DOI: 10.1148/radiol.2411040165
(Radiology 2006;241:310-324.)
© RSNA, 2006
Case 99: Canavan Disease1
Steven J. Michel, MD and
Curtis A. Given, II, MD
1 From the Department of Diagnostic Radiology, University of Kentucky Chandler Medical Center, Lexington, Ky. Received January 28, 2004; revision requested April 12; revision received May 13; accepted May 24; final version accepted July 26.
Correspondence: Address correspondence to S.J.M., Northwest Radiologists, 2930 Squalicum Pkwy, Suite 101, Bellingham, WA 98225 (email: s_j_michel{at}yahoo.com).
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HISTORY
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A 21-month-old boy, born without complications after an uncomplicated pregnancy, failed to achieve expected developmental milestones. As an infant, he developed nystagmus and poor muscular head control. Physical examination findings were notable for generalized hypotonia and macrocephaly. Magnetic resonance (MR) imaging and single-voxel MR spectroscopy were performed.
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IMAGING FINDINGS
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There was diffuse, bilateral, and symmetric increased T2 signal intensity throughout the cerebral white matter (Figs 1–3). These findings were noted to a lesser degree in the cerebellar white matter, thalamus, globi pallidi, and dorsal brainstem (Figs 1, 2). The white matter abnormality specifically involved the subcortical white matter. There was no lobar predominance of white matter abnormalities. Hydrocephalus, mass effect, and midline shift were absent. Single-voxel point-resolved spatially localized MR spectroscopy was performed for localization within the right parietal periventricular white matter and revealed a marked increase in both the N-acetylaspartate (NAA) peak and the ratio of NAA to creatinine (Fig 4). The choline peak was not elevated.
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Figure 1: Transverse T2-weighted (repetition time msec/echo time msec, 4900/105) MR image of the brain obtained through the posterior fossa demonstrates extensive signal hyperintensity of temporal lobe white matter with relative sparing of cerebellar white matter.
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Figure 3: Transverse T2-weighted (4900/105) MR image of the brain obtained through the centrum semiovale shows bilaterally symmetric increased signal intensity within cerebral white matter with involvement of subcortical arcuate fibers (arrow).
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Figure 4: Single-voxel MR spectroscopic image of right parietal white matter reveals markedly elevated NAA peak. Spectrum shows ratios of NAA to creatine (Cr) (4.41) and NAA to choline (Cho) (7.54). Cr2 = methylene protons of creatine. The choline and creatinine peaks are within normal limits.
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DISCUSSION
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Differential diagnostic considerations based on imaging findings include dysmyelinating diseases such as metachromatic leukodystrophy, adrenoleukodystrophy, Pelizaeus-Merzbacher disease (PMD), Alexander disease, and Canavan disease. Metachromatic leukodystrophy causes bilateral symmetric white matter hyperintensity on T2-weighted MR images; however, this disease spares the subcortical white matter. The subcortical white matter was not spared in this patient. Adrenoleukodystrophy leads to bilateral symmetric T2 hyperintensity within the cerebral white matter. As with metachromatic leukodystrophy, the subcortical white matter fibers are classically spared. Additionally, adrenoleukodystrophy tends to progress in an orderly fashion from one portion of the brain to the next with an advancing edge of contrast enhancement.
PMD demonstrates bilateral symmetric white matter T2 hyperintensity with involvement of the subcortical arcuate fibers. However, patients with PMD may also have marked cerebellar atrophy and progressive enlargement of cortical sulci; these findings were not seen in this patient (1). Patients with PMD do not present with macrocephaly, and MR spectroscopy has revealed normal NAA and creatinine levels (2).
Canavan disease demonstrates bilateral symmetric T2 white matter hyperintensity, including involvement of the subcortical arcuate fibers. This disease appears diffusely throughout the cerebral white matter, does not enhance at computed tomography (CT) or MR imaging, and demonstrates variable involvement of the basal ganglia and cerebellar white matter (3–5). Patients with Alexander disease present with clinical and imaging findings similar to those of patients with Canavan disease; this condition often results in a clinical conundrum. For example, both Canavan disease and Alexander disease demonstrate macrocephaly with bilaterally symmetric increased T2 signal intensity of cerebral white matter and involvement of subcortical arcuate fibers.
Historically, Canavan disease has been differentiated from Alexander disease by means of brain biopsy (6). MR spectroscopy, however, has been shown to be a useful diagnostic tool in making this distinction. There is an accumulation of NAA in patients with Canavan disease because of a deficiency in the myelin synthesis pathway; thus, MR spectroscopy reveals a markedly elevated NAA peak. Alexander disease has not demonstrated elevation of the NAA peak in clinical cases because of the defect in glial fibrillary acidic protein, and it is pathologically characterized by widespread Rosenthal fibers (7–9). The combination of the T2 signal hyperintensity in the white matter and the markedly elevated NAA level on MR spectroscopic images allowed Canavan disease to be diagnosed in this patient (10). Our imaging findings were clinically confirmed by elevated urine NAA levels and identification of a gene mutation within the aspartoacylase enzyme at polymerase chain reaction assay.
Canavan disease, or spongiform degeneration of cerebral white matter, is an autosomal recessive dysmyelinating disease believed to result from a deficiency of aspartoacylase, which is a key enzyme in the myelin synthesis pathway (11). This deficiency leads to an abnormal accumulation of NAA in the serum and urine. Patients present with spasticity and macrocephaly within the 1st year of life, as did our patient; poor muscular head control and blindness are additional findings (12). Death usually occurs within the first few years of life, although a more protracted course has been reported (13). Canavan disease is characterized pathologically by vacuolization of subcortical white matter tracts throughout the cerebrum and, to a lesser extent, the cerebellum (14). Cortical gray matter injury occurs in a similar fashion but with less ferocity. CT findings include diffuse decreased attenuation of subcortical white matter without contrast enhancement. MR imaging demonstrates diffuse, bilateral, and symmetric increased T2 signal intensity of cerebral subcortical white matter (3). Involvement of the basal ganglia was present to some degree in this patient and has been variably noted in the literature (3–5). Several investigators have shown the markedly elevated NAA peak on MR spectroscopic images in patients with Canavan disease (11,15). There is also an increase in the NAA-to-choline ratio and the NAA-to-creatinine ratio; these findings are considered indicative of Canavan disease given the associated white matter abnormalities.
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FOOTNOTES
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| Part one of this case appeared 4 months previously and may contain larger images.
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References
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- Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. RadioGraphics 2002;22:461–476.[Abstract/Free Full Text]
- Takanashi J, Sugita K, Osaka H, Ishii M, Niimi H. Proton MR spectroscopy in Pelizaeus-Merzbacher disease. AJNR Am J Neuroradiol 1997;18:533–535.[Abstract]
- McAdams HP, Geyer CA, Done SL, Deigh D, Mitchell M, Ghaed VN. CT and MR imaging of Canavan disease. AJNR Am J Neuroradiol 1990;11:397–399.[Medline]
- Rushton AR, Shaywitz BA, Duncan CC, Geehr RB, Manuelidis EE. Computed tomography in the diagnosis of Canavan's disease. Ann Neurol 1981;10:57–60.[CrossRef][Medline]
- Andriola MR. Computed tomography in the diagnosis of Canavan's disease. Ann Neurol 1982;11:323–324.[CrossRef][Medline]
- MacGregor DL, Humphrey RP, Armstrong DL, Becker LE. Brain biopsies for neurodegenerative disease in children. J Pediatr 1978;92:903–905.[CrossRef][Medline]
- Imamura A, Orii KE, Mizuno S, Hoshi H, Kondo T. MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease. Brain Dev 2002;24:723–726.[CrossRef][Medline]
- Brockmann K, Dechent P, Meins M, et al. Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease. J Neurol 2003;250:300–306.[CrossRef][Medline]
- Johnson AB, Brenner M. Alexander's disease: clinical, pathologic, and genetic features. J Child Neurol 2003;18(9):625–632.[Abstract/Free Full Text]
- Barkovich AJ. Pediatric neuroimaging. New York, NY: Raven, 2000; 117.
- Wittsack HJ, Kugel H, Roth B, Heindel W. Quantitative measurements with localized 1H MR spectroscopy in children with Canavan's disease. J Magn Reson Imaging 1996;6:889–893.[Medline]
- Gordon N. Canavan disease: a review of recent developments. Eur J Paediatr Neurol 2001;5:65–69.[CrossRef][Medline]
- Zafeiriou DI, Kleijer WJ, Maroupoulos G, et al. Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings. Brain Dev 1999;21:205–208.[CrossRef][Medline]
- 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;12:103–115.[CrossRef][Medline]
- Grodd W, Krageloh-Mann I, Klose U, Sauter R. Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy. Radiology 1991;181(1):173–181.[Abstract/Free Full Text]
Congratulations to the 239 individuals and eight resident groups that submitted the most likely diagnosis (Canavan disease) for Diagnosis Please, Case 99. The names and locations of the individuals and resident groups, as submitted, are as follows:
Individual responses
- Hisashi Abe, MD, Osaka, Japan
- Gholamali Afshang, MD, Tinley Park, Ill
- Jorge Ahualli, San Miguel de Tucumán, Tucumán, Argentina
- Dr Erhan Akpinar, Ankara, Turkey
- Canan Altay, MD, Balcova, Izmir, Turkey
- Albert J. Alter, Madison, Wis
- A. Anbarasu, MD, FRCR, Coventry, United Kingdom
- Rajeev Anugu, MD, Bryn Mawr, Pa
- Giovanni Maria Argiolas, MD, Cagliari, Italy
- Manohar Aribandi, MD, Danville, Pa
- Lionel Arrivé, Paris, France
- Aaron Scott Bailey, MD, San Antonio, Tex
- Ken Baliga, Rockford, Ill
- Gregory J. Balmforth, MD, Tucson, Ariz
- Arivalagan Bapusamy, Newcastle upon Tyne, United Kingdom
- Sebastian Bazzano, MD, PhD, Rancagua, Chile
- Rich Benedikt, MD, San Antonio, Tex
- Sanjay Bhat, Temple, Tex
- Gustav Blomquist IV, Houston, Tex
- Dr Adrian Brady, FFRRCSI, Cork, Ireland
- Steve Breiter, MD, Baltimore, Md
- Eric L. Bressler, MD, Minnetonka, Minn
- Daniel F. Broderick, MD, Jacksonville, Fla
- Ghislain Brousseau, MD, Charlesbourg, Quebec, Canada
- Douglas C. Brown, MD, Virginia Beach, Va
- Michael P. Buetow, MD, Okemos, Mich
- Peter C. Buetow, MD, Bellingham, Wash
- Dr Marcelo F. Cabrini, Buenos Aires, Argentina
- Özgür Çkmak, MD, Antalya, Turkey
- Marc A. Camacho, MD, MS, Richmond, Va
- Martín Campi, Godoy Cruz, Mendoza, Argentina
- Dairong Cao, Fuzhou, Fujian, China
- Carlos Capiel, Jr, MD, Mar del Plata, Buenos Aires, Argentina
- Dr Carlos R. Castillo, Buenos Aires, Argentina
- Paloma Cebrián Villar, Salamanca, Spain
- Luisa F. Cervantes, Miami, Fla
- Alan Dong Shing Chan, MD, West Sacramento, Calif
- Govind Chavhan, MD, Toronto, Ontario, Canada
- Bang-Bin Chen, MD, Taipei, Taiwan
- Dra Marina Chiesa, Córdoba, Argentina
- Dr Dinesh Chinchure, Hyderabad, India
- Haris Chrysikopoulos, MD, Kerkyra, Greece
- Dr Christopher Chu, Cabarita, New South Wales, Australia
- Neal R. Conti, MD, Seattle, Wash
- Peter Corr, Al Ain, United Arab Emirates
- Alberto Cuñat, Valencia, Spain
- Marco Antonio Cura, MD, San Antonio, Tex
- Anil Kumar Dasyam, Pittsburgh, Pa
- Wayne L. Davis, MD, Missoula, Mont
- Marc G. de Baets, MD, Lugano, Switzerland
- Peter C. De Baets, MD, Damme, Belgium
- Helder de Castro Marques, MD, Juiz de Fora, Minas Gerais, Brazil
- José Luiz F. De Mendonca, MD, Brasilia, Brazil
- Wagner Diniz de Paula, MD, Brasilia, Brazil
- Jon De Witte, Bishop, Ga
- Seena Dehkharghani, MD, Phoenix, Ariz
- Mustafa Kemal Demir, MD, Ataköy, Istanbul, Turkey
- Thaworn Dendumrongsup, MD, Hat, Yai, Songkla, Thailand
- Nam Ky Do, Duluth, Ga
- Arthur B. Dublin, MD, MBA, FACR, Sacramento, Calif
- Michael D. Edwards, MD, Oak Ridge, Tenn
- Seyed Emamian, MD, PhD, Rockville, Md
- Volkher Engelbrecht, MD, PhD, Amberg, Germany
- Juliet H. Fallah, MD, Chicago, Ill
- Shella Farooki, MD, Dublin, Ohio
- Laura Z. Fenton, MD, Denver, Colo
- Geoffrey L. Fey, MD, Richmond, Va
- Ricardo Fonseca, MD, Nashville, Tenn
- Akira Fujikawa, Tokyo, Japan
- Dr Ram Prakash Galwa, Chandigarh, India
- Douglas Gardner, MD, Windsor, Ontario, Canada
- William Gawman, MD, Waterloo, Ontario, Canada
- Fouad Gellad, MD, Timonium, Md
- Gilles Genin, MD, Annecy, France
- Dietrich Gerhardt, MD, Bettendorf, Iowa
- Moshe Goldfeld, Nahariya, Israel
- Mark G. Goldshein, MD, Andover, Mass
- Eduardo Gonzalez Toledo, MD, PhD, Shreveport, La
- Francisco J. Gonzalez, MD, Cantabria, Spain
- José Dilermando Gotardo, São Paulo, Brazil
- Sadashiva Gowda, Jr, MD, Davangere, Karnataka, India
- James Wagter Graham, MD, Landstuhl, Germany
- Dan Gridley, Phoenix, Ariz
- D. Joseph Grunz, MD, Ladue, Mo
- Flavius Guglielmo, MD, Basking Ridge, NJ
- Preeti Gupta, MD, Worcester, Mass
- Horacio Gutierrez, MD, Longmont, Colo
- Jeffrey Haithcock, MD, Irving, Tex
- Ferris M. Hall, MD, Boston, Mass
- Srinivasan Harish, Hamilton, Ontario, Canada
- Andreas Harzheim, MD, Cologne, Germany
- Soichiro Hase, Niihama, Japan
- D. Cressler Heasley, Jr, MD, Dallas, Tex
- Raúl Hernández, Madrid, Spain
- Helen T. Ho, MD, Chicago, Ill
- Lowrey H. Holthaus, MD, Richmond, Va
- Ronald J. Homer, MD, Weston, Conn
- Suzanne Homer, MD, Weston, Conn
- Alberto Iaia, MD, Wilmington, Del
- Waleed Ibrahim, MD, Detroit, Mich
- Rajapandian Ilangovan, MD, FRCR, London, United Kingdom
- Kiriakos Kalampoukas, MD, Athens, Greece
- Tomy Paul Kalapparambath, Troy, Mich
- Sangam Kanekar, MD, Hershey, Pa
- Kamil Karaali, MD, Antalya, Turkey
- Katsuhiko Kato, MD, PhD, Nagoya, Japan
- Nurettin Katranci, MD, Antalya, Turkey
- Abdul-Majid Khan, MD, Bloomfield Hills, Mich
- John C. Kirkham, MD, Richmond, Va
- Jacobo Kirsch, MD, Cleveland, Ohio
- Takuji Kiryu, MD, PhD, Gifu, Japan
- Steven A. Klein, MD, Shrewsbury, Mass
- Mehmet Kocak, MD, Milwaukee, Wis
- Masamichi Koyama, Tokyo, Japan
- Dr Mahesh Kumar, Greater Manchester, United Kingdom
- Mark Kutler, MD, Dallas, Tex
- Stefanos Lachanis, MD, Athens, Greece
- Mario Laguna, West Allis, Wis
- Douglas R. Lake, Charleston, SC
- Matias Landi, Mar del Plata, Buenos Aires, Argentina
- Michael Laucella, MD, Bayshore, NY
- Dr Martin Lecompte, Ottawa, Ontario, Canada
- John T. Lim, MD, Newport Coast, Calif
- David A. Lisle, Brisbane, Australia
- Pablo Longhi Lorenzzoni, Porto Alegre, Brazil
- Patricia Lowry, MD, Richmond, Va
- Marina Lucchesi, Junin, Buenos Aires, Argentina
- Franklin Marden, MD, Fairfax, Va
- Paulo Mariz Filho, MD, Salvador, Buenos Aires, Brazil
- Michael B. Martin, MD, Austin, Tex
- Fernando Mas-Estelles, Valencia, Spain
- John A. Mattingly, MD, Belleville, Ill
- Waldir Maymone, Rio de Janeiro, Brazil
- Walter P. Maynard, MD, Inglewood, Calif
- Frank McKowne, MD, Vancouver, Wash
- Rogério Melo, Belo Horizonte, Brazil
- Koen Pieter Mermuys, MD, Heverlee, Belgium
- Nikolaos Michailidis, MD, Thessaloniki, Greece
- Juan A. Millan, MD, Seattle, Wash
- Manabu Minami, MD, Tsukuba, Ibaraki, Japan
- Mansour Mirfakhraee, MD, Shreveport, La
- Robert L. Mittl, Jr, MD, Charlotte, NC
- Sankar Ranjan Mondal, MD, Nassau, Bahamas
- Eduardo Mondello, MD, Buenos Aires, Argentina
- Gregg E. Moral, MD, Cedarburg, Wis
- Dr Subramaniyam Murugan, Ramnagar, Coimbatore, India
- Mahesh Kumar Neelala Anand, FRCR, Greater Manchester, United Kingdom
- Tammam Naim Nehme, MD, East Wenatchee, Wash
- Honorio Chiminazzo Neto, Campinas, São Paulo, Brazil
- Mizuki Nishino, MD, Boston, Mass
- Albert Nizzero, MD, Sudbury, Ontario, Canada
- Hiroshi Nobusawa, MD, Tokyo, Japan
- Ingo Nölte, Mannheim, Germany
- Patrick O'Keeffe, Boston, Mass
- Laura Oleaga, MD, Bilbao, Spain
- Michael Opatowsky, MD, Dallas, Tex
- Sanford M. Ornstein, MD, Phoenix, Ariz
- Dr Klaus Orth, Aachen, Germany
- Carlos Ovejero Vela, MD, Barcelona, Spain
- Ann Burleson Owen, MD, Murfreesboro, Tenn
- Dr Deepak M. Pai, Newcastle upon Tyne, United Kingdom
- Neeraj J. Panchal, MD, San Diego, Calif
- Harish Panicker, MD, Hermitage, Pa
- Narendrakumar P. Patel, MD, Newburgh, NY
- Prakash N. Patel, MD, New City, NY
- Ernesto Oscar Pearson, MD, Besançon, France
- Yeliz Pekcevik, Izmir, Turkey
- Javier Perich, Barcelona, Spain
- John M. Plotke, MD, Naperville, Ill
- Sanjay P. Prabhu, MBBS, Melbourne, Australia
- Henry F. W. Pribram, MD, Laguna Beach, Calif
- Prashant Raghavan, MD, Charlottesville, Va
- Karthikram Raghuram, Birmingham, Ala
- Anuradha T. Rao, Houston, Tex
- Enrique Remartinez Escobar, MD, Melilla, Spain
- Matthew C. Rheinboldt, MD, Nashville, Tenn
- Mathieu Rodallec, Paris, France
- Scott J. Rowen, MD, Orange, Calif
- Stuart A. Royal, MS, MD, Birmingham, Ala
- Hedieh Saghari, MD, Phoenix, Ariz
- Guis Saint-Martin Astacio, MD, Leblon, Rio de Janeiro, Brazil
- Tsutomu Sakamoto, MD, Tokyo, Japan
- Gustavo Santos de Souza, MD, Brasilia, Brazil
- Dr Robert Sauer, St Pölten, Austria
- Steven Schepers, MD, Herent, Belgium
- Janet Scheraga, Syracuse, NY
- Steven M. Schultz, MD, Fort Worth, Tex
- Joel M. Schwartz, MD, New City, NY
- Simona Secci, MD, Cagliari, Italy
- Dra Mariela Alejandra Severi, Córdoba, Argentina
- Dr A. Krishna Prasad Shanbhogue, Chandigarh, India
- Matt Shapiro, MD, Charlottesville, Va
- Hideki Shima, MD, Tokyo, Japan
- Taro Shimono, MD, Osaka, Japan
- David F. Sobel, MD, La Jolla, Calif
- Gustavo Socolsky, MD, Tucamán, Argentina
- James D. Sprinkle, Jr, MD, Spotsylvania, Va
- Anouk Stein, MD, Phoenix, Ariz
- Scott Stevens, MD, Cincinnati, Ohio
- Kouichi Sugiyama, Numazu, Japan
- Vinod Sukumaran II, MD, Trivandrum, India
- Venkateswar Rao Surabhi, Herndon, Va
- Amit Suri, MD, DNB, Norfolk, United Kingdom
- Norio Takahashi, MD, Fukui, Japan
- Eliko Tanaka, MD, Yokohama, Japan
- Toyohiko Tanaka, MD, Otsu, Shiga, Japan
- Weawdao Techawattanakul, MD, Chiengrai, Thailand
- Douglas L. Teich, MD, Brookline, Mass
- Rogério Teles de Melo, Belo Horizonte, Brazil
- Kazuma Terauchi, Fujieda, Shizuoka, Japan
- Khin Khin Tha, MBBS, PhD, Sapporo, Japan
- Eugene Tong, MD, Austin, Tex
- Hüseyin Gürkan Töre, MD, Ankara, Turkey
- William C. Torreggiani, MB, Dublin, Ireland
- Dr Özgür Tosun, Bilkent, Ankara, Turkey
- Unni Udayasankar, MD, FRCR, Atlanta, Ga
- Hiroyuki Ueda, Kyoto, Japan
- Eleni Vafeiadou, Thessaloniki, Greece
- Ricardo Vallejos, San Isidro, Buenos Aires, Argentina
- Piet Vanhoenacker, MD, Moorsel, Belgium
- Alexander Vidershayn, Brooklyn, NY
- Julio Vietti, Buenos Aires, Argentina
- Christopher P. Vittore, MD, Rockford, Ill
- Jesús Ig. Vivancos, MD, Tenerife, Spain
- Dr Silvio Vollmer, Cipolleti, Rio Negro, Argentina
- Nicolaus A. Wagner-Bartak, MD, Houston, Tex
- Peter Waibel, MD, St Gallen, Switzerland
- Steven T. Welch, MD, Kansas City, Mo
- Christopher Wen, MD, Long Beach, Calif
- Joseph R. Whitnah, MD, Mercer Island, Wash
- David Wilkes, MD, Dallas, Tex
- Edward Williams, Isle of Man, United Kingdom
- Scott R. Wottrich, MD, Atlanta, Ga
- Kei Yamada, Kyoto, Japan
- Ensar Yekeler, MD, Istanbul, Turkey
- Stanko Yovichevich, MD, Sydney, Australia
- Joe Yut, Olathe, Kan
- Thomas T. Zacharia, MD, New York, NY
- Yu Zhang, San Francisco, Calif
Resident group responses
- Baylor University Medical Center-Dallas Radiology Residents, Dallas, Tex
- Clinica Radiologica Luiz Felippe Mattoso Radiology Residents, Rio de Janeiro, Brazil
- Diagnóstico Maipú Radiology Residents, Vicente Lopez, Buenos Aires, Argentina
- Hospital Italiano de Córdoba Radiology Residents, Córdoba, Argentina
- Kyoto City Hospital Radiology Residents, Kyoto, Japan
- Prince of Songkla University Radiology Residents, Hat Yai, Songlka, Thailand
- Trakya University Radiology Residents, Edirne, Turkey
- University of Pennsylvania Radiology Residents, Philadelphia, Pa
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HISTORY
IMAGING FINDINGS
