Cerebral 1H MR spectroscopy revealing white matter NAA decreases in glutaric aciduria type I

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Molecular Genetics and Metabolism 88 (2006) 285–289 www.elsevier.com/locate/ymgme

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Cerebral 1H MR spectroscopy revealing white matter NAA decreases in glutaric aciduria type I P.E. Sijens a,¤, G.P.A. Smit b, L.C. Meiners a, M. Oudkerk a, F.J. van Spronsen c a

Department of Radiology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands Department of Pediatrics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands c Beatrix Children’s Hospital, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands b

Received 3 January 2006; accepted 4 January 2006 Available online 20 February 2006

Abstract MR spectroscopy in two patients with glutaric aciduria type I revealed reductions in the white matter N-acetylaspartate signal, in the more severe case accompanied by a loss of glutamate and the appearance of lactate signals. © 2006 Elsevier Inc. All rights reserved. Keywords: Glutaric aciduria type I; Magnetic resonance spectroscopy; Brain metabolism

Introduction

Case reports

Glutaric aciduria type I (GA I) is a rare inborn error of tryptophan, lysine, and hydroxylysine metabolism caused by the deWciency of glutaryl-CoA dehydrogenase. Impaired degradation of these amino acids renders accumulation of 3-OH glutaric acid (glutaric acid and gluconic acid may also be found) and neurotoxicity [1,2]. In MR imaging the observations include enlarged sylvian Wssures, white matter and basal ganglia changes, and atrophy of brain tissue [3]. 1 H MR single voxel spectroscopy studies indicated decreased N-acetylaspartate/creatine ratio (NAA/Cr), slightly increased choline/Cr ratio, and increased inositol/ Cr ratio in one case of GA I [3] as opposed to normal metabolite levels in another [4]. Very recently NAA/Cr decrease was as well as a presence of lactate was observed in a third case of GA I [5]. The purpose of this study was to use multiple voxel MR spectroscopy (MRS) to map and quantitatively assess brain metabolism in two more cases of GA I.

Patient 1

*

Corresponding author. E-mail address: [email protected] (P.E. Sijens).

1096-7192/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2006.01.001

Female and Wrst child of nonconsanguineous healthy parents of Turkish descent. A younger sister was healthy. Pregnancy and delivery were uneventful. Psychomotor retardation was noticed from age 17 months on. Macrocephaly was not found as a presenting sign, dystonia and dyskinesia were not prominent, and a muscle biopsy performed at age two showed normal morphology. Hypertonia initially was prominent and later choreoathetotic movement disorders gradually developed. MRI scanning of the cerebrum was interpreted as Leigh’s disease. From age Wve years epileptic seizures were regularly noticed, increasing in duration, and severity. Anti-epileptic treatment could not suppress these attacks. Subsequent neuroimaging revealed a tumor in the region of the right insula, causing a slight midline shift. In both hemispheres increased signal intensity was seen diVusely in the frontoparietal white matter with slight extension to the temporal white matter. The arcuate Wbres were spared. This diVuse white matter disease did not have the appearance of transependymal CSF leakage caused by high ventricular pressure. Furthermore high signal was seen bilaterally in the dorsal putamen, the right

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thalamus, and right head of the caudate nucleus. The left pretemporal CSF space was enlarged. On the right side this was not seen in the presence of the tumor. Besides the tumor, the white matter Wndings, and the enlarged pretemporal CSF space on the left were consistent with the MRI abnormalities found in GA I. Pathological anatomical analysis revealed a primitive neuro-ectodermal tumor. The patient died from increased intracranial pressure due to the tumor at age six years. Metabolic work up in the same period in blood revealed largely increased glutarylcarnitine (not quantiWed) and lactate concentrations varying between 1.3 and 4.8 mmol/L. Ketone bodies were not measured. Urine analysis revealed abnormalities in the organic acid proWle: glutaric aciduria and 3-OH glutaric aciduria were demonstrated. Varying concentrations of glutaric acid were found in urine and up to 33 mmol/mol creatinine 3hydroxic glutaric acid. Enzyme assay: glutaryl-CoA dehydrogenase activity mmol/h/g protein 0.01 (mean controls 5.0 § 1.6) measured by Ernst Christensen Copenhagen University Hospital, conWrming the diagnosis of glutaric aciduria type I. No DNA mutation studies were performed.

delivery were uneventful. Developmental milestones until age 10 months were within normal limits. At the age of 10 months Wrst generalised convulsions occurred. From that moment on psychomotor retardation was noticed, gradually evolving into spastic tetraparesis. In blood carnitine was low (total 18; free 6 mmol/L), and an increased amount of glutarylcarnitine was found (0.94 mmol/L). Lactate concentrations varied between 1.7 and 7.3 mmol/L; ketone bodies were not measured. The urine contained huge amounts (not further quantiWed) of glutaric acid and 3-hydroxic glutaric acid. The enzyme assay revealed glutaryl-CoA dehydrogenase activity mmol/h/g protein 0.48 (mean controls 5.0 § 1.6) measured by Ernst Christensen Copenhagen University Hospital. In cultured Wbroblasts deWciency of glutaryl-CoA dehydrogenase conWrmed the diagnosis glutaric aciduria type I. MRI scan of the cerebrum revealed delayed myelination, fronto-temporal volume loss, and widened Sylvian Wssures together with ventriculomegaly. In cultured Wbroblasts deWciency of glutarylCoA dehydrogenase conWrmed the diagnosis glutaric aciduria type I. Mutation analysis showed S119L and R161Q. Methods: MR spectroscopy

Patient 2 Male and the second child of healthy nonconsanguineous Dutch parents. An older sister was healthy. Pregnancy and

Standard MRI and multivoxel MRS were performed at 1.5 T (Sonata, Siemens, and Germany). 2D chemical shift imaging of a supraventricular volume of interest was combined with point resolved spectroscopy (TR/TE 1500/135 ms) to be able to diVerentiate between any

Fig. 1. 1H MRS in GA I (Patient 1) (TR/TE D 1500/135 ms). Supraventricular 8 £ 8 £ 1.5 cm3 volume of interest (A,B), spectral map (C), and spectra showing a low NAA signal and the presence of lactate in cerebral white matter (D) voxel position indicated in blue. (E) The gray matter spectra are normal. (For interpretation of the references in color in this Wgure legend, the reader is referred to the web version of this article.)

P.E. Sijens et al. / Molecular Genetics and Metabolism 88 (2006) 285–289 lipid and lactate signals detected at a chemical shift position of 1.3 ppm [6]. A transverse plane of, typically, 8 £ 8 D 64 voxels of 2 cm2 each was thus measured of which the inner 6 £ 6 D 36 voxels were used in quantitative analysis. To diVerentiate between gray and white matter metabolite levels, the spectral maps of Figs. 1 and 2 were separated into the two central columns essentially containing gray matter, and the four adjacent columns containing white matter (the sums of 12 and 24 voxels, respectively). The results in both patients were compared with those in four age-matched children suVering from nothing beyond occasional epilepsy or headaches, conditions assumed not to aVect MR spectra, and serving as controls.

Results In Patient 1, examined at age Wve, MRS showed essentially normal gray matter spectra. However, glutamate (the signal detected at 2.35 ppm includes glutamine) and NAA were reduced relative to Cr (Table 1). More severe abnormalities were found in the white matter consisting of

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more drastic reductions in the levels of glutamate and NAA and the presence of lactate signal (Fig. 1). Lactate and inositol, though visible in Fig. 1, are not tabulated because their peak areas were inaccurate due to low signal-to-noise ratios. The tumor was not included in the MRS volume of interest of Patient 1. In Patient 2, also examined at age Wve, the metabolite levels in a similar supraventricular volume of interest were near normal both in white and gray matter (Fig. 2), with exception of a slight reduction in the white matter NAA levels compared to those in gray matter. In Fig. 3 the NAA metabolite maps for Patient 1, Patient 2, and an otherwise healthy control of age six who was examined by MRI/MRS because of his frequency of headaches, are shown for comparison. In the cortical gray matter brain tissue of both GA I patients the NAA level was higher than (Patient 1) or similar to the NAA level in the white matter (Patient 2).

Fig. 2. 1H MRS in GA I (Patient 2) (TR/TE D 1500/135 ms). Supraventricular 7 £ 8 £ 2 cm3 volume of interest (A,B), spectral map (C), and spectra showing normal metabolite signals without the presence of lactate in cerebral white matter (D) voxel position indicated in blue. (E) The gray matter spectra are normal. (For interpretation of the references in colour in this Wgure legend, the reader is referred to the web version of this article.) Table 1 MRS signals in % of gray matter Cr White matter

Controls (n D 4) Patient 1 Patient 2

Gray matter

Cho

Cr

Glu

NAA

Cho

Cr

Glu

NAA

99 § 10 110 104

94 § 14 67* 60*

16 § 4 4** 16

187 § 23 82** 168

86 § 9 104 86

100 100 100

23 § 2 16** 10**

166 § 13 122** 172

Z-scores outside the ¡1.96 to 1.96 range (*P < 0.05) and the ¡2.58 to 2.58 range (**P < 0.01) indicated, assuming normal distribution.

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Fig. 3. 1H MRS: interpolated metabolic maps for NAA in Patient 1 (A), Patient 2 (B), and in a 6-year-old control (C), scaled from minimum peak integral value (dark blue) to its maximum (dark red). In Patient 1, NAA is reduced in the white matter, especially in the right hemisphere (blue), in Patient 2 the NAA contents in gray and white matter are similar, and in the control the NAA content in white matter is higher than that in gray matter. (For interpretation of the references in colour in this Wgure legend, the reader is referred to the web version of this article.)

At this level of the brain in controls, the NAA level in gray matter is lower than that in the white matter (Fig. 3C). Tryptophan, lysine, hydroxylysine, or glutaric acid signals were detected, and the signals of inositol were not signiWcantly diVerent from normal. Discussion NAA Although its precise role in neurotransmission has not been established, NAA is known to be a measure of the integrity and content of neurons. The loss of NAA signal in the white matter, both in comparison with the NAA in the gray matter and with the white matter NAA levels in controls of the same age, were observed in both patients, and though to a lesser extent in Patient 2. The white matter NAA loss in both cases of GA I indicates that in this disease the neuronal degeneration is not limited to the gray matter of the basal ganglia region [1,3,5] (not included in our volume of interest examined by MRS), but extends to the supraventricular white matter as well. Our result regarding the loss of NAA in white matter Wts previous observations of NAA/Cr ratio reduction in the frontal white matter [3,5]. In one of the three previous cases of GA I documented by MRS no spectral changes were observed in the single brain voxel examined (basal ganglia) possibly reXecting that in that particular case GA I was not conWrmed in cultured Wbroblasts and/or DNA analysis [4]. Lactate The presence of lactate in the white matter of Patient 1 could reXect leakage of lactate from the tumor located elsewhere in the brain [7]. Furthermore, one cannot exclude that the Wndings in Patient 1 are secondary to the brain tumor and raised intracranial pressure rather than the metabolic disease. However, white matter’s very low glutamate level was incompatible with the characteristics of tumor metabo-

lism (typically causing very high glutamate levels within and outside tumor). An alternative explanation is as follows. Compromised function of mitochondrial respiratory chain mediated by metabolites accumulating in GA I has been described in animal studies [8–10]. These Wndings could lead to ‘slow onset excitotoxicity’ explaining the lactate peak and also the comparatively reduced Cr level in Patient 1’s white matter. The result would be a formation of necrosis as has been manifest in GA I by decreased attenuation on CT [11], increased signal intensity on T2 weighted MRI [12], and reduced uptake of Xuorodeoxyglucose on positron emission tomography [2]. In support of the latter interpretation is also that in the most recent previously published MRS characterization of a case of GA I a presence of lactate was noted in the basal ganglia and in the normal appearing frontal gray and white matter junction [5]. Glutamate The low glutamate level in the gray matter of both patients and in the white matter of Patient 1 Wts with the known reduction of cellular glutamate level by the presence of glutaric acid, one of the metabolites elevated in GA I [13]. Inhibition of glutamate uptake, as demonstrated for the structurally related compound glutaric acid [9], and may contribute to the 3-OH glutaric acid induced neuronal damage in GA I. The diVerential Wnding for NAA in the white and gray matter of both GA I patients may be explained by diVerences in energy metabolism or diVerent receptor subtypes Wnally leading to cell death (as indicated by decreased NAA) in the white matter (secondary, i.e., ‘slow-onset’, or primary excitotoxicity). In line with this is that the lactate signals and Cr reduction were also observed in Patient 1’s white matter. Our observations indicate that MRS can thus provide more insight into the pathomechanisms involved in acute neurodegeneration of GA I. Further progress should be expected as in more and more institutions MRS measurement becomes integrated with MRI in clinical routine.

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