Canavan disease is a rare, autosomal recessive inherited, neurological disorder, classified as a leukodystrophy. The underlying genetic defect is an enzyme defect of aspartoacyclase. This enzyme normally breaks down N-acetylaspartate acid, or NAA, into the building blocks of myelin, the fatty membrane that surrounds nerves. With loss of this enzyme, the NAA builds up in the cells, impairing the normal function of the nervous system. With time, the brain has a characteristic spongy degeneration.
The symptoms of Canavan disease appear in early infancy and progress rapidly. These symptoms include mental retardation, feeding difficulties, abnormal muscle tone, poor head control, and abnormally enlarged head. With time, paralysis, blindness, or hearing loss may occur.
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Van Bogaert-Bertrand INCIDENCE Very rare AGE RANGE-MEDIAN Birth GEOGRAPHY Eastern European Jewish
Canavan disease prenatal diagnosis and genetic counseling.
Matalon R, Matalon KM.
Department of Pediatrics and Human Biological Chemistry and Genetics, Children's Hospital, Galveston, TX 77555-0359, USA.
Obstet Gynecol Clin North Am 2002 Jun;29(2):297-304 Abstract quote
Canavan disease is a severe leukodystrophy more common among Ashkenazi Jews. The enzyme defect, apartoacylase, has been identified, and the gene cloned. Only two mutations account for over 98% of all Jewish alleles with Canavan disease.
The carrier frequency among healthy Jews is 1:37-58. Carrier detection and prenatal diagnosis can be accurately carried out using molecular analysis.
When mutations are unknown, analysis of amniotic fluid for NAA using stable isotope dilution technique can be used for prenatal diagnosis.
PATHOGENESIS CHARACTERIZATION MUTATIONS
The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients.
Elpeleg ON, Shaag A.
Metabolic Disease Unit, Shaare-Zedek Medical Center, Jerusalem, Israel.
J Inherit Metab Dis 1999 Jun;22(4):531-4 Abstract quote
Canavan disease is an infantile neurodegenerative disease that is caused by mutations in the gene encoding the enzyme aspartoacylase. It has mainly been reported in Jewish families. Genotyping of newly diagnosed patients is essential for the carrier identification and prenatal diagnosis.
The sequence of the coding region was determined in 15 non-Jewish patients and 9 new mutations were identified: Y109X, P183H, V186F, M195R, P280L, P280S, A287T, 245insA, and a tentative missplicing mutation which leads to skipping of exon 5.
The common pan-European mutation, A305E, was identified in 40% of the alleles and the overall detection rate was 93%.
Canavan disease: mutations among Jewish and non-jewish patients.
Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R.
Research Institute, Miami Children's Hospital, FL 33155.
Am J Hum Genet 1994 Jul;55(1):34-41 Abstract quote
Canavan disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Sixty-four probands were analyzed for mutations in the ASPA gene.
Three point mutations--693C-->A, 854A-->C, and 914C-->A--were identified in the coding sequence. The 693C-->A and 914C-->A base changes, resulting in nonsense tyr231-->ter and missense ala305-->glu mutations, respectively, lead to complete loss of ASPA activity in in vitro expression studies. The 854A-->C transversion converted glu to ala in codon 285. The glu285-->ala mutant ASPA has 2.5% of the activity expressed by the wild-type enzyme. A fourth mutation, 433 --2(A-->G) transition, was identified at the splice-acceptor site in intron 2. The splice-site mutation would lead to skipping of exon 3, accompanied by a frameshift, and thus would produce aberrant ASPA. Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-->ala mutation was predominant (82.9%) in this population, followed by the tyr231-->ter (14.8%) and 433 --2(A-->G) (1.1%) mutations. The three mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. The ala305-->glu mutation was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes.
Predominant occurrence of certain mutations among Ashkenazi Jewish and non-Jewish patients with Canavan disease would suggest a founding-father effect in propagation of these mutant chromosomes.
Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.
Kaul R, Balamurugan K, Gao GP, Matalon R.
Research Institute, Miami Children's Hospital, Florida 33155.
Genomics 1994 May 15;21(2):364-70 Abstract quote
Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease.
The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey.
The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA.
Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review.
Nathan S. Kline Institute for Psychiatric Research, Center for Neurochemistry, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA.
Neurochem Int 2002 Apr;40(4):295-300 Abstract quote
Molecular water pumps (MWPs) are characterized as biochemical systems existing at a compartmental boundary of living cells that can actively pump water against its gradient. A role for the observed intercompartmental transport of N-acetyl-L-aspartate (NAA), between neurons and oligodendrocytes in the CNS, as an efflux MWP for the removal of neuronal metabolic water has been proposed.
In this review, accumulating evidence in support of such a role for NAA is presented, and the dynamics of the NAA cycle in myelinated neurons are considered. Based on the results of recent investigations, it is calculated that 1 mol of NAA is synthesized for every 40 mol of glucose (Glc) equivalent oxidized in the brain, and each mol of NAA may transport 121 mol of metabolic water out of neurons. In addition, turnover of total brain NAA is very rapid and appears to be only 16.7 h. Thus, the most important characteristic of NAA in the brain may not be its static level, but a dynamic aspect related to its rapid turnover.
The relationship of NAA as a potential MWP to Canavan disease (CD), a genetic spongiform leukodystrophy in which the catabolic portion of the NAA cycle is deficient, and in a newly recognized brain disorder, hypoacetylaspartia, where the anabolic portion of the NAA cycle appears to be deficient, are discussed.
Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase.
Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW.
Department of Neurosciences, New Jersey Medical School, Newark, New Jersey 07103, USA.
J Neurochem 2001 Aug;78(4):736-45 Related Articles, Links
Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase.
Chakraborty G, Mekala P, Yahya D, Wu G, Ledeen RW.
Department of Neurosciences, New Jersey Medical School, Newark, New Jersey 07103, USA.
Despite its growing use as a radiological indicator of neuronal viability, the biological function of N-acetylaspartate (NAA) has remained elusive. This is due in part to its unusual metabolic compartmentalization wherein the synthetic enzyme occurs in neuronal mitochondria whereas the principal metabolizing enzyme, N-acetyl-L-aspartate amidohydrolase (aspartoacylase), is located primarily in white matter elements. This study demonstrates that within white matter, aspartoacylase is an integral component of the myelin sheath where it is ideally situated to produce acetyl groups for synthesis of myelin lipids. That it functions in this manner is suggested by the fact that myelin lipids of the rat optic system are well labeled following intraocular injection of [14C-acetyl]NAA. This is attributed to uptake of radiolabeled NAA by retinal ganglion cells followed by axonal transport and transaxonal transfer of NAA into myelin, a membrane previously shown to contain many lipid synthesizing enzymes. This study identifies a group of myelin lipids that are so labeled by neuronal [14C]NAA, and demonstrates a different labeling pattern from that produced by neuronal [14C]acetate. High performance liquid chromatographic analysis of the deproteinated soluble materials from the optic system following intraocular injection of [14C]NAA revealed only the latter substance and no radiolabeled acetate, suggesting little or no hydrolysis of NAA within mature neurons of the optic system. These results suggest a rationale for the unusual compartmentalization of NAA metabolism and point to NAA as a neuronal constituent that is essential for the formation and/or maintenance of myelin. The relevance of these findings to Canavan disease is discussed.
A method for fast multislice T1 measurement: feasibility studies on phantoms, young children, and children with Canavan's disease.
Haselgrove J, Moore J, Wang Z, Traipe E, Bilaniuk L.
Department of Radiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
J Magn Reson Imaging 2000 Apr;11(4):360-7 Abstract quote
We have developed a multislice protocol for quantitative T1 measurements in which the processing time and the acquisition time are under 2 minutes each for a complete brain study of 15 slices.
An echoplanar, inversion-recovery image sequence is designed to collect data suitable for analysis using a linear regression algorithm. The precision is approximately twice the noise to signal ratio of the images. The accuracy of the protocol is better than 1% for T1 in the range 0-2 seconds and deviates slightly for longer T1 values. The protocol is insensitive to B1 field values.
If needed, the data can be postprocessed using a slow, nonlinear algorithm to give an accuracy of less than 1% and a precision of approximately the noise to signal ratio throughout a range of T1 values from 0 to 4 seconds.
Use of localized proton nuclear magnetic resonance spectroscopy in Canavan's disease.
Aydinli N, Caliskan M, Calay M, Ozmen M.
Department of Pediatrics, Istanbul University Faculty of Medicine, Capa.
Turk J Pediatr 1998 Oct-Dec;40(4):549-57 Abstract quote
Canavan's disease is characterized by megalencephaly, leukodystrophy and early motor and mental retardation. On computerized tomography and magnetic resonance imaging, severe changes compatible with white matter disease due to demyelination is observed.
It has been demonstrated that urinary N-acetylaspartate levels are increased because of a deficiency of aspartoacylase (N-acyl-L-aspartate aminohydrolase) in these patients. In this study, with the use of proton nuclear magnetic resonance spectroscopy, we were able to demonstrate elevated levels of N-acetylaspartate compared to choline and creatine in the frontal region white matter of three patients.
The in vivo measurement of N-acetylaspartate, choline and creatine in the brain by magnetic resonance spectroscopy offers an additional noninvasive diagnostic test for establishing the diagnosis of Canavan's disease.
Magnetic resonance imaging in juvenile Canavan disease.
Toft PB, Geiss-Holtorff R, Rolland MO, Pryds O, Muller-Forell W, Christensen E, Lehnert W, Lou HC, Ott D, Hennig J, et al.
John F. Kennedy Institute, Glostrup, Denmark.
Eur J Pediatr 1993 Sep;152(9):750-3 Abstract quote
We present a 2-year-old boy and a 6-year-old girl with mild Canavan disease (CD). Aspartoacylase activity in skin fibroblasts was deficient. Magnetic resonance imaging (MRI) of the brain did not show the prominent leucodystrophy previously reported in CD, but there was a hyperintense signal from the lentiform nuclei and the heads of the caudate nuclei on the T2-weighted MR images.
This suggests a specific vulnerability of the corpus striatum in these patients. In the older patient, the white matter became affected at the age of 6 years. Proton magnetic resonance spectroscopy (1H-MRS) of white matter revealed a normal concentration of N-acetyl-L-aspartate (NAA) and a markedly decreased concentration of choline containing compounds (Cho) in the boy but a normal ratio of NAA to Cho in the girl.
We conclude that deficient NAA catabolism affects myelin metabolism. This may present as changes in the striatum and/or as a low concentration of Cho before leucodystrophy appears on MRI.
Canavan disease: CT and MR imaging of the brain.
Brismar J, Brismar G, Gascon G, Ozand P.
Department of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
AJNR Am J Neuroradiol 1990 Jul-Aug;11(4):805-10 Abstract quote
Canavan disease (spongy degeneration of the brain) is a rare lethal neurodegenerative disorder of infancy; fewer than 100 cases have been reported. We describe a series of nine patients with enzymatic defects and clinical features consistent with Canavan disease; in two patients the disease was proved by biopsy.
All patients were examined with CT and seven with MR. In every instance, both CT and MR showed white-matter disease, sometimes sparing the external and internal capsules, the corpus callosum, and the deep cerebellar white matter. Atrophic changes were found in six patients; the changes were marked in one and slight in five.
There was no obvious correlation between the severity of the white-matter disease and the clinical presentation--one patient with severe white-matter disease was clinically normal.
The CT and MR findings in Canavan disease are nonspecific and somewhat nonuniform: its preautopsy diagnosis relies primarily on biochemical findings.
LABORATORY MARKERS AMNIOTIC FLUID
Reliable prenatal diagnosis of Canavan disease (aspartoacylase deficiency): comparison of enzymatic and metabolite analysis.
Bennett MJ, Gibson KM, Sherwood WG, Divry P, Rolland MO, Elpeleg ON, Rinaldo P, Jakobs C.
Kimberly H. Courtwright and Joseph W. Summers Metabolic Disease Center, Baylor University Medical Center, Dallas, TX 75246.
J Inherit Metab Dis 1993;16(5):831-6 Abstract quote
Prenatal diagnosis has been undertaken in 17 pregnancies in 15 families at risk for aspartoacylase deficiency.
Amniocentesis was at 14-18 weeks gestation followed by measurement of amniotic fluid N-acetyl-L-aspartate (NAA) levels in all pregnancies and amniocyte aspartoacylase activity in most pregnancies. In one case amniocentesis was performed at 11 weeks gestation in conjunction with chorionic villus sampling. At 14-18 weeks of gestation, control levels of NAA were 0.30-2.55 mumol/L. The fetus was predicted to be affected in 8 of the pregnancies, 4 of which were confirmed by enzyme analysis on fetal tissue and 2 by the clinical and metabolic expression of Canavan disease in a newborn.
In two cases there was no fetal tissue available for enzyme confirmation. One of these had the highest amniotic fluid NAA level (8.68 mumol/L) and in the other pregnancy there were two amniocenteses, both with markedly elevated levels. Of 9 fetuses predicted to be normal, 8 newborns were clinically and biochemically normal. A single case with amniotic fluid NAA in the normal range (1.56 mumol/L, measured in one laboratory only) resulted in an aborted fetus in whom aspartoacylase was deficient in cultured skin fibroblasts.
We propose that amniotic fluid NAA levels remain the best predictor of an affected fetus and recommend that the assay be performed in multiple laboratories.
A radiometric assay for aspartoacylase activity in cultured oligodendrocytes.
Madhavarao CN, Hammer JA, Quarles RH, Namboodiri MA.
Department of Anatomy, Physiology and Genetics, USUHS, Bethesda, Maryland 20814, USA.
Anal Biochem 2002 Sep 15;308(2):314-9 Abstract quote
Recent studies have shown that aspartoacylase (ASPA), the defective enzyme in Canavan disease, is detectable in the brain only in the oligodendrocytes. Studying the regulation of ASPA is central to the understanding the pathogenesis of Canavan disease and to the development of therapeutic strategies.
Toward this goal, we have developed a sensitive method for the assay of ASPA in cultured oligodendrocytes. The method involves: (a) chemical synthesis of [14C]N-acetylaspartate (NAA) from L-[14C]Asp; (b) use of [14C]NAA as substrate in the assay; and (c) separation and quantitation of the product L-[14C]Asp using a TLC system. This method can detect as low as 10pmol of product and has been optimized for cultured oligodendrocytes.
Thus, this method promises to be a valuable tool for understanding the biochemical mechanisms involved in the cell-specific expression and regulation of ASPA in oligodendrocytes.
Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease.
Nathan S. Kline Institute for Psychiatric Research, Center for Neurochemistry, Orangeburg, NY 10962, USA.
J Mol Neurosci 2000 Oct;15(2):61-9 Abstract quote
Canavan disease (CD) is a globally distributed early-onset leukodystrophy. It is genetic in nature, and results from an autosomally inherited recessive trait that is characterized by loss of the axon's myelin sheath while leaving the axons intact, and spongiform degeneration especially in white matter. There is also a buildup of N-acetyl-L-aspartate (NAA) in brain, as well as NAA acidemia and NAA aciduria.
The cause of the altered NAA metabolism has been traced to several mutations in the gene for the production of aspartoacylase, located on chromosome 17, which is the primary enzyme involved in the catabolic metabolism of NAA.
In this review, an attempt is made to correlate the change in NAA metabolism that results from the genetic defects in CD with the processes involved in the development of the CD syndrome. In addition, present efforts to counter the results of the genetic defects in this disease are also considered.
Cranial ultrasound findings in aspartoacylase deficiency (Canavan disease).
Buhrer C, Bassir C, von Moers A, Sperner J, Michael T, Scheffner D, Kaufmann HJ.
Kinderklinik KAVH, Universitatsklinikum Rudolf Virchow, Berlin Free University, Germany.
Pediatr Radiol 1993;23(5):395-7 Abstract quote
Canavan disease (CD) is a rare leukodystrophy which is lethal in infancy or early childhood. The underlying biochemical abnormality in CD is a hereditary deficiency of N-aspartoacylase transmitted in an autosomal recessive fashion.
We report on the ultrasound (US), CT, and MRI findings of three unrelated boys with biochemically confirmed CD. At 6 and 9 months of age, two CD patients with rapid neurological deterioration showed markedly enhanced acoustic attenuation of the white matter with the exception of the corpus callosum, giving the appearance of a reversed pattern of echogenicity of cortical gray and subcortical white matter. While gyri and sulci had an almost normal US appearance, the periventricular gray matter featured prominently with increased echogenicity.
In contrast another CD patient with a more protracted course had ventricular enlargement when examined by US at 5 and 9 months but no alteration in white matter echogenicity. MRI showed impaired myelinization in all three patients with Canavan disease.
UPPER AIRWAY ABNORMALITIES
Upper airway abnormalities in Canavan disease.
Francois J, Manaligod JM.
Department of Otolaryngology-Head and Neck Surgery, University of Iowa College of Medicine, 200 Hawkins Drive, 52242, Iowa, IA, USA
Int J Pediatr Otorhinolaryngol 2002 Dec 2;66(3):303-7 Abstract quote
OBJECTIVE: To describe upper airway anatomical abnormalities associated with Canavan disease.
METHODS: Retrospective case report.
RESULTS: Physical examination and laryngoscopy demonstrated oropharyngeal narrowing, macroglossia, and bronchial asymmetry in a child with Canavan disease. Tracheostomy decreased problems with chronic aspiration and obstructive sleep apnea.
CONCLUSIONS: Oropharyngeal obstruction and bronchial asymmetry are previously undescribed upper airway abnormalities found in an individual with Canavan disease. Tracheostomy is an effective method of managing chronic aspiration and obstruction in these patients.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
Canavan disease: neuromorphological and biochemical analysis of a brain biopsy specimen.
de Coo IF, Gabreels FJ, Renier WO, de Pont JJ, van Haelst UJ, Veerkamp JH, Trijbels JM, Jaspar HH, Renkawek K.
Institute of Neurology, University Hospital Nijmegen, The Netherlands.
Clin Neuropathol 1991 Mar-Apr;10(2):73-8 Abstract quote
In this study we present a patient with Canavan disease or Van Bogaert and Bertrand type of spongiform leukodystrophy, proven by brain biopsy.
We performed morphological studies and biochemical assays on fresh homogenates of the grey and white matter. Quantitative neuromorphological analysis of the cortex showed normal values except for poor dendritic arborization of the inner layers. No signs of neuronal damage were observed. The Na-K-ATPase activity was increased. Pyruvate and ketone bodies oxidation rates and the activity of cytochrome-c oxidase were normal.
We conclude that there is neither a primary neuronal damage nor a primary mitochondrial dysfunction in the oxidative processes despite the abnormal morphology of mitochondria in this disease.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS SURVIVAL 3-10 years
Children are usually blind, paralyzed, and prone to seizures
TREATMENT GENE THERAPY
Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.
Janson C, McPhee S, Bilaniuk L, Haselgrove J, Testaiuti M, Freese A, Wang DJ, Shera D, Hurh P, Rupin J, Saslow E, Goldfarb O, Goldberg M, Larijani G, Sharrar W, Liouterman L, Camp A, Kolodny E, Samulski J, Leone P.
Robert Wood Johnson Medical School-UMDNJ and Cooper Hospital, 08103, USA.
Hum Gene Ther 2002 Jul 20;13(11):1391-412 Abstract quote
This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective.
The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition.
This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests.
This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.
The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats.
Baslow MH, Kitada K, Suckow RF, Hungund BL, Serikawa T.
Nathan S. Kline Institute for Psychiatric Research, Center for Neurochemistry, Orangeburg, New York 10962, USA.
Neurochem Res 2002 May;27(5):403-6 Abstract quote
Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from an autosomally inherited recessive trait. CD is characterized by loss of the axon's myelin sheath, while leaving the axons intact, and spongiform degeneration, especially in white matter.
It is an osmotic disease that affects both gray and white matter and is caused by the inability of oligodendrocytes to hydrolyze N-acetyl-L-aspartate (NAA) because of a lack of aspartoacylase activity. As a result, there is a build-up of NAA in brain with both cellular and extracellular edema, as well as NAA acidemia and NAA aciduria.
Recent studies have indicated that several compounds have the ability to reduce brain levels of NAA in normal mice and rats. In this investigation, these compounds have been tested, using a CD-like rat model of the human disease to evaluate their potential for use in the treatment of the disease.
Of seven substances tested in an acute 5-day study, only lithium chloride treatment resulted in a significant reduction of about 13% in whole-brain NAA levels in the CD-like rat model.
This is the first pharmacological investigation of the effect of drugs on the level of brain NAA in an animal model of CD, and the first report of a substance that can reduce the brain NAA level in this model.
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