White matter pathology in phenylketonuria

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Abstract

Early-treated phenylketonuria (PKU) is associated with a range of neuropsychological impairments. Proposed mechanisms for these impairments include dopamine depletion and white matter pathology. Neuroimaging studies demonstrate high-signal intensity in the periventricular white matter in most PKU patients, which can extend into subcortical and frontal regions in more severe cases. A review of histopathology and neuroimaging studies reveals that diffuse white matter pathology in untreated PKU patients is likely to reflect hypomyelination (lack of myelin formation), while in early-treated patients white matter abnormalities observed on magnetic resonance imaging (MRI) is likely to reflect intramyelinic edema. Research demonstrates that this pathology is associated with metabolic control and may be reversed with adherence to a strict low-phenylalanine (Phe) diet. While the functional significance of white matter pathology in PKU is not certain, there is some evidence that these abnormalities are associated with functional impairments when the pathology extends into subcortical and frontal regions.

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)

  • N.H. Pfaendner et al.

    MR imaging-based volumetry in patients with early-treated phenylketonuria

    AJNR Am. J. Neuroradiol.

    (2005)
  • C.A. Dyer

    Pathophysiology of phenylketonuria

    Ment. Retard. Dev. Disabil. Res. Rev.

    (1999)
  • N. Malamud

    Neuropathology of phenylketonuria

    J. Neuropathol. Exp. Neurol.

    (1966)
  • C.A. Dyer et al.

    Evidence for central nervous system glial cell plasticity in phenylketonuria

    J. Neuropathol. Exp. Neurol.

    (1996)
  • F.A. Hommes et al.

    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.

    (1982)
  • F.A. Hommes et al.

    Myelin turnover in hyperphenylalaninaemia. A re-evaluation with the HPH-5 mouse

    J. Inherit. Metab. Dis.

    (1992)
  • R. Koch et al.

    Neuropathology of a 4-month-old infant born to a woman with phenylketonuria

    Dev. Med. Child Neurol.

    (2008)
  • D. Villasana et al.

    Neurological deterioration in adult phenylketonuria

    J. Inherit. Metab. Dis.

    (1989)
  • K.D. Pearsen et al.

    Phenylketonuria: MR imaging of the brain with clinical correlation

    Radiology

    (1990)
  • J. Weglage et al.

    Different degrees of white matter abnormalities in untreated phenylketonurics: findings in magnetic resonance imaging

    J. Inherit. Metab. Dis.

    (1993)
  • P.J. Anderson et al.

    Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities

    Dev. Med. Child Neurol.

    (2004)
  • U. Bick et al.

    Disturbed myelination in patients with treated hyperphenylalaninaemia: evaluation with magnetic resonance imaging

    Eur. J. Pediatr.

    (1991)
  • U. Bick et al.

    White matter abnormalities in patients with treated hyperphenylalaninaemia: magnetic resonance relaxometry and proton spectroscopy findings

    Eur. J. Pediatr.

    (1993)
  • V. Leuzzi et al.

    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.

    (2007)
  • V. Leuzzi et al.

    Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients

    J. Inherit. Metab. Dis.

    (1995)
  • H.C. Lou et al.

    An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninemia

    J. Inherit. Metab. Dis.

    (1992)
  • J. Pietz et al.

    Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment

    Radiology

    (1996)
  • D.W. Shaw et al.

    MR imaging of phenylketonuria

    AJNR Am. J. Neuroradiol.

    (1991)
  • A.J. Thompson et al.

    Brain MRI changes in phenylketonuria. Associations with dietary status

    Brain

    (1993)
  • V. Leuzzi et al.

    Neuroradiological (MRI) abnormalities in phenylketonuric subjects: clinical and biochemical correlations

    Neuropediatrics

    (1993)
  • P.B. Toft et al.

    Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia

    J. Inherit. Metab. Dis.

    (1994)
  • J. Weglage et al.

    Progression of cerebral white matter abnormalities in early treated patients with phenylketonuria during adolescence

    Neuropediatrics

    (1997)
  • J.H. Walter et al.

    Complete reversal of moderate/severe brain MRI abnormalities in a patient with classical phenylketonuria

    J. Inherit. Metab. Dis.

    (1997)
  • V. Leuzzi et al.

    Neuropsychological and neuroradiological (MRI) variations during phenylalanine load: protective effect of valine, leucine, and isoleucine supplementation

    J. Child Neurol.

    (1997)
  • P.J. Anderson et al.

    Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?

    Dev. Neuropsychol.

    (2007)
  • V. Leuzzi et al.

    Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria

    J. Inherit. Metab. Dis.

    (2000)
  • H.E. Moller et al.

    Blood–brain barrier phenylalanine transport and individual vulnerability in phenylketonuria

    J. Cereb. Blood Flow Metab.

    (1998)
  • E.J. Novotny et al.

    In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy

    Pediatr. Res.

    (1995)
  • J. Pietz et al.

    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.

    (1995)
  • H.E. Moller et al.

    In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment

    Neuropediatrics

    (1995)
  • A. Rupp et al.

    Variability of blood–brain ratios of phenylalanine in typical patients with phenylketonuria

    J. Cereb. Blood Flow Metab.

    (2001)
  • R. Koch et al.

    Blood–brain phenylalanine relationships in persons with phenylketonuria

    Pediatrics

    (2000)
  • J. Weglage et al.

    Individual blood–brain barrier phenylalanine transport determines clinical outcome in phenylketonuria

    Ann. Neurol.

    (2001)
  • H.E. Moller et al.

    Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria

    Pediatrics

    (2003)
  • R.A. Moats et al.

    Brain phenylalanine concentration in the management of adults with phenylketonuria

    J. Inherit. Metab. Dis.

    (2000)
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    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.

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