Clinical Neuroradiology

Review Article

Brain MRI Abnormalities in Phenylketonuria An Update on MR Imaging and MR Volumetry* Stefan Hähnel1

Abstract Phenylketonuria (PKU), a systemic metabolic disease that mainly involves cerebral white matter, is the most common congenital disorder of amino acid metabolism. Untreated patients usually exhibit epilepsy, microcephaly, severe mental retardation, and hyperactive behavior. In this review, the most important neuroradiologic findings in PKU regarding MR imaging and MR volumetry are summarized. Key Words: Phenylketonuria · White matter diseases · MR imaging · MR volumetry · Diffusion-weighted MR imaging Clin Neuroradiol 2008;18:19–24 DOI: 10.1007/s00062-008-8002-z

Hirnveränderungen bei Phenylketonurie: Ein Update mit Blick auf MR-Tomographie und MRVolumetrie Zusammenfassung Die Phenylketonurie (PKU), eine systemische metabolische Erkrankung, die hauptsächlich die weiße Hirnsubstanz schädigt, ist eine der häufigen kongenitalen Störungen des Aminosäurestoffwechsels. Unbehandelte Patienten zeigen meist eine Epilepsie, Mikrozephalie, schwere mentale Retardierung und hyperaktives Verhalten. In dieser Übersicht fassen wir die wichtigsten neuroradiologischen Befunde bei PKU zusammen. Schlüsselwörter: Phenylketonurie · Erkrankungen der weißen Substanz · MR-Tomographie · MR-Volumetrie · Diffusions MRT

Epidemiologic, Clinical and Histopathologic Aspects of Phenylketonuria Phenylketonuria (PKU) is an inborn error of amino acid metabolism that results from mutations in the phenylalanine hydroxylase (PAH, EC 1.14.16.1) gene located on chromosome 12 at the locus 12q24.1 [1]. The disease is transmitted as an autosomal recessive disorder with considerable variability in incidence among different ethnic populations. In the USA, the incidence is ap-

proximately 1 in 10,000 persons, ranging between 1 in 8,000 persons among Caucasians and 1 in 50,000 among African Americans [1]. PKU arises from a severe PAH deficiency that limits the hepatic hydroxylation of phenylalanine (Phe) to tyrosine [1] (Figure 1). In affected patients, plasma and tissue levels of Phe and its related ketoacids are elevated. Untreated patients typically develop a characteristic clinical picture that may include mental retardation, seizures, growth retardation, hyper-

*Dedicated to Professor Klaus Sartor, MD, on the occasion of his retirement. 1

Division of Neuroradiology, Department of Neurology, University of Heidelberg Medical Center, Germany.

Received: November 23, 2007; revision accepted: January 25, 2008

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel

19

Hähnel S. Brain MRI Abnormalities in Phenylketonuria

reflexia, eczematous dermatitis, and hypopigmentation [2]. Brain pathology of untreated patients is characterized by reduced brain weight and hypo- and demyelination of cerebral white matter [2]. Although gray matter changes in cortical layering, tissue mass (atrophy), and reduced dendritic arborization have been reported, the primary neuropathologic finding of PKU is that of diffuse abnormalities within white matter [3, 4]. Reduction in brain size is largely due to white matter volume loss. Specific white matter abnormalities include delayed or defective myelination, diffuse white matter vacuolization (status spongiosus), demyelination, and gliosis [3, 4]. Malamud [3] suggested that findings varied between older and younger patients, with older patients tending to show more changes of demyelination and younger patients showing more changes of status spongiosus. Generally, it remains unclear whether the white matter changes in PKU represent a failure of myelin production, destruction of myelin, or a combination of both processes.

his or her life. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: Phe and aspartic acid [5]. Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a protein-free diet. Since Phe is necessary for the synthesis of many proteins, it is required but levels must be strictly controlled. In addition, tyrosine, which is normally derived from Phe, must be supplemented. The link between histopathologic and MR imaging findings in PKU and clinical features is not clearly understood yet. This might be one reason for the fact that treatment policies for PKU are quite different among European countries, ranging from the French practice to discontinue diet at 5 years of age to the British recommendation for a lifelong diet [4]. Treatment policies in the US and Canada revealed similar inconsistencies [5]. According to German guidelines, our patient group underwent dietary treatment until the age of 18 years.

Conventional MR Imaging The typical MR imaging features of early-treated PKU are hyperintensities on T2-weighted or FLAIR images that are located mainly in the occipital-parietal regions; in more severe cases they may extend into the frontal and parietal lobes, including the arcuate fibers [6] (Figure 2). The abnormal MR signal is most markedly found in the Phe-sensitive oligodendrocytes, which are located in brain areas that normally myelinate postpartum, e.g., in the subcortical and periventricular white matter, in the corpus callosum, in the optic tract, and in the forebrain. Rarely, basal ganglia, brain stem, and cerebellum are affected [4, 7, 8]. In a study with earlytreated PKU patients, who were systematically evaluated using MR imaging, Pietz et al. [9] reported marked diffuse cortical atroGTP phy in three of 51 patients (5.9%). T2 white matter abnormalities have Biosynthesis been shown to be reversible, with improvement in metabolic control and reduced serum Phe levels from dietary Phenylalanine NAD+ Tetrahydrobiopterin restriction [10, 11], but the quantitative relationship between the level of T2 abnormality within white matter and the DHPR PAH extent of clinical disease remains unclear. While white matter changes have Tyrosine NADH + H+ Dihydrobiopterin been shown in some reports to correlate Figure 1. Schematic illustration of the hydroxylation of phenylalanine to tyrosine. with blood levels of Phe, the degree of Dietary Treatment By the application of a Phe-restricted diet beginning in the first days of life, the phenotype of untreated PKU can be prevented. This requires severely restricting or eliminating foods high in Phe, such as breast milk, meat, chicken, fish, nuts, cheese and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Babies who are diagnosed with PKU must immediately be put on a special milk/formula substitute (diet powder). Later in life, the diet continues to exclude Phe-containing foods. If PKU is diagnosed early enough, an affected newborn can grow up with normal brain development, but only by eating a special diet low in Phe for the rest of

20

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel

Hähnel S. Brain MRI Abnormalities in Phenylketonuria

white matter abnormality has not shown consistent correlation with measures of intelligence quotient (IQ), dietary control, visual evoked potential, or neuropsychological testing [6]. The etiology of T2 hyperintensities in PKU is unclear. Several groups have suggested that T2 hyperintensities reflect increased water content within white matter of patients with PKU [6]. The increased white matter water content has been suggested to reflect edema associated with the myelination or to reflect gliosis within the tissue. Diffusion-weighted MR imaging (DWI) may provide additional quantitative information about the nature of parenchymal changes and for assessing and monitoring patients with PKU. The purpose of the recently published study of Phillips et al. [12] was to investigate white matter abnormalities in PKU patients by using quantitative diffusion measurements and to compare these measurements with those obtained from healthy subjects. One pediatric and two adult patients with classic PKU were examined. Apparent diffusion coefficient (ADC) maps were calculated in each of the

a

cardinal directions and averaged to produce an average ADC map. Diffusion images were also obtained for six healthy volunteers. All three PKU patients revealed T2 hyperintensities that were detected on T2-weighted FSE and FLAIR images. Eight regions of interest (ROIs) within cerebral white matter were examined on the ADC maps. ROIs were compared between the three subjects and six healthy adults by using a standard t-test. All three PKU patients demonstrated decreased water diffusion within their white matter. These results of Phillips et al. [12], however, are preliminary and warrant further study to delineate the potential variables that may be the reason for restricted diffusion in PKU. The diffusion findings need to be evaluated in a larger number of PKU patients and normals to determine their reliability and sensitivity compared with conventional MR imaging. Further investigation needs to be performed to determine the sensitivity of diffusion imaging for detecting abnormalities in normal-appearing white matter of PKU patients on T2-weighted images. Additionally, it is not known if the diffusion images seen in this report are reversible similar to those

b

Figures 2a and 2b. 18-year-old man with PKU. Axial T2-weighted MR images showing typical almost symmetric white matter hyperintensities in the occipital and frontal white matter (a, b).

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel

21

Hähnel S. Brain MRI Abnormalities in Phenylketonuria

a

b Figures 3a to 3c. Segmentation of the pons. Manually drawn region of interest (ROI; a, b) and three-dimensional projection (c).

c seen with the T2 abnormalities when the diet is well controlled [10, 11]. DWI should also be correlated with other clinical factors, such as IQ, neuropsychological results, visual evoked potentials, dietary control, and metabolic parameters. MR Volumetry Pfaendner et al. [13] performed an MR volumetric study of several brain substructures in 31 adult patients

22

with PKU as compared with 27 healthy volunteers. The onset of dietary restriction in the PKU group ranged from day 4 to day 77 of life, and dietary restriction was not stopped before the age of 18 years. A variety of metabolic and neuropsychological parameters were acquired. For volumetric measurements the software BRAINS2 provided by the Image Processing Lab of the University of Iowa, USA (http://www.psychiatry. uiowa.edu/ipl), was used [14]. Volumes were calculated on tissue-classified images [15]. The substructures were defined as described in the following. Brain (brain) was defined as intracranial volume including the whole supra- and infratentorial brain tissue superior to the foramen magnum and cerebrospinal fluid. Optic nerve, optic chiasm, pituitary gland, and mamillary bodies were excluded. For that purpose a BRAINS2 mask was generated and corrected by manual tracing. Cerebellar volume (cbl), was defined as the infratentorial brain tissue volume excluding the pons. Those parts of the cerebellar peduncles which were located dorsally to the coronal slice in which the vestibulocochlear nerve enters the brain stem at the pontomedullary sulcus were included in the cerebellar volume. A BRAINS2 mask was generated and corrected by means of manual tracing. Cerebrum (cbr) was defined as the entire supraten-

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel

Hähnel S. Brain MRI Abnormalities in Phenylketonuria

Table 1. Volumetric data of the analyzed brain structures and two-dimensional extension of the torial brain tissue volume excluding corpus callosum. PKU versus normal group. call: corpus callosum; caud: nucleus caudatus; cbl: subarachnoid spaces. Pons (pons) cerebellum; cbr: cerebrum; hippo: hippocampus; lent: nucleus lentiformis; NS: not significant; was defined as the infratentorial PKU: phenylketonuria; SD: standard deviation; thal: thalamus; ventr: lateral ventricles. brain tissue volume superior to the Structure PKU Normal foramen magnum excluding the cerMean value ± SD Mean value ± SD p value ebellar volume (Figure 3). The volume of the lateral ventricles (ventr) brain 1,460.32 ± 179.72 1,674.20 ± 99.7 < 0.001 was completely traced manually. cbr 960.64 ± 117.45 1,101.10 ± 95.5 < 0.001 cbl 132.30 ± 9.35 140.30 ± 11.3 NS Choroid plexus was excluded. Adpons 29.27 ± 6.38 34.90 ± 6.9 < 0.005 ditionally, the two-dimensional excall 5.70 ± 0.71 6.31 ± 0.74 < 0.005 tension of the corpus callosum (call) hippo 5.24 ± 0.80 6.13 ± 1.43 < 0.001 in the midsagittal plane by manual caud 7.32 ± 1.01 7.42 ± 0.85 NS tracing was measured. lent 9.90 ± 0.70 9.96 ± 0.79 NS In the study of Pfaendner et al. thal 12.10 ± 0.88 11.75 ± 0.67 NS [13], cerebrum, corpus callosum, ventr 13.71 ± 1.75 12.50 ± 2.15 < 0.005 hippocampus, intracranial volume, Note: all volumes are given in ml, call is given in cm2 and pons were found to be significantly smaller in PKU patients than different in different patients. These findings are supin normals. The volume of the lateral ventricles was ported by Koch et al. [22] and Weglage et al. [23] who significantly larger in PKU patients than in normals. found no correlation between blood and brain Phe The most severely affected structures were pons (∆rel levels and therefore favor an individual blood-brain = 16%), hippocampus (∆rel = 14.5%), cerebrum (∆rel barrier Phe transport system. Brain tissue volumetry = 13%), and corpus callosum (∆rel = 10%). No signifiperformed before and after the stop of the dietary cant differences were found for the basal ganglia, for treatment could clarify whether volume loss occurs in the cerebellum, and for the thalamus. There were no PKU after diet cessation. significant correlations found between the volume of any of the different brain structures and the metabolic Conclusion parameters. A significant correlation was only found PKU, a primarily white matter disease, is characterbetween IQverb and hippocampus (r = 0.471; p < 0.01), ized by typical MR imaging findings such as symmetbut not between the volume of any of the different ric hyperintensities of cerebral white matter of the brain structures and the metabolic parameters. The parietal and occipital lobes. In severe cases, also the results of the volumetric measurements are summafrontal and temporal lobes may be involved. Interestrized in Table 1. These findings of Pfaendner et al. [13] ingly, water diffusion in these lesions as measured by are in accordance with other, nonquantitative imaging DWI seems to be decreased. The basal ganglia, brain studies [8, 16–19]. However, it has not been previously stem, and cerebellum are rarely affected. These hyreported that the size of the hippocampus is reduced perintensities may be reversible with good dietary in PKU. It could be speculated that this finding might control. The most severely affected structures with be the morphological correlate for impaired memory respect to volume loss in patients with PKU treated function in these patients. early in life are cerebrum, corpus callosum, hippocamAccording to the results of Rupp et al. [20] and pus, and pons. These volumetric findings may help to Pietz et al. [21] who found a strong linear correlation determine whether patients with PKU should be recbetween blood Phe values and brain Phe values, a corommended to receive lifelong dietary treatment or relation between blood Phe values and brain volume not. However, no correlations between the volume of could be expected as well. However, Pfaendner et al. any of the different brain structures and the metabolic [13] found no such correlation between blood Phe valparameters are evident. Further study is needed to deues and brain volume. This lack of correlation in our termine the relationship between volumetric MR data, study could be explained by the fact that the impact of MR imaging, and clinical parameters in patients with Phe on brain development is most marked in the early PKU. years of life and blood-brain transport of Phe could be

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel

23

Hähnel S. Brain MRI Abnormalities in Phenylketonuria

Conflict of Interest Statement I certify that there is no actual or potential conflict of interest in relation to this article.

References 1. Scriver CR, Kaufman S, Eisensmith RC, et al. The hyperphenylaninemias. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The metabolic basis of inherited disease, 7th edn, vol 1. New York: McGraw-Hill, 1995:1015–75. 2. Brenton DP, Pietz J. Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr 2000;159:Suppl 2:S114–20. 3. Malamud N. Neuropathology of phenylketonuria. J Neuropathol Exp Neurol 1966;25:254–68. 4. Pietz J. Neurological aspects of adult phenylketonuria. Curr Opin Neurol 1998;11:679–88. 5. Brenton DP, Tarn AC, Cabrera-Abreu JC, et al. Phenylketonuria: treatment in adolescence and adult life. Eur J Pediatr 1996;155:Suppl 1:S93–6. 6. Ullrich K, Moller H, Weglage J, et al. White matter abnormalities in phenylketonuria: results of magnetic resonance measurements. Acta Paediatr Suppl 1994;407:78–82. 7. Dyer CA. Comments on the neuropathology of phenylketonuria. Eur J Pediatr 2000;159:Suppl 2:S107–8. 8. Huttenlocher PR. The neuropathology of phenylketonuria: human and animal studies. Eur J Pediatr 2000;159:Suppl 2:S102–6. 9. Pietz J, Meyding Lamade UK, Schmidt H. Magnetic resonance imaging of the brain in adolescents with phenylketonuria and in one case of 6 pyruvoyl tetrahydropteridine synthase deficiency. Eur J Pediatr 1996; 155:Suppl 1:S69–73. 10. Cleary MA, Walter JH, Wraith JE, et al. Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change. J Pediatr 1995;127:251–5. 11. Thompson AJ, Tillotson S, Smith I, et al. Brain MRI changes in phenylketonuria. Associations with dietary status. Brain 1993;116:811–21. 12. Phillips MD, McGraw P, Lowe MJ, et al. Diffusion-weighted imaging of white matter abnormalities in patients with phenylketonuria. AJNR Am J Neuroradiol 2001;22:1583–6. 13. Pfaendner NH, Reuner G, Pietz J, et al. MR imaging-based volumetry in patients with early-treated phenylketonuria. AJNR Am J Neuroradiol 2005;26:1681–5. 14. Magnotta VA, Harris G, Andreasen NC, et al. Structural MR image processing using the BRAINS2 toolbox. Comput Med Imaging Graph 2002; 26:251–64.

24

15. Harris G, Andreasen NC, Cizadlo T, et al. Improving tissue classification in MRI: a three-dimensional multispectral discriminant analysis method with automated training class selection. J Comput Assist Tomogr 1999;23:144–54. 16. Hanley WB, Feigenbaum AS, Clarke JT, et al. Vitamin B12 deficiency in adolescents and young adults with phenylketonuria. Eur J Pediatr 1996;155:Suppl 1:S145–7. 17. Hanley WB, Koch R, Levy HL, et al. The North American Maternal Phenylketonuria Collaborative Study, developmental assessment of the offspring: preliminary report. Eur J Pediatr 1996;155:Suppl 1: S169–72. 18. Leuzzi V, Trasimeni G, Gualdi GF, et al. Biochemical, clinical and neuroradiological (MRI) correlations in late-detected PKU patients. J Inherit Metab Dis 1995;18:624--34. 19. Villasana D, Butler IJ, Williams JC, et al. Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis 1989;12:451–7. 20. Rupp A, Kreis R, Zschocke J, et al. Variability of blood-brain ratios of phenylalanine in typical patients with phenylketonuria. J Cereb Blood Flow Metab 2001;21:276–84. 21. Pietz J, Rupp A, Burgard P, et al. No evidence for individual bloodbrain barrier phenylalanine transport to influence clinical outcome in typical phenylketonuria patients. Ann Neurol 2002;52:382–3, author reply 383–4. 22. Koch R, Moats R, Guttler F, et al. Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics 2000;106:1093–6. 23. Weglage J, Wiedermann D, Denecke J, et al. Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria. Ann Neurol 2001;50:463–7.

Address for Correspondence Stefan Hähnel, MD Division of Neuroradiology Department of Neurology University of Heidelberg Medical Center Im Neuenheimer Feld 400 69120 Heidelberg Germany Phone (+49/6221) 56-7566, Fax -4673 e-mail: [email protected]

Clin Neuroradiol 2008 · No. 1 © Urban & Vogel