria patients and clinical outcome: A systematic review
2023, Molecular Genetics and MetabolismNeuropsychological assessment of adults with phenylketonuria using the NIH toolbox
2023, Molecular Genetics and MetabolismPhenylketonuria and the brain
2023, Molecular Genetics and Metabolism
- ☆
References to electronic databases: Phenylketonuria, OMIM 261600 and 261630. Phenylalanine hydroxylase, EC 1.14.16.1.
Funding statement: The authors report no financial interests or potential conflicts of interest.