Skip to main content Accessibility help
×
Home
  • Print publication year: 2009
  • Online publication date: August 2010

11 - MRS in cerebral metabolic disorders

Summary

Key points

MR spectroscopy is a valuable tool to direct biochemistry work-up of patients with inborn errors of metabolism.

Multivoxel MR spectroscopic imaging is the best method to study the heterogeneous anatomic distribution of metabolic diseases.

The interpretation of MR spectra and MR images together increases diagnostic accuracy.

Abnormal MR spectral peaks are diagnostic of a few hereditary metabolic disorders.

Lactate is elevated in about half of patients with mitochondrial disorders, in most patients with leukoencephalopathies with demyelination or rarefaction of white matter, and in few with organic acidopathies targeting the subcortical gray matter nuclei.

In patients with leukoencephalopathy, H-MRSI is a valuable tool for identifying one of the following three underlying tissue pathophysiologies: hypomyelination, demyelination, and rarefaction of white matter.

MRS may be useful to monitor response to therapy when available.

Introduction

The advent of magnetic resonance (MR) imaging has changed the clinical approach to the evaluation of metabolic disorders. MR imaging is highly sensitive and plays a prominent role in the diagnostic evaluation of patients with metabolic disorders of the central nervous system (CNS). However, the structural and signal abnormalities detected on conventional MR imaging are often not specific enough to suggest a definite diagnosis in many of these complex disorders.

With advances in MR technology, proton MR spectroscopy (1H-MRS) has become more widely available, and now it can be performed with conventional MR imaging in the same study session. Nowadays, a complete imaging exam lasts no longer than 30 min at 1.5 Tesla or higher magnetic fields.

References
Bizzi, A, Castelli, G, Bugiani, M, Barker, PB, Herskovits, EH, Danesi, U, et al. Classification of childhood white matter disorders using proton MR spectroscopic imaging. AJNR Am J Neuroradiol 2008; 29: 1270–5.
Posse, S, Otazo, R, Caprihan, A, Bustillo, J, Chen, H, Henry, PG, et al. Proton echo-planar spectroscopic imaging of J-coupled resonances in human brain at 3 and 4 Tesla. Magn Reson Med 2007; 58: 236–44.
Schulze, A. Creatine deficiency syndromes. Mol Cell Biochem 2003; 244: 143–50.
Stockler, S, Hanefeld, F, Frahm, J. Creatine replacement therapy in guanidinoacetate methyltransferase deficiency, a novel inborn error of metabolism. Lancet 1996; 348: 789–90.
Stockler, S, Holzbach, U, Hanefeld, F, Marquardt, I, Helms, G, Requart, M, et al. Creatine deficiency in the brain: A new, treatable inborn error of metabolism. Pediatr Res 1994; 36: 409–13.
Bianchi, MC, Tosetti, M, Fornai, F, Alessandri, MG, Cipriani, P, Vito, G, et al. Reversible brain creatine deficiency in two sisters with normal blood creatine level. Ann Neurol 2000; 47: 511–3.
Bizzi, A, Bugiani, M, Salomons, GS, Hunneman, DH, Moroni, IME, et al. X-linked creatine deficiency syndrome: A novel mutation in creatine transporter gene SLC6A8. Ann Neurol 2002; 52: 227–31.
Martin, E, Capone, A, Schneider, J, Hennig, J, Thiel, T. Absence of N-acetylaspartate in the human brain: impact on neurospectroscopy? Ann Neurol 2001; 49: 518–21.
Kreis, R, Ernst, T, Ross, B. Absolute quantitation of water and metabolites in the human brain. II Metabolite concentrations. J Magn Reson B 1993; 102: 9–19.
Kreis, R, Pietz, J, Penzien, J, Herschkowitz, N, Boesch, C. Identification and quantitation of phenylalanine in the brain of patients with phenylketonuria by means of localized in vivo 1H magnetic-resonance spectroscopy. J Magn Reson B 1995; 107: 242–51.
Leuzzi, V, Tosetti, M, Montanaro, D, Carducci, C, Artiola, C, Carducci, C, et al. The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. J Inherit Metab Dis 2007; 30: 209–16.
Knaap, MS, Wevers, RA, Struys, EA, Verhoeven, NM, Pouwels, PJ, Engelke, UF, et al. Leukoencephalopathy associated with a disturbance in the metabolism of polyols. Ann Neurol 1999; 46: 925–8.
Bizzi, A, Danesi, U, Moroni, I, Castelli, G, Bugiani, M, Erbetta, A, et al. Encefalomiopatie mitocondriali in eta' pediatrica: incidenza dell'accumulo di acido lattico documentato con immagini di spettroscopia RM del protone. [in Italian.] Riv Neuroradiol 2001; 14: 149–52.
Bizzi, A, Danesi, U, Bugiani, M, Moroni, I, Erbetta, A, Savoiardo, M, et al. Incidence of cerebral lactic acidosis in children with mitochondrial encephalomyopathy. Int Soc Magn Res in Medicine (ISMRM); 2002; Honolulu, Hawai'I, USA; 2002: 984.
Brockmann, K, Bjornstad, A, Dechent, P, Korenke, CG, Smeitink, J, Trijbels, JM, et al. Succinate in dystrophic white matter: A proton magnetic resonance spectroscopy finding characteristic for complex II deficiency. Ann Neurol 2002; 52: 38–46.
Frahm, J, Hanefeld, F. Localized proton magnetic resonance spectroscopy of brain disorders in childhood. In: Bachelard, H, ed. Magnetic Resonance Spectroscopy and Imaging in Neurochemistry. New York: Plenum Press; 1997: 329–401.
Ghezzi D, Goffrini P, Uziel G, Horvath R, Klopstock T, Lochmüller H, et al. SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy. Nat Genet 2009; 41: 654–6.
Bugiani, M, Lamantea, E, Invernizzi, F, Moroni, I, Bizzi, A, Zeviani, M, et al. Effects of riboflavin in children with complex II deficiency. Brain Dev 2006; 28: 576–81.
Righini, A, Ramenghi, , Parini, R, Triulzi, F, Mosca, F. Water apparent diffusion coefficient and T2 changes in the acute stage of maple syrup urine disease: Evidence of intramyelinic and vasogenic–interstitial edema. J Neuroimaging 2003; 13: 162–5.
Jan, W, Zimmerman, RA, Wang, ZJ, Berry, GT, Kaplan, PB, Kaye, EM. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003; 45: 393–9.
Battisti, C, Tarugi, P, Dotti, MT, Stefano, N, Vattimo, A, Chierichetti, F. Adult onset Niemann–Pick type C disease: A clinical, neuroimaging and molecular genetic study. Mov Disord 2003; 18: 1405–09.
Sylvain, M, Arnold, DL, Scriver, CR, Schreiber, R, Shevell, MI. Magnetic resonance spectroscopy in Niemann–Pick disease type C: Correlation with diagnosis and clinical response to cholestyramine and lovastatin. Pediatr Neurol 1994; 10: 228–32.
Canavan, MM. Schilder's encephalitis periaxialis diffusa. Arch Neurol Psychatry 1931; 25: 299.
Matalon, R, Michals, K, Sebesta, D, Deanching, M, Gashkoff, P, Casanova, J. Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am J Med Genet 1988; 29: 463–71.
Gambetti, P, Mellman, WJ, Gonatas, NK. Familial spongy degeneration of the central nervous system (Van Bogaert–Bertrand disease). An ultrastructural study. Acta Neuropathol (Berl) 1969; 12: 103–15.
Grodd, W, Krageloh-Mann, I, Petersen, D, Trefz, FK, Harzer, K. In vivo assessment of N-acetylaspartate in brain in spongy degeneration (Canavan's disease) by proton spectroscopy [Letter]. Lancet 1990; 336: 437–8.
Austin, SJ, Connelly, A, Gadian, DG, Benton, JS, Brett, EM. Localized 1H NMR spectroscopy in Canavan's disease: A report of two cases. Magn Reson Med 1991; 19: 439–45.
Barker, PB, Bryan, RN, Kumar, AJ, Naidu, S. Proton NMR spectroscopy of Canavan's disease. Neuropediatrics 1992; 23: 263–7.
Righini, A, Ramenghi, , Parini, R, Triulzi, F, Mosca, F. Water apparent diffusion coefficient and T2 changes in the acute stage of Maple Syrup Urine Disease: Evidence of intramyelinic and vasogenic-interstitial edema. J Neuroimaging 2003; 13: 162–5.
Hanefeld, FA, Brockmann, K, Pouwels, PJ, Wilken, B, Frahm, J, Dechent, P. Quantitative proton MRS of Pelizaeus–Merzbacher disease: Evidence of dys- and hypomyelination. Neurology 2005; 65: 701–06.
Bonavita, SSR, Moore, DF, Frei, K, Choi, B, Patronas, MDN, Virta, A, et al. Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations. Neurology 2001; 56: 785–8.
Pizzini, F, Fatemi, AS, Barker, PB, Nagae-Poetscher, LM, Horska, A, Zimmerman, AW, et al. Proton MR spectroscopic imaging in Pelizaeus–Merzbacher disease. Am J Neuroradiol 2003; 24: 1683–9.
Toft, PB, Geiss-Holtorff, R, Rolland, MO, Pryds, O, Muller-Forell, W, Christensen, E, et al. Magnetic resonance imaging in juvenile Canavan disease. Eur J Pediatr 1993; 152: 750–3.
Varho, T, Komu, M, Sonninen, P, Holopainen, I, Nyman, S, Manner, T, et al. A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla diseaseNeurology. 1999; 52(8):1668–72. [Published erratum appears in Neurology 1999; 53(5): 1162.]
Ruivo, R, Sharifi, A, Boubekeur, S, Morin, P, Anne, C, Debacker, C, et al. Molecular pathogenesis of sialic acid storage diseases: Insight gained from four missense mutations and a putative polymorphism of human sialin. Biol Cell 2008; 100: 551–9.
Morse, RP, Kleta, R, Alroy, J, Gahl, WA. Novel form of intermediate salla disease: Clinical and neuroimaging features. J Child Neurol 2005; 20: 814–6.
Shah, DK, Tingay, DG, Fink, AM, Hunt, RW, Dargaville, PA. Magnetic resonance imaging in neonatal nonketotic hyperglycinemia. Ped Neurol 2005; 33: 50–2.
Heindel, W, Kugel, H, Roth, B. Noninvasive detection of increased glycine content by proton MR spectroscopy in the brains of two infants with nonketotic hyperglycinemia. Am J Neuroradiol 1993; 14: 629–35.
Gabis, L, Parton, P, Roche, P, Lenn, N, Tudorica, A, Huang, W. In vivo 1H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia. J Neuroimaging 2001; 11: 209–11.
Di Mauro, S, Schon, EA. Mitochondrial respiratory-chain diseases. Review. N Engl J Med 2003; 348: 2656–68.
Bianchi, MC, Sgandurra, G, Tosetti, M, Battini, R, Cioni, G. Brain magnetic resonance in the diagnostic evaluation of mitochondrial encephalopathies. Review. Biosci Rep 2007; 27: 69–85.
Farina, L, Chiapparini, L, Uziel, G, Bugiani, M, Zeviani, M, Savoiardo, M. MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. Am J Neuroradiol 2002; 23: 1095–100.
Moroni, I, Bugiani, M, Bizzi, A, Castelli, G, Lamantea, E, Uziel, G. Cerebral white matter involvement in children with mitochondrial encephalopathies. Neuropediatrics 2002; 33: 79–85.
Krägeloh-Mann, I, Grodd, W, Schöning, M, Marquard, K, Nägele, T, Ruitenbeek, W. Proton spectroscopy in five patients with Leigh's disease and mitochondrial enzyme deficiency. Dev Med Child Neurol 1993; 35: 769–76.
Bianchi, MC, Tosetti, M, Battini, R, Manca, ML, Mancuso, M, Cioni, G, et al. Proton MR spectroscopy of mitochondrial diseases: Analysis of brain metabolic abnormalities and their possible diagnostic relevance. Am J Neuroradiol 2003; 24: 1958–66.
Cross, JH, Connelly, A, Gadian, DG, Kendall, BE, Brown, GK, Brown, RM, et al. Clinical diversity of pyruvate dehydrogenase deficiency. Ped Neurol 1994; 10: 276–83.
Lin, DD, Crawford, TO, Barker, PB. Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. Am J Neuroradiol 2003; 24: 33–41.
Matthews, PM, Andermann, F, Silver, K, Karpati, G, Arnold, DL. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology 1993; 43: 2484–90.
Stefano, N, Matthews, PM, Ford, B, Genge, A, Karpati, G, Arnold, DL. Short-term dichloroacetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 1995; 45: 1193–8.
Krägeloh-Mann, I, Grodd, W, Niemann, G, Haas, G, Ruitenbeek, W. Assessment and therapy monitoring of Leigh disease by MRI and proton spectroscopy. Ped Neurol 1992; 8: 60–4.
Grosso, S, Balestri, P, Mostardini, R, Federico, A, Stefano, N. Brain mitochondrial impairment in ethylmalonic encephalopathy. J Neurol 2004; 251: 755–6.
Knaap, MS, Voorn, P, Barkhof, F, Coster, R, Krageloh-Mann, I, Feigenbaum, A, et al. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53: 252–8.
Coburn, B. A rare disorder, ethylmalonic encephalopathy, is caused by mutations in a mitochondrial protein. Clin Genet 2004; 65: 460–2.
Scheper, GC, Klok, T, Andel, RJ, Berkel, CG, Sissler, M, Smet, J, et al. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 2007; 39: 534–9.
Stefano, N, Dotti, MT, Mortilla, M, Federico, A. Magnetic resonance imaging and spectroscopic changes in brains of patients with cerebrotendinous xanthomatosis. Brain 2001; 124: 121–31.
Federico, A, Dotti, MT, Volpi, N. Muscle mitochondrial changes in cerebrotendinous xanthomatosis [Letter]. Ann Neurol 1991; 30: 734–5.
Dotti, MT, Manneschi, L, Federico, A. Mitochondrial enzyme deficiency in cerebrotendinous xanthomatosis. J Neurol Sci 1995; 129: 106–08.
Choi, CG, Yoo, HW. Localized proton MR spectroscopy in infants with urea cycle defect. Am J Neuroradiol 2001; 22: 834–7.
Franco, LP, Anderson, J, Okoh, J, Pomper, MG, Braverman, N, Barker, PB. Proton MR spectroscopy in hyperhomocysteinemia with elevated blood methionine levels. J Magn Reson Imaging 2006; 23: 404–07.
Bisschops, RH, Graaf, Y, Mali, WP, Grond, J. Elevated levels of plasma homocysteine are associated with neurotoxicity. Atherosclerosis 2004; 174: 87–92.
Bergman, AJ, Knaap, MS, Smeitink, JA, Duran, M, Dorland, L, Valk, J, et al. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: Clinical and biochemical considerations. Review. Pediatr Res 1996; 40: 404–9.
Trinh, BC, Melhem, ER, Barker, PB. Multi-slice proton MR spectroscopy and diffusion-weighted imaging in methylmalonic acidemia: Report of two cases and review of the literature. Am J Neuroradiol 2001; 22: 831–3.
Commodari, F, Arnold, DL, Sanctuary, BC, Shoubridge, EA. 1H NMR characterization of normal human cerebrospinal fluid and the detection of methylmalonic acid in a vitamin B12 deficient patient. NMR Biomed 1991; 4: 192–200.
Yalçinkaya, C, Dinçer, A, Gündüz, E, Fiçicioğlu, C, Koçer, N, Aydin, A. MRI and MRS in HMG-CoA lyase deficiency. Ped Neurol 1999; 20: 375–80.
Knaap, MS, Bakker, HD, Valk, J. MR imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. Am J Neuroradiol 1998; 19: 378–82.
Iles, RA, Jago, JR, Williams, SR, Chalmers, RA. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency studied using 2-dimensional proton nuclear magnetic resonance spectroscopy. FEBS Lett 1986; 203: 49–53.
D'Incerti, L, Farina, L, Moroni, I, Uziel, G, Savoiardo, M. L-2-Hydroxyglutaric aciduria: MRI in seven cases. Neuroradiology 1998; 40: 727–33.
Moroni, I, Bugiani, M, D'Incerti, L, Maccagnano, C, Rimoldi, M, Bissola, L, et al. L-2-Hydroxyglutaric aciduria and brain malignant tumors: A predisposing condition? Review. Neurology 2004; 62: 1882–4.
Knaap, MS, Breiter, SN, Naidu, S, Hart, AA, Valk, J. Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach. Radiology 1999; 213: 121–33.
Voorn, JP, Pouwels, PJ, Hart, AA, Serrarens, J, Willemsen, MA, Kremer, HP, et al. Childhood white matter disorders: Quantitative MR imaging and spectroscopy. Radiology 2006; 241: 510–7.
Bugiani, M, Al Shahwan, S, Lamantea, E, Bizzi, A, Bakhsh, E, Moroni, I, et al. GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 2006; 67: 273–9.
Uhlenberg, B, Schuelke, M, Ruschendorf, F, Ruf, N, Kaindl, AM, Henneke, M, et al. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus–Merzbacher-like disease. Am J Hum Genet 2004; 75: 251–60.
Orthmann-Murphy, JL, Salsano, E, Abrams, CK, Bizzi, A, Uziel, G, Freidin, MM, et al. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 2008 [Epub ahead of print].
Knaap, MS, Naidu, S, Pouwels, PJ, Bonavita, S, Coster, R, Lagae, L, et al. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Neuroradiol 2002; 23: 1466–74.
Farina, L, Bizzi, A, Finocchiaro, G, Pareyson, D, Sghirlanzoni, A, Bertagnolio, B, et al. MR imaging and proton MR spectroscopy in adult Krabbe disease. Am J Neuroradiol 2000; 21: 1478–82.
Stefano, N, Dotti, MT, Mortilla, M, Pappagallo, E, Luzi, P, Rafi, MA, et al. Evidence of diffuse brain pathology and unspecific genetic characterization in a patient with an atypical form of adult-onset Krabbe disease. J Neurol 2000; 247: 226–8.
Kruse, B, Barker, PB, Zijl, PC, Duyn, JH, Moonen, CT, Moser, HW. Multislice proton magnetic resonance spectroscopic imaging in X-linked adrenoleukodystrophy. Ann Neurol 1994; 36: 595–608.
Oz, G, Tkác, I, Charnas, LR, Choi, IY, Bjoraker, KJ, Shapiro, EG, et al. Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients. Neurology 2005; 64: 434–41.
Marino, S, Luca, M, Dotti, MT, Stromillo, ML, Formichi, P, Galluzzi, P, et al. Prominent brain axonal damage and functional reorganization in “pure” adrenomyeloneuropathy. Neurology 2007; 69: 1261–9.
Eichler, FS, Barker, PB, Cox, C, Edwin, D, Ulug, AM, Moser, HW, et al. Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy. Neurology 2002; 58: 901–07.
Brenner, M, Johnson, AB, Boespflug-Tanguy, O, Rodriguez, D, Goldman, JE, Messing, A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 2001; 27: 117–20.
Rodriguez, D, Gauthier, F, Bertini, E, Bugiani, M, Brenner, M, N'guyen, S, et al. Infantile Alexander disease: Spectrum of GFAP mutations and genotype–phenotype correlation. Am J Hum Genet 2001; 69: 1134–40.
Alexander, WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 1949; 72: 373–81, 3 pl.
Farina, L, Pareyson, D, Minati, L, Ceccherini, I, Chiapparini, L, Romano, S, et al. Can MR imaging diagnose adult-onset Alexander disease? Am J Neuroradiol 2008; 29: 1190–6.
Knaap, MS, Naidu, S, Breiter, SN, Blaser, S, Stroink, H, Springer, S, et al. Alexander disease: Diagnosis with MR imaging. Am J Neuroradiol 2001; 22: 541–52.
Grodd, W, Krageloh-Mann, I, Klose, U. Metabolic and destructive brain disorders in children: Findings with localized proton MR spectroscopy. Radiology 1991; 181: 173–81.
Meins, M, Brockmann, K, Yadav, S, Haupt, M, Sperner, J, Stephani, U, et al. Infantile Alexander disease: A GFAP mutation in monozygotic twins and novel mutations in two other patients. Neuropediatrics 2002; 33: 194–8.
Brockmann, K, Dechent, P, Wilken, B, Rusch, O, Frahm, J, Hanefeld, F. Proton MRS profile of cerebral metabolic abnormalities in Krabbe disease. Neurology 2003; 60: 819–25.
Knaap, MS, Barth, PG, Stroink, H, Nieuwenhuizen, O, Arts, WF, Hoogenraad, F, et al. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995; 37: 324–34.
Hanefeld, F, Holzbach, U, Kruse, B, Wilichowski, E, Christen, HJ, Frahm, J. Diffuse white matter disease in three children: An encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 1993; 24: 244–8.
Schiffmann, R, Moller, JR, Trapp, BD, Shih, HH, Farrer, RG, Katz, DA, et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann Neurol 1994; 35: 331–40.
Tedeschi, G, Schiffmann, R, Barton, NW, Shih, HH, Gospe, SM, Brady, RO, et al. Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination. Neurology 1995; 45: 1526–32.
Knaap, MS, Barth, PG, Gabreels, FJ, Franzoni, E, Begeer, JH, Stroink, H, et al. A new leukoencephalopathy with vanishing white matter. Neurology 1997; 48: 845–55.
Leegwater, PA, Konst, AA, Kuyt, B, Sandkuijl, , Naidu, S, Oudejans, CB, et al. The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27. Am J Hum Genet 1999; 65: 728–34.
Knaap, MS, Leegwater, PA, Könst, AA, Visser, A, Naidu, S, Oudejans, CB, et al. Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 2002; 51: 264–70.
Hanefeld, F, Kruse, B, Bruhn, H, Frahm, J. In vivo proton magnetic resonance spectroscopy of the brain in a patient with L-2-hydroxyglutaric acidemia. Pediatr Res 1994; 35: 614–6.
Rodriguez, D, Gelot, A, della Gaspera, B, Robain, O, Ponsot, G, Sarliève, LL, et al. Increased density of oligodendrocytes in childhood ataxia with diffuse central hypomyelination (CACH) syndrome: Neuropathological and biochemical study of two cases. Acta Neuropathol 1999; 97: 469–80.
Wong, K, Armstrong, RC, Gyure, KA, Morrison, AL, Rodriguez, D, Matalon, R, et al. Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome. Acta Neuropathol 2000; 100: 635–46.
Leegwater, PA, Yuan, BQ, Steen, J, Mulders, J, Könst, AA, Boor, PK, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001; 68: 831–8.
Ilja Boor, PK, Groot, K, Mejaski-Bosnjak, V, Brenner, C, Knaap, MS, Scheper, GC, et al. Megalencephalic leukoencephalopathy with subcortical cysts: An update and extended mutation analysis of MLC1. Hum Mutat 2006; 27: 505–12.
Knaap, MS, Barth, PG, Vrensen, GF, Valk, J. Histopathology of an infantile-onset spongiform leukoencephalopathy with a discrepantly mild clinical course. Acta Neuropathol 1996; 92: 206–12.
Topcu, M, Saatci, I, Topcuoglu, MA, Kose, G, Kunak, B. Megalencephaly and leukodystrophy with mild clinical course: A report on 12 new cases. Brain Dev 1998; 20: 142–53.
Bugiani, M, Moroni, I, Bizzi, A, Nardocci, N, Bettecken, T, Gärtner, J, et al. Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics 2003; 34(4): 211–4.
Stefano, N, Balestri, P, Dotti, MT, Grosso, S, Mortilla, M, Morgese, G, et al. Severe metabolic abnormalities in the white matter of patients with vacuolating megalencephalic leukoencephalopathy with subcortical cysts. A proton MR spectroscopic imaging study. J Neurol 2001; 248: 403–09.
Moser, HW, Barker, PB. Magnetic resonance spectroscopy: A new guide for the therapy of adrenoleukodystrophy. Neurology 2005; 64: 406–07.
Leone, P, Janson, CG, Bilaniuk, L, Wang, Z, Sorgi, F, Huang, L. Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 2000; 48: 27–38.
Stefano, N, Matthews, PM, Arnold, DL. Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 1995; 34: 721–7.
Moats, RA, Moseley, KD, Koch, R, Nelson Jr M. Brain phenylalanine concentrations in phenylketonuria: Research and treatment of adults. Pediatrics 2003; 112: 1575–9.