- Email: [email protected]
Clinical and MRI findings in a case ofd -2-hydroxyglutaric aciduria
ELSEVIER
Brain & Development 1995; 17:139-41
Case report
Clinical and MRI findings in a case of D-2-hydroxyglutaric aciduria Katsuo Sugita a,*, Hiroaki Kakinuma b, Yoshitomo Okajima a, Atsushi Ogawa a, Hiroo Watanabe c, Hiroo Niimi a a Department of Pediatrics, Faculty of Medicine, University of Chiba, 1-8-1 Inohana, Chuou-ku, Chiba-shi 260, Chiba, Japan b Department of Pediatrics, National Shimoshizu Hospital, Chiba, Japan c Department of Pediatrics, Faculty of Medicine, University of Gifu, Gifu, Japan Received 10 August 1994; accepted 9 December 1994
We report the 3rd ca~,~e in the literature of a 3-year-old boy with D-2-hydroxyglutaric (D-2-HG) aciduria, who presented primarily generalized hypotonia and feeding difficulty during the neonatal period, with eventual development of generalired myoclonic seizures. Gas chromatographic analysis of urinary organic acids showed persistent excretion of D-2-HG. The clinical manifestations are quite similar to those of the 2nd reported case with D-2-HG aciduria. Serial MRI performed 1 year and 2 1 / 2 years after birth demonstrated bilateral symmetrical periventricular lesions in the parieto-occipital white matter, which might reflect the cortical blindness in our patient. Keywords: D-2-Hydroxyghataric aciduria; M a g n e t i c r e s o n a n c e imaging; M R I
1. I N T R O D U C T I O N 2-Hydroxyglutaric (2-HG) acid is a normal component of human urine, and occurs in the D and L configurations. Ten cases of L-2-HG aciduria have been reported [1-3]; their clinical and neuroimaging similarities allow the definition of a characteristic phenotype for a novel neurometabolic disease. On the other hand, there have only been two cases of D-2-HG aciduria reported previously [4,5]. The clinical manifestations in both cases of D-2-HG aciduria are quite different from each other, leadirtg to difficulty in regarding this disorder as an entity. We report a third case of D-2-HG aciduria and a comparison with the previous two cases.
2. CASE R E P O R T The patient, a male infant, was born to non-consanguineous parents at 38 weeks gestational age by means of a
* Corresponding author. Fax: (81) (43) 226-2145. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00123-5
normal, spontaneous vaginal delivery. His birth weight was 3018 g, and the Apgar scores were 9 and 9 at 1 and 5 min, respectively. The patient showed generalized hypotonia with weak feeding and crying. He was transported to a neonatal intensive care unit for further examination and treatment. One month after birth, he had generalized myoclonic seizures and so anticonvulsants were administered, which resulted in partial reduction of the seizures. Growth parameters were within normal limits, but psychomotor development was severely delayed. He was admitted because of measles pneumonitis at 6 months after birth, when cardiomegaly was detected on routine chest radiography. Hypertrophy and reduced contractility, with an ejection fraction of 0.45 at the left ventricle, were detected on electrocardiography and echocardiography, respectively, He then became increasingly less responsive to his environment, although he continued to feed well. Because of the delayed psychomotor development and the refractory seizures, this patient was referred to Chiba University Hospital for further evaluation and management. On admission at 1 year and 1 month of age, he was unable to respond to any visual or auditory stimuli. The visual-evoked cortical potential (VECP) exhibited a prolonged P100 latency on both sides. Biochemical assaying for serum very long-chain
140
K. Sugita et aL / Brain & Development 1995; 17:139-41
A
D-2-HG
i.~ L-2-HG
B
D-2-HG -.~'~-" L-2-HG C
D-2-HG
Fig. 2. An axial inversion-recovery spin-echo (TR 2080/TI 800) image shows marked bilateral prolongation of the T1 relaxation time in the parieto-occipital white matter, adjacent to the lateral ventricles (arrow). The amount of periventricular white matter in the cerebral hemispheres is diminished, particularly posteriorly.
Fig. l. Gas-liquid chromatography of 2-hydroxyglutaricacid. A: authentic DL-2-HG. B: authentic DL-2-HG+patient's urine. C: urinary D-2-HG from patient.
fatty acids and lysosomal enzymes, including GM1 and galactocerebroside /3-galactosidase, glucocerebrosidase, and arylsulfatases A, B and C, revealed them to be within normal limits.
Gas chromatographic analysis of urinary organic acids revealed a large peak of 2-HG acid. The absolute configuration of 2-HG was determined by capillary gas-liquid chromatography according to the method described by Duran and Kamerling with a slight modification [6,7]. In Fig. 1, gas chromatograms of the derivatives of commercially available DL-2-HG and the patient's urine are presented. The 2-HG form in the patient's urine was demonstrated to have the D-configuration. The urinary D-2-HG concentration was 1240 mmol/mol creatinine. The levels of plasma and CSF D-2-HG
Table 1 Clinical symptoms of D-2-hydroxyglutaric aciduria (Case) Author Age/sex First symptom Motor system (1) Chalmers et al. [4]
13y/M
Anemia
No retardation
(2) Craigen et al. [9]
23mo/M
Seizures
Involuntary movement Generalized hypotonia
(3) Present case
36mo/M
Seizures
Generalized hypotonia
Others
Neuroradiology
Recurrent chest infection Protein-losing gastroenteropathy Skin hyperpigmentation Lt. ovarian cyst Cortical blindness Hypertrophic cardiomegaly Blt. dilated ureter and pelvis Cortical blindness
Not described
MRI: normal myelination MRI: diminished white manner
K. Sugita et al. /Brain & Development 1995; 17." 139-41
acid were also high, being 287 /zmol/l and 44 /xmol/1, respectively. MRI, performed at the age of 1 year in the manner previously reported [8] demonstrated bilateral symmetrical lesions, such as those of adrenoleukodystrophy, in the parieto-occipital white matter {Fig. 2), which was similar to the repeated MRI findings at 2 1 / 2 years of age. He has had three episodes of urinary tract infection due to different bacterial species, at 8, 10 and 21 months, which were treated with alternate combination therapy with antibiotics. Ultrasound examination demonstrated bilateral dilatation of the ureter and pelvis.
141
D-2-HG aciduria case are quite different from those in L-2-HG aciduria, because the most remarkable abnormalities do not concern the periventricular white matter but the subcortical white matter in the latter [1]. Furthermore, repeated MRI did not show progression of the white matter lesions in our case for one and half years. In addition to these clinical and neuroimaging findings, this patient had severe bilateral dilatation of the ureter and pelvis, which resulted from recurrent urinary infections due to vesico-ureteral reflux. Furthermore, our patient showed marked cardiomegaly on chest radiograph and a reduced ejection fraction of the cardiac contraction. Both these clinical findings were not described for the previous two D-2-HG cases.
3. D I S C U S S I O N D-2-HG aciduria is an organic acid disease, with no confirmative genetic inheriitance. This patient is the third case ever reported in the literature, but is quite different clinically from the first case, which presented protein-losing enteropathy and normal mental development [4] (Table 1). Recently, Craigen et al. [9] reported more detailed clinical findings for a 2nd case, which was described first by Gibson et al. [5]. This 2nd case reportedly showed neurological abnormalities similar to cur patient, i.e. neonatal onset, severe psychomotor developmental delay, early onset of refractory seizures and cortical blindness. Furthermore, the levels of plasma and CSF D-2-HG acid in both cases were remarkably high, in comparison to the normal plasma level in the 1st case. Regarding cortical blindness, Craigen et al. [9] reported normal visual evoked potentials and MRI findings of normal myelination at 23 months of age in the 2nd case. MRI examination in our case demonstrated bilateral periventricular decreased-signal lesion~'i on IR sequences, which were quite similar to those observed in childhood adrenoleukodystrophy with visual pathway involvement [10]. The abnormal MRI findings of optic radiation and no response of VECP in this case constitute further evidence of cortical blindness in D-2-HG aciduria as well as in ALD. On the other hand, Barth et al. reported an identical abnormal pattern with subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamen and dentate nuclei in the 8 L-2-HG aciduria cases reported [1]. Moreover, progressive deterioration was well established by serial CTs in one L-2-HG case [3]. The MRI findings in our
REFERENCES 1. Barth PG, Hoffmann GF, Jaeken J, et al. L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992; 32: 66-71. 2. Divry P, Jakobs C, Vianey-Saban C, et al. L-2-Hydroxyglutaric aciduria: two further cases. J Inher Metab Dis 1993; 16: 505-7. 3. Wilcken B, Pitt J, Heath D, Walsh P, Wilson G, Buchanan N. L-2-hydroxyglutarie aciduria: three Australian cases. J Inher Metab Dis 1993; 16: 501-4. 4. Chalmers RA, Lawson AM, Watts RWE, et al. D-2-Hydroxyglutaric aciduria: case report and biochemical studies. J Inher Metab Dis 1980; 3: 11-5. 5. Gibson KM, Craigen W, Herman GE, Jakobs C. D-2-Hydroxyglutaric aciduria in a newborn with neurological abnormalities: a new neurometabolic disorder? J Inher Metab Dis 1993; 16: 497500. 6. Kamerling JP, Gerwig GJ, Vliegenhart JFG, Duran M, Ketting D, Wadman SK. Determination of the configurations of lactic and glyceric acids from human serum and urine by capillary gas-liquid chromatography. J Chromatogr 1977; 143: 117-23. 7. Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. L-2-Hydroxyglutaricaciduria: an inborn error of metabolism? J Inher Metab Dis 1980; 3: 109-12. 8. Sugita K, Takeuchi A, Iai M, Tanabe Y. Neurologic sequelae and MRI in low-birth weight patients. Pediatr Neurol 1989; 5: 365-9. 9. Craigen WJ, Jakobs C, Sekul EA, et al. D-2-Hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction. Pediatr Neurol 1994; 10: 49-53. 10. Jensen ME, Sawyer RW, Braun IF, Rizzo WB. MRI appearance of childhood adrenoleukodystrophy with auditory, visual and motor pathway involvement. Radiographics 1990; 10: 53-66.
Brain & Development 1995; 17:139-41
Case report
Clinical and MRI findings in a case of D-2-hydroxyglutaric aciduria Katsuo Sugita a,*, Hiroaki Kakinuma b, Yoshitomo Okajima a, Atsushi Ogawa a, Hiroo Watanabe c, Hiroo Niimi a a Department of Pediatrics, Faculty of Medicine, University of Chiba, 1-8-1 Inohana, Chuou-ku, Chiba-shi 260, Chiba, Japan b Department of Pediatrics, National Shimoshizu Hospital, Chiba, Japan c Department of Pediatrics, Faculty of Medicine, University of Gifu, Gifu, Japan Received 10 August 1994; accepted 9 December 1994
We report the 3rd ca~,~e in the literature of a 3-year-old boy with D-2-hydroxyglutaric (D-2-HG) aciduria, who presented primarily generalized hypotonia and feeding difficulty during the neonatal period, with eventual development of generalired myoclonic seizures. Gas chromatographic analysis of urinary organic acids showed persistent excretion of D-2-HG. The clinical manifestations are quite similar to those of the 2nd reported case with D-2-HG aciduria. Serial MRI performed 1 year and 2 1 / 2 years after birth demonstrated bilateral symmetrical periventricular lesions in the parieto-occipital white matter, which might reflect the cortical blindness in our patient. Keywords: D-2-Hydroxyghataric aciduria; M a g n e t i c r e s o n a n c e imaging; M R I
1. I N T R O D U C T I O N 2-Hydroxyglutaric (2-HG) acid is a normal component of human urine, and occurs in the D and L configurations. Ten cases of L-2-HG aciduria have been reported [1-3]; their clinical and neuroimaging similarities allow the definition of a characteristic phenotype for a novel neurometabolic disease. On the other hand, there have only been two cases of D-2-HG aciduria reported previously [4,5]. The clinical manifestations in both cases of D-2-HG aciduria are quite different from each other, leadirtg to difficulty in regarding this disorder as an entity. We report a third case of D-2-HG aciduria and a comparison with the previous two cases.
2. CASE R E P O R T The patient, a male infant, was born to non-consanguineous parents at 38 weeks gestational age by means of a
* Corresponding author. Fax: (81) (43) 226-2145. 0387-7604/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0387-7604(94)00123-5
normal, spontaneous vaginal delivery. His birth weight was 3018 g, and the Apgar scores were 9 and 9 at 1 and 5 min, respectively. The patient showed generalized hypotonia with weak feeding and crying. He was transported to a neonatal intensive care unit for further examination and treatment. One month after birth, he had generalized myoclonic seizures and so anticonvulsants were administered, which resulted in partial reduction of the seizures. Growth parameters were within normal limits, but psychomotor development was severely delayed. He was admitted because of measles pneumonitis at 6 months after birth, when cardiomegaly was detected on routine chest radiography. Hypertrophy and reduced contractility, with an ejection fraction of 0.45 at the left ventricle, were detected on electrocardiography and echocardiography, respectively, He then became increasingly less responsive to his environment, although he continued to feed well. Because of the delayed psychomotor development and the refractory seizures, this patient was referred to Chiba University Hospital for further evaluation and management. On admission at 1 year and 1 month of age, he was unable to respond to any visual or auditory stimuli. The visual-evoked cortical potential (VECP) exhibited a prolonged P100 latency on both sides. Biochemical assaying for serum very long-chain
140
K. Sugita et aL / Brain & Development 1995; 17:139-41
A
D-2-HG
i.~ L-2-HG
B
D-2-HG -.~'~-" L-2-HG C
D-2-HG
Fig. 2. An axial inversion-recovery spin-echo (TR 2080/TI 800) image shows marked bilateral prolongation of the T1 relaxation time in the parieto-occipital white matter, adjacent to the lateral ventricles (arrow). The amount of periventricular white matter in the cerebral hemispheres is diminished, particularly posteriorly.
Fig. l. Gas-liquid chromatography of 2-hydroxyglutaricacid. A: authentic DL-2-HG. B: authentic DL-2-HG+patient's urine. C: urinary D-2-HG from patient.
fatty acids and lysosomal enzymes, including GM1 and galactocerebroside /3-galactosidase, glucocerebrosidase, and arylsulfatases A, B and C, revealed them to be within normal limits.
Gas chromatographic analysis of urinary organic acids revealed a large peak of 2-HG acid. The absolute configuration of 2-HG was determined by capillary gas-liquid chromatography according to the method described by Duran and Kamerling with a slight modification [6,7]. In Fig. 1, gas chromatograms of the derivatives of commercially available DL-2-HG and the patient's urine are presented. The 2-HG form in the patient's urine was demonstrated to have the D-configuration. The urinary D-2-HG concentration was 1240 mmol/mol creatinine. The levels of plasma and CSF D-2-HG
Table 1 Clinical symptoms of D-2-hydroxyglutaric aciduria (Case) Author Age/sex First symptom Motor system (1) Chalmers et al. [4]
13y/M
Anemia
No retardation
(2) Craigen et al. [9]
23mo/M
Seizures
Involuntary movement Generalized hypotonia
(3) Present case
36mo/M
Seizures
Generalized hypotonia
Others
Neuroradiology
Recurrent chest infection Protein-losing gastroenteropathy Skin hyperpigmentation Lt. ovarian cyst Cortical blindness Hypertrophic cardiomegaly Blt. dilated ureter and pelvis Cortical blindness
Not described
MRI: normal myelination MRI: diminished white manner
K. Sugita et al. /Brain & Development 1995; 17." 139-41
acid were also high, being 287 /zmol/l and 44 /xmol/1, respectively. MRI, performed at the age of 1 year in the manner previously reported [8] demonstrated bilateral symmetrical lesions, such as those of adrenoleukodystrophy, in the parieto-occipital white matter {Fig. 2), which was similar to the repeated MRI findings at 2 1 / 2 years of age. He has had three episodes of urinary tract infection due to different bacterial species, at 8, 10 and 21 months, which were treated with alternate combination therapy with antibiotics. Ultrasound examination demonstrated bilateral dilatation of the ureter and pelvis.
141
D-2-HG aciduria case are quite different from those in L-2-HG aciduria, because the most remarkable abnormalities do not concern the periventricular white matter but the subcortical white matter in the latter [1]. Furthermore, repeated MRI did not show progression of the white matter lesions in our case for one and half years. In addition to these clinical and neuroimaging findings, this patient had severe bilateral dilatation of the ureter and pelvis, which resulted from recurrent urinary infections due to vesico-ureteral reflux. Furthermore, our patient showed marked cardiomegaly on chest radiograph and a reduced ejection fraction of the cardiac contraction. Both these clinical findings were not described for the previous two D-2-HG cases.
3. D I S C U S S I O N D-2-HG aciduria is an organic acid disease, with no confirmative genetic inheriitance. This patient is the third case ever reported in the literature, but is quite different clinically from the first case, which presented protein-losing enteropathy and normal mental development [4] (Table 1). Recently, Craigen et al. [9] reported more detailed clinical findings for a 2nd case, which was described first by Gibson et al. [5]. This 2nd case reportedly showed neurological abnormalities similar to cur patient, i.e. neonatal onset, severe psychomotor developmental delay, early onset of refractory seizures and cortical blindness. Furthermore, the levels of plasma and CSF D-2-HG acid in both cases were remarkably high, in comparison to the normal plasma level in the 1st case. Regarding cortical blindness, Craigen et al. [9] reported normal visual evoked potentials and MRI findings of normal myelination at 23 months of age in the 2nd case. MRI examination in our case demonstrated bilateral periventricular decreased-signal lesion~'i on IR sequences, which were quite similar to those observed in childhood adrenoleukodystrophy with visual pathway involvement [10]. The abnormal MRI findings of optic radiation and no response of VECP in this case constitute further evidence of cortical blindness in D-2-HG aciduria as well as in ALD. On the other hand, Barth et al. reported an identical abnormal pattern with subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamen and dentate nuclei in the 8 L-2-HG aciduria cases reported [1]. Moreover, progressive deterioration was well established by serial CTs in one L-2-HG case [3]. The MRI findings in our
REFERENCES 1. Barth PG, Hoffmann GF, Jaeken J, et al. L-2-Hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 1992; 32: 66-71. 2. Divry P, Jakobs C, Vianey-Saban C, et al. L-2-Hydroxyglutaric aciduria: two further cases. J Inher Metab Dis 1993; 16: 505-7. 3. Wilcken B, Pitt J, Heath D, Walsh P, Wilson G, Buchanan N. L-2-hydroxyglutarie aciduria: three Australian cases. J Inher Metab Dis 1993; 16: 501-4. 4. Chalmers RA, Lawson AM, Watts RWE, et al. D-2-Hydroxyglutaric aciduria: case report and biochemical studies. J Inher Metab Dis 1980; 3: 11-5. 5. Gibson KM, Craigen W, Herman GE, Jakobs C. D-2-Hydroxyglutaric aciduria in a newborn with neurological abnormalities: a new neurometabolic disorder? J Inher Metab Dis 1993; 16: 497500. 6. Kamerling JP, Gerwig GJ, Vliegenhart JFG, Duran M, Ketting D, Wadman SK. Determination of the configurations of lactic and glyceric acids from human serum and urine by capillary gas-liquid chromatography. J Chromatogr 1977; 143: 117-23. 7. Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK. L-2-Hydroxyglutaricaciduria: an inborn error of metabolism? J Inher Metab Dis 1980; 3: 109-12. 8. Sugita K, Takeuchi A, Iai M, Tanabe Y. Neurologic sequelae and MRI in low-birth weight patients. Pediatr Neurol 1989; 5: 365-9. 9. Craigen WJ, Jakobs C, Sekul EA, et al. D-2-Hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction. Pediatr Neurol 1994; 10: 49-53. 10. Jensen ME, Sawyer RW, Braun IF, Rizzo WB. MRI appearance of childhood adrenoleukodystrophy with auditory, visual and motor pathway involvement. Radiographics 1990; 10: 53-66.