- Email: [email protected]
Basal ganglia lesions in a patient with 3-hydroxyisobutyric aciduria
Brain & Development 28 (2006) 600–603 www.elsevier.com/locate/braindev
Case report
Basal ganglia lesions in a patient with 3-hydroxyisobutyric aciduria Masayuki Sasaki *, Naoto Yamada, Michio Fukumizu, Kenji Sugai Department of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan Received 15 August 2005; received in revised form 12 February 2006; accepted 18 March 2006
Abstract 3-Hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. We report the case of a 7-year-old boy with 3HiB-uria who has suffered more than 20 ketoacidotic episodes since the age of 15 months. In the most recent ketoacidotic episode, which was particularly severe, he developed mild dystonia and choreoathetosis. Magnetic resonance imaging (MRI) revealed bilateral swelling and signal abnormalities of the putamina and heads of the caudate nuclei. The abnormal movements showed a gradual improvement over several months, in correlation with neuroradiological findings. 3HiB-uria should be recognized as one of the group of branched chain organic acidemias that can produce lesions in the basal ganglia. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Organic aciduria; Ketoacidosis; Putamen; Caudate nucleus; Swelling
1. Introduction
2. Case report
3-Hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. Only 12 patients have been reported in the literature, and as yet no enzyme defect has been detected [1]. Several patients with 3HiB-uria have exhibited dysmorphic features of the face [2]. A few reports described congenital brain malformations, especially migration disorders [2]. The phenotypic variation is so wide that some patients show a mild clinical course [3–5], and others a poor prognosis [2,6]. So far, no consistent neuroradiological findings have been established for this disorder, and no basal ganglia lesions have been reported. This is the first demonstration of basal ganglia involvement in a patient with 3HiB-uria.
This patient was one of the subjects documented in a previous report [3]. He had an elder brother who died as a result of ketoacidosis. This patient showed mild motor delay due to mild hypotonia. He started walking at 19 months. He experienced many ketoacidotic episodes from the age of 15 months. As previously reported [3], the diagnosis of 3HiB-uria was made by gas chromatography/mass spectrometry using urine obtained at 19 months of age, at a time when he was not ketoacidotic. At 30 months, brain magnetic resonance imaging (MRI) revealed only a mild white matter abnormality, with no abnormalities noted in the basal ganglia [3]. By the age of 7 years he had experienced more than 20 episodes of ketoacidosis, although following diagnosis, treatment with protein restriction (2 g/kg/day) and L-carnitine supplements (100 mg/kg) had reduced the frequency of attacks. When ketoacidotic, he suffered drowsiness and vomiting, but after hydration therapy for 1 day he usually recovered rapidly. His mental ability was normal. At 6 years of age a computed
*
Corresponding author. Tel.: +81 42 341 2711; fax: +81 42 344 6745. E-mail address: [email protected] (M. Sasaki). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.03.007
M. Sasaki et al. / Brain & Development 28 (2006) 600–603
tomography (CT) scan of his brain performed between ketoacidotic episodes was normal. At 7 years and 5 months he developed vomiting and drowsiness, and was admitted to our hospital for hydra-
601
tion therapy. His cerebrospinal fluid was clear. No infection was detected on blood examination. The urine was positive for ketone bodies and the blood was mildly acidotic, with slightly elevated levels of lactate and pyru-
Fig. 1. Axial MRI findings at 3 days (upper row), 2 months (middle row), and 6 months (lower row) after the onset of the most recent ketoacidotic episode. At 3 days (upper row), a T1-weighted image (a) reveals bilateral swelling and low signal intensity in the putamina and heads of the caudate nuclei. T2-weighted (b) and FLAIR (c) images reveal high signal intensity areas in the same regions. At 2 months (middle row), MRI shows reduction of the swelling, and high signal intensity in the abnormal area. The T1-weighted image (d) exhibits an abnormal high intensity area in the region. Focal high intensity areas are seen in the T2-weighted (e) and FLAIR (f) images. These findings could represent hemorrhage or calcification. At 6 months (lower row), the areas of abnormal intensity have improved.
602
M. Sasaki et al. / Brain & Development 28 (2006) 600–603
vate. Vitamin B1 and blood glucose concentrations were normal. Two days after the onset of ketoacidosis, he was still drowsy. It took 3 more days for him to recover to a fully alert level of consciousness, which represented a much longer duration of illness than he had suffered in previous episodes. Two days after the onset of this ketoacidotic episode, CT scans of the brain showed bilateral areas of low density and swelling in the putamina and heads of the bilateral caudate nuclei. The following day, MRI revealed swelling and high intensity areas bilaterally in the basal ganglia, from both T2-weighted images and fluid attenuated inversion recovery (FLAIR) images. Low intensity areas were observed in the same regions in T1-weighted images (Fig. 1, upper row). After 3 weeks, the patient could walk again and his mental abilities were not impaired. He showed involuntary movements (dystonia and choreoathetosis) bilaterally in the upper extremities, but these improved gradually. MRI was performed immediately after this episode, and again 2 months and 6 months later. The areas of abnormal signal intensity gradually improved (Fig. 1, middle and lower row). Two months after the episode, the swelling and high intensity areas observed in the T2-weighted images had resolved. In T1-weighted images, however, areas of high signal intensity were seen in the heads of the caudate nuclei and the rostral parts of the putamina. These findings were suggestive of hemorrhage or calcification. Six months after the episode, the MRI findings had almost returned to normal.
3. Discussion In this report, we have described a patient with a recurrent acute illness manifested by disturbances of consciousness, vomiting, and extrapyramidal signs. One year before the most recent ketoacidotic episode, a brain CT scan did not reveal any abnormalities, despite more than 20 previous episodes. However, during this last episode, CT and MRI demonstrated bilateral lesions in the basal ganglia. These consisted of swelling and edema in the putamina and heads of the caudate nuclei. This episode was much more severe and the disturbance of consciousness lasted much longer than in previous occurrences. There was no evidence that the basal ganglia lesions in this case were caused by any disorder other than the ketoacidosis associated with 3HiB-uria. Although basal ganglia lesions have not been reported in previous 3HiB-uria cases, it appears that in this patient the ketoacidotic episode was of sufficient severity to produce basal ganglia pathology. The findings may reflect a particular vulnerability of the basal
ganglia in this disorder. The possibility remains that in this patient and others, transient basal ganglia lesions have been missed because MRI and CT scanning has been carried out between (rather than during) ketoacidotic episodes. Basal ganglia lesions have been demonstrated in a variety of childhood disorders, including mitochondrial disorders [7] (e.g., MELAS syndrome), Leigh disease, inborn errors of metabolism (e.g., organic acidemia [8,9], sphingolipidosis), infection, hypoxic-ischemic encephalopathy, Wernicke encephalopathy due to vitamin B1 deficiency [10], and trauma or toxins. Leigh disease is a well-known heterogeneous disease in which damage to the basal ganglia (especially the bilateral putamina [7]) and brain stem is mediated by hyperlactic acidemia. The basal ganglia are regions with high energy and oxygen demands, and are therefore vulnerable in hypoxia or in conditions such as mitochondrial disorders where energy production is disturbed. Basal ganglia lesions, especially in the globus pallidus, are relatively frequent in inborn errors of metabolism where branched chain amino acid catabolism is affected (e.g., methylmalonic acidemia and propionic acidemia [8,9]). In these disorders, mitochondrial function is likely to be disturbed during ketoacidotic episodes with hyperlactic acidemia. While 3HiB-uria instead involves valine metabolism, it also manifests hyperlactic acidemia during ketoacidotic episodes. Mitochondrial function is likely to be disturbed in this disorder as it is in other branched chain organic acidemias, with consequences for vulnerable regions of the brain. The findings from this case indicate that 3HiBuria should be recognized as another amongst this group of inborn errors of metabolism that is capable of producing lesions in the basal ganglia.
References [1] Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The molecular and metabolic bases of inherited disease. New York, NY: MacGraw-Hill; 2001. p. 2125–63. [2] Chitayat D, Meagher-Villemure K, Mamer OA, O‘Gorman A, Hoar DI, Silver K, et al. Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 1992;121:86–9. [3] Sasaki M, Kimura M, Sugai K, Hashimoto T, Yamaguchi S. 3-Hydroxyisobutyric aciduria in two brothers. Pediatr Neurol 1998;18:253–5. [4] Ko FJ, Nyhan WL, Wolff J, Barshop B, Sweetman L. 3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism. Pediatr Res 1991;30:322–6. [5] Boulat O, Benador N, Girardin E, Bachmann C. 3-Hydroxyisobutyric aciduria with a mild clinical course. J Inherit Metab Dis 1995;18:204–6. [6] Sasaki M, Iwata H, Sugai K, Fukumizu M, Kimura M, Yamaguchi S. A severely brain-damaged case of 3-hydroxyisobutyric aciduria. Brain Dev 2001;23:243–5.
M. Sasaki et al. / Brain & Development 28 (2006) 600–603 [7] Barkovich AJ. Pediatric neuroimaging. Mitochondrial disorder. Philadelphia, PA: Lippincott Williams & Wilkins; 2000, 127–32. [8] Andreula CF, De Blasi R, Carella A. CT and MR studies of methylmalonic acidemia. Am J Neuroradiol 1991;12: 410–2.
603
[9] Brismar J, Ozand PT. CT and MR of the brain in disorders of propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459–73. [10] Sasaki M, Matsuda H, Omura I, Sugai K, Hashimoto T. Transient seizure disappearance due to bilateral striatal necrosis in a patient with intractable epilepsy. Brain Dev 2000;22:50–5.
Case report
Basal ganglia lesions in a patient with 3-hydroxyisobutyric aciduria Masayuki Sasaki *, Naoto Yamada, Michio Fukumizu, Kenji Sugai Department of Child Neurology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan Received 15 August 2005; received in revised form 12 February 2006; accepted 18 March 2006
Abstract 3-Hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. We report the case of a 7-year-old boy with 3HiB-uria who has suffered more than 20 ketoacidotic episodes since the age of 15 months. In the most recent ketoacidotic episode, which was particularly severe, he developed mild dystonia and choreoathetosis. Magnetic resonance imaging (MRI) revealed bilateral swelling and signal abnormalities of the putamina and heads of the caudate nuclei. The abnormal movements showed a gradual improvement over several months, in correlation with neuroradiological findings. 3HiB-uria should be recognized as one of the group of branched chain organic acidemias that can produce lesions in the basal ganglia. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Organic aciduria; Ketoacidosis; Putamen; Caudate nucleus; Swelling
1. Introduction
2. Case report
3-Hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. Only 12 patients have been reported in the literature, and as yet no enzyme defect has been detected [1]. Several patients with 3HiB-uria have exhibited dysmorphic features of the face [2]. A few reports described congenital brain malformations, especially migration disorders [2]. The phenotypic variation is so wide that some patients show a mild clinical course [3–5], and others a poor prognosis [2,6]. So far, no consistent neuroradiological findings have been established for this disorder, and no basal ganglia lesions have been reported. This is the first demonstration of basal ganglia involvement in a patient with 3HiB-uria.
This patient was one of the subjects documented in a previous report [3]. He had an elder brother who died as a result of ketoacidosis. This patient showed mild motor delay due to mild hypotonia. He started walking at 19 months. He experienced many ketoacidotic episodes from the age of 15 months. As previously reported [3], the diagnosis of 3HiB-uria was made by gas chromatography/mass spectrometry using urine obtained at 19 months of age, at a time when he was not ketoacidotic. At 30 months, brain magnetic resonance imaging (MRI) revealed only a mild white matter abnormality, with no abnormalities noted in the basal ganglia [3]. By the age of 7 years he had experienced more than 20 episodes of ketoacidosis, although following diagnosis, treatment with protein restriction (2 g/kg/day) and L-carnitine supplements (100 mg/kg) had reduced the frequency of attacks. When ketoacidotic, he suffered drowsiness and vomiting, but after hydration therapy for 1 day he usually recovered rapidly. His mental ability was normal. At 6 years of age a computed
*
Corresponding author. Tel.: +81 42 341 2711; fax: +81 42 344 6745. E-mail address: [email protected] (M. Sasaki). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.03.007
M. Sasaki et al. / Brain & Development 28 (2006) 600–603
tomography (CT) scan of his brain performed between ketoacidotic episodes was normal. At 7 years and 5 months he developed vomiting and drowsiness, and was admitted to our hospital for hydra-
601
tion therapy. His cerebrospinal fluid was clear. No infection was detected on blood examination. The urine was positive for ketone bodies and the blood was mildly acidotic, with slightly elevated levels of lactate and pyru-
Fig. 1. Axial MRI findings at 3 days (upper row), 2 months (middle row), and 6 months (lower row) after the onset of the most recent ketoacidotic episode. At 3 days (upper row), a T1-weighted image (a) reveals bilateral swelling and low signal intensity in the putamina and heads of the caudate nuclei. T2-weighted (b) and FLAIR (c) images reveal high signal intensity areas in the same regions. At 2 months (middle row), MRI shows reduction of the swelling, and high signal intensity in the abnormal area. The T1-weighted image (d) exhibits an abnormal high intensity area in the region. Focal high intensity areas are seen in the T2-weighted (e) and FLAIR (f) images. These findings could represent hemorrhage or calcification. At 6 months (lower row), the areas of abnormal intensity have improved.
602
M. Sasaki et al. / Brain & Development 28 (2006) 600–603
vate. Vitamin B1 and blood glucose concentrations were normal. Two days after the onset of ketoacidosis, he was still drowsy. It took 3 more days for him to recover to a fully alert level of consciousness, which represented a much longer duration of illness than he had suffered in previous episodes. Two days after the onset of this ketoacidotic episode, CT scans of the brain showed bilateral areas of low density and swelling in the putamina and heads of the bilateral caudate nuclei. The following day, MRI revealed swelling and high intensity areas bilaterally in the basal ganglia, from both T2-weighted images and fluid attenuated inversion recovery (FLAIR) images. Low intensity areas were observed in the same regions in T1-weighted images (Fig. 1, upper row). After 3 weeks, the patient could walk again and his mental abilities were not impaired. He showed involuntary movements (dystonia and choreoathetosis) bilaterally in the upper extremities, but these improved gradually. MRI was performed immediately after this episode, and again 2 months and 6 months later. The areas of abnormal signal intensity gradually improved (Fig. 1, middle and lower row). Two months after the episode, the swelling and high intensity areas observed in the T2-weighted images had resolved. In T1-weighted images, however, areas of high signal intensity were seen in the heads of the caudate nuclei and the rostral parts of the putamina. These findings were suggestive of hemorrhage or calcification. Six months after the episode, the MRI findings had almost returned to normal.
3. Discussion In this report, we have described a patient with a recurrent acute illness manifested by disturbances of consciousness, vomiting, and extrapyramidal signs. One year before the most recent ketoacidotic episode, a brain CT scan did not reveal any abnormalities, despite more than 20 previous episodes. However, during this last episode, CT and MRI demonstrated bilateral lesions in the basal ganglia. These consisted of swelling and edema in the putamina and heads of the caudate nuclei. This episode was much more severe and the disturbance of consciousness lasted much longer than in previous occurrences. There was no evidence that the basal ganglia lesions in this case were caused by any disorder other than the ketoacidosis associated with 3HiB-uria. Although basal ganglia lesions have not been reported in previous 3HiB-uria cases, it appears that in this patient the ketoacidotic episode was of sufficient severity to produce basal ganglia pathology. The findings may reflect a particular vulnerability of the basal
ganglia in this disorder. The possibility remains that in this patient and others, transient basal ganglia lesions have been missed because MRI and CT scanning has been carried out between (rather than during) ketoacidotic episodes. Basal ganglia lesions have been demonstrated in a variety of childhood disorders, including mitochondrial disorders [7] (e.g., MELAS syndrome), Leigh disease, inborn errors of metabolism (e.g., organic acidemia [8,9], sphingolipidosis), infection, hypoxic-ischemic encephalopathy, Wernicke encephalopathy due to vitamin B1 deficiency [10], and trauma or toxins. Leigh disease is a well-known heterogeneous disease in which damage to the basal ganglia (especially the bilateral putamina [7]) and brain stem is mediated by hyperlactic acidemia. The basal ganglia are regions with high energy and oxygen demands, and are therefore vulnerable in hypoxia or in conditions such as mitochondrial disorders where energy production is disturbed. Basal ganglia lesions, especially in the globus pallidus, are relatively frequent in inborn errors of metabolism where branched chain amino acid catabolism is affected (e.g., methylmalonic acidemia and propionic acidemia [8,9]). In these disorders, mitochondrial function is likely to be disturbed during ketoacidotic episodes with hyperlactic acidemia. While 3HiB-uria instead involves valine metabolism, it also manifests hyperlactic acidemia during ketoacidotic episodes. Mitochondrial function is likely to be disturbed in this disorder as it is in other branched chain organic acidemias, with consequences for vulnerable regions of the brain. The findings from this case indicate that 3HiBuria should be recognized as another amongst this group of inborn errors of metabolism that is capable of producing lesions in the basal ganglia.
References [1] Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The molecular and metabolic bases of inherited disease. New York, NY: MacGraw-Hill; 2001. p. 2125–63. [2] Chitayat D, Meagher-Villemure K, Mamer OA, O‘Gorman A, Hoar DI, Silver K, et al. Brain dysgenesis and congenital intracerebral calcification associated with 3-hydroxyisobutyric aciduria. J Pediatr 1992;121:86–9. [3] Sasaki M, Kimura M, Sugai K, Hashimoto T, Yamaguchi S. 3-Hydroxyisobutyric aciduria in two brothers. Pediatr Neurol 1998;18:253–5. [4] Ko FJ, Nyhan WL, Wolff J, Barshop B, Sweetman L. 3-Hydroxyisobutyric aciduria: an inborn error of valine metabolism. Pediatr Res 1991;30:322–6. [5] Boulat O, Benador N, Girardin E, Bachmann C. 3-Hydroxyisobutyric aciduria with a mild clinical course. J Inherit Metab Dis 1995;18:204–6. [6] Sasaki M, Iwata H, Sugai K, Fukumizu M, Kimura M, Yamaguchi S. A severely brain-damaged case of 3-hydroxyisobutyric aciduria. Brain Dev 2001;23:243–5.
M. Sasaki et al. / Brain & Development 28 (2006) 600–603 [7] Barkovich AJ. Pediatric neuroimaging. Mitochondrial disorder. Philadelphia, PA: Lippincott Williams & Wilkins; 2000, 127–32. [8] Andreula CF, De Blasi R, Carella A. CT and MR studies of methylmalonic acidemia. Am J Neuroradiol 1991;12: 410–2.
603
[9] Brismar J, Ozand PT. CT and MR of the brain in disorders of propionate and methylmalonate metabolism. Am J Neuroradiol 1994;15:1459–73. [10] Sasaki M, Matsuda H, Omura I, Sugai K, Hashimoto T. Transient seizure disappearance due to bilateral striatal necrosis in a patient with intractable epilepsy. Brain Dev 2000;22:50–5.