Phenylketonuria
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Cited by 4 publications
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Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging
A multimodal MR study including relaxometry, diffusion tensor imaging (DTI), and MR spectroscopy was performed on patients with classical phenylketonuria (PKU) and matched controls, to improve our understanding of white matter (WM) lesions. Relaxometry yields information on myelin loss or malformation and may substantiate results from DTI attributed to myelin changes. Relaxometry was used to determine four brain compartments in normal-appearing brain tissue ( Key words: phenylketonuria; myelin; white matter; diffusion tensor imaging; relaxometry Phenylketonuria (PKU; McKusick 261600) is the most frequent inherited disorder of amino acid metabolism (1,2). A severe lack of phenylalanine (Phe) hydroxylase (Enzyme Commission 1.14.16.1) induces hyperphenylalaninemia, which causes disturbed brain development and impairments of myelin in untreated PKU patients. Early dietary treatment with restricted Phe intake is essential and blood Phe levels serve as indicator for the dietary strictness needed. Many PKU patients loosen or even stop the diet as adolescents. As dietary treatment of PKU was introduced in the early 1960s, the oldest treated patients have only reached midadulthood. Thus, the consequences of severely elevated Phe concentrations on brain structure and function are not yet clear. It was noted that single patients developed severe neurological symptoms years after ending dietary treatment (2).Despite early treatment, MRI has demonstrated diffuse white matter (WM) hyperintensities on T 2 -weighted and fluid attenuation inversion-recovery (FLAIR) images (3-5). The origin of the partly reversible WM changes is not well understood since to date there is no histologic study in early-treated PKU patients. Histopathologic findings in WM specimens from untreated or late-treated PKU patients, who are usually characterized by severe neurologic deficits due to disturbed brain development, included hypomyelination, spongy changes, gliosis, and demyelination (Ref. 6 and references therein). To gain insight into the nature of alterations in the microstructure of brain tissue in vivo, diffusion-weighted MRI and diffusion tensor imaging (DTI) studies have been performed. Diffusionweighted MRI demonstrated reduced apparent diffusion coefficients (ADCs) in WM lesions (7-10). Initial conference abstracts of DTI studies are inconclusive, reporting the fractional anisotropy (FA) to be mostly normal in myelinated fibers in classical PKU (10,11).The WM abnormalities on T 2 -weighted MRI and diffusion changes have been discussed in relation to the finding of increased myelin turnover in an animal model of PKU (12) and the neuropathologic findings in untreated PKU (2,8,9). They were mostly attributed to some form of dysmyelination including defective (re)myelination and reversible WM edema with intramyelinic vacuole formation (6). Demyelination would be expected to increase ADCs instead of reducing them. Accordingly, demyelination in multiple sclerosis demonstrates increased diffusion coefficients (13) and increasing myelination in ...
Characterization of white matter alterations in phenylketonuria by magnetic resonance relaxometry and diffusion tensor imaging
A multimodal MR study including relaxometry, diffusion tensor imaging (DTI), and MR spectroscopy was performed on patients with classical phenylketonuria (PKU) and matched controls, to improve our understanding of white matter (WM) lesions. Relaxometry yields information on myelin loss or malformation and may substantiate results from DTI attributed to myelin changes. Relaxometry was used to determine four brain compartments in normal-appearing brain tissue ( Key words: phenylketonuria; myelin; white matter; diffusion tensor imaging; relaxometry Phenylketonuria (PKU; McKusick 261600) is the most frequent inherited disorder of amino acid metabolism (1,2). A severe lack of phenylalanine (Phe) hydroxylase (Enzyme Commission 1.14.16.1) induces hyperphenylalaninemia, which causes disturbed brain development and impairments of myelin in untreated PKU patients. Early dietary treatment with restricted Phe intake is essential and blood Phe levels serve as indicator for the dietary strictness needed. Many PKU patients loosen or even stop the diet as adolescents. As dietary treatment of PKU was introduced in the early 1960s, the oldest treated patients have only reached midadulthood. Thus, the consequences of severely elevated Phe concentrations on brain structure and function are not yet clear. It was noted that single patients developed severe neurological symptoms years after ending dietary treatment (2).Despite early treatment, MRI has demonstrated diffuse white matter (WM) hyperintensities on T 2 -weighted and fluid attenuation inversion-recovery (FLAIR) images (3-5). The origin of the partly reversible WM changes is not well understood since to date there is no histologic study in early-treated PKU patients. Histopathologic findings in WM specimens from untreated or late-treated PKU patients, who are usually characterized by severe neurologic deficits due to disturbed brain development, included hypomyelination, spongy changes, gliosis, and demyelination (Ref. 6 and references therein). To gain insight into the nature of alterations in the microstructure of brain tissue in vivo, diffusion-weighted MRI and diffusion tensor imaging (DTI) studies have been performed. Diffusionweighted MRI demonstrated reduced apparent diffusion coefficients (ADCs) in WM lesions (7-10). Initial conference abstracts of DTI studies are inconclusive, reporting the fractional anisotropy (FA) to be mostly normal in myelinated fibers in classical PKU (10,11).The WM abnormalities on T 2 -weighted MRI and diffusion changes have been discussed in relation to the finding of increased myelin turnover in an animal model of PKU (12) and the neuropathologic findings in untreated PKU (2,8,9). They were mostly attributed to some form of dysmyelination including defective (re)myelination and reversible WM edema with intramyelinic vacuole formation (6). Demyelination would be expected to increase ADCs instead of reducing them. Accordingly, demyelination in multiple sclerosis demonstrates increased diffusion coefficients (13) and increasing myelination in ...
Among the different MR sequences, DWI seems to be the most sensitive and reliable in detecting and grading the typical WMAs of cPKU patients.
A five-year-old girl presented with one-year history of gradual onset repeated falls while walking, dysarthria, increasing stiffness, toe walking and abnormal posturing of limbs. There was no diurnal variation and symptoms progressively worsened. On examination, she had masklike facies with horizontal smile and generalized dystonia. Ocular examination revealed waxy pallor of the disc, arteriolar attenuation and alteration in retinal pigmentation with normal foveal reflex suggesting retinitis pigmentosasine-pigmento ( Fig. 1). Magnetic resonance imaging (MRI) of brain revealed bilateral symmetrical hypointensity in the globus-pallidus with central hyperintensity, giving an 'eyeof-tiger' appearance on T2 weighted and FLAIR images (Fig. 2). Retinitis pigmentosa in eyes and characteristic MRI findings gave the diagnosis of Pantothenate kinase associated neurodegeneration (PKAN).PKAN, formerly known as Hallovorden-Spatz syndrome is an autosomal recessive disorder caused by mutation of the pantothenate kinase-2 gene [1]. The MRI finding, 'eye-of-the-tiger'sign is pathognomonic of classic PKAN [2]. The hypointensity on T2 weighted image is because of iron deposition and the central hyperintensity is due to the glioses and spongioses due to cell death [3]. There is an absolute correlation between the presence of a mutation in PANK2 and the eye-of-the-tiger sign; that is, all patients with the PANK2 mutation have this MR imaging pattern, which also is not seen in any mutation-negative patients [4].Eye-of-tiger-sign can sometimes be seen in few cases of neuroferritinopathy, but in these cases careful scurtinization will reveal involvement of other basal ganglia nuclei (caudate and putamen), thalamus and cerebral cortex which is not seen in PKAN [1]. Another condition, where the 'eye of tiger' like appearance is seen is dihydropteridine reductase deficiency in which there will be associated features like cortical calcifications and cysts. Even the clinical presentation varies with microcephaly, parkinsonism, oculogyric crisis and disturbed psychomotor development [5]. The eye-of-the-tiger sign can also be seen in non-NBIA conditions such as corticobasal ganglia degeneration and progressive supranuclear palsy [1]. However the clinical features like age of onset differentiate these from PKAN.In conclusion, though important neuroimaging finding like 'eye-of-the-tiger' sign can be seen in other conditions, the presence of this finding along with other clinical clues Fig. 1 Ophthalmoscopic findings of right fundus: Retinal examination shows waxy pallor of the disc, arteriolar attenuation and alteration in retinal pigmentation. Macula is normal with normal foveal reflex. Features are consistent with retinitis pigmentosa sine pigmento M. Kamate (*) : R. Mali : V. Tonne : S. Bubanale
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