INTRODUCTION AND BACKGROUND — Aspartoacylase deficiency (Canavan disease; MIM #271900) is an autosomal recessive spongiform leukodystrophy that is prevalent in, but not restricted to, Ashkenazi Jewish individuals. The disease typically begins in infancy and is marked by relentless progression.
Canavan disease was first described in the early 20th century as spongy degeneration of central nervous system myelin in infancy. The discovery of N-acetylaspartic aciduria due to aspartoacylase deficiency in a leukodystrophy was made in 1987 [1]. The realization that this leukodystrophy was actually Canavan disease with abnormal N-acetylaspartic acid (NAA) metabolism was not made until 1988 [2]. Elevated urinary NAA excretion and aspartoacylase deficiency had been reported two years previously, but without a direct association to spongy degeneration of myelin in infancy [1]. The aspartoacylase gene was cloned in 1993, and numerous mutations have been identified since then [3-6].
Although the Canavan disease eponym is widely used, aspartoacylase deficiency is preferable. Of interest, Canavan's own report was linked to Schilder disease or Krabbe disease (galactocerebrosidase deficiency) and not spongy degeneration.
ETIOLOGY — Aspartoacylase deficiency is caused by mutations in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in the brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing spongiform degeneration are uncertain.
Genetics — Aspartoacylase deficiency is transmitted in an autosomal recessive fashion. The gene encoding aspartoacylase is located on chromosome 17pter-p13 [4]. Several mutations have been defined in ASPA, but just four of them account for >99 percent of aspartoacylase deficiency cases in Ashkenazi Jews [3,5,7-10].
In non-Ashkenazi individuals, a broad range of distinctly different mutations, including large deletions, has been identified [8-15]. Unique ASPA mutations have been identified in the Japanese and Scandinavian populations [16,17].
Biochemistry — NAA, formed from acetyl-CoA and aspartic acid, is the second most prevalent free amino acid in the brain. It is localized to neurons, where it is synthesized within mitochondria and transferred to oligodendrocytes via axoglial contact zones between the innermost oligodendrocyte plasma membrane and the axonal membrane [18]. In neurons, NAA is converted to N-acetylaspartylglutamate (NAAG) and is taken up by astrocytes, where it is hydrolyzed to NAA and glutamate. The NAA is then taken up by oligodendrocytes, the primary location of aspartoacylase [19-21].
Aspartoacylase catalyzes the conversion of NAA to aspartate (aspartic acid) and acetate. By mechanisms that are largely unknown, deficiency of aspartoacylase leads to oligodendrocyte dysfunction, the prominent spongiform changes, and absence of myelin [22,23]. Levels of NAA are markedly increased in plasma, urine, and cerebrospinal fluid [24,25].
Loss-of-function mutations of the ASPA gene lead to structural changes, including decreased thermal or conformational stability, which result in diminished or nearly absent enzymatic activity [26,27].
Pathogenesis — Abnormal myelination, with associated prominence of swollen, vacuolated astrocytes, is a fundamental hallmark of aspartoacylase deficiency. However, the specific role of NAA in the pathogenesis of this disease is unknown [28-30].
●One suggestion is that a reduction in aspartic acid as a result of aspartoacylase deficiency adversely affects the recycling of aspartate for NAA synthesis and the availability of aspartate for intercellular signaling [31].
●Another plausible hypothesis is that of a cytotoxic mechanism involving NAA or its metabolic product, NAAG [32,33].
•It has been proposed that the extracellular concentration of NAA increases up to 1000-fold secondary to absent or markedly decreased aspartoacylase activity, resulting in disruption of the oligodendrocyte-axon interface and interruption of myelination [34-36]. However, NAA concentration in the brain of patients with aspartoacylase deficiency is less than twofold elevated [37]. In an animal model, deficient aspartoacylase expression resulted in altered oligodendrocyte maturation, markedly reduced myelination, and increased levels of GFAP protein, a marker of gliosis [38]. In addition, NAA is taken up by astrocytes, producing the prominent vacuolization within their cytoplasm, and leading to macrocephaly. In this model, NAA is cytotoxic for astrocytes and not oligodendrocytes. The turnover of NAA is regarded as highly dynamic [39]. As such, failure of NAA degradation could provide a profound osmotic force, resulting in the observed vacuolar changes in the brain [40,41]. The disruption of mitochondria in astrocytes may be a secondary phenomenon, but a primary alteration in mitochondrial metabolism has been proposed as potentially related to the prominent cellular alterations. N-acetylaspartate synthase deficiency corrected the myelin and neuronal phenotype in a mouse model of Canavan disease [42,43]. These findings strongly support the notion that elevation of NAA is the major disease mechanism, and suggests a therapeutic approach.
•A further potential pathogenetic mechanism involves NAAG as a trigger of glutamate excitotoxicity [44]. The possibility of an acetate deficit secondary to low or absent aspartoacylase activity (NAA is hydrolyzed to acetate and L-aspartate) also has been suggested [45,46]. This seems less likely, as alternate acetate sources are readily available via other metabolic pathways [47].
•Finally, oxidative stress may play a role in the pathogenesis of aspartoacylase deficiency, based upon evidence that NAA produces lipid peroxidation and protein oxidation and reduces antioxidants in rat brain [48,49]. NAA-derived acetyl groups may be a means by which oligodendrocytes preserve energetic resources during myelination by uncoupling fatty acid synthesis from oxidative metabolism [50]. Further support for this hypothesis was found in the salutary effect of anaplerotic therapy in a Canavan disease mouse model [51].
These hypotheses are not mutually exclusive [52].
EPIDEMIOLOGY — Aspartoacylase deficiency is most prevalent among Ashkenazi Jewish individuals [25,28]. It has been described in other populations as well, including a large series from Saudi Arabia [53]. The carrier frequency among the Ashkenazi ranges from 1:37 to 1:57, yielding a range of approximate prevalence rates between 1:6000 and 1:14,000 [54,55]. The disorder is much less common in non-Ashkenazi populations [7-10]. However, sufficient data are not available to calculate a prevalence rate in groups other than Jewish people.
CLINICAL FEATURES — The initial presentation of aspartoacylase deficiency, generally at about age three months, features lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement [56]. However, poor feeding, irritability, and visual inattention have been described in neonates.
Macrocephaly becomes prominent by three to six months, and thereafter hypotonia progresses to spasticity, hyperreflexia, extensor plantar responses, and tonic extensor spasms. The extensor spasms may occur in response to noise, but infants with aspartoacylase deficiency do not exhibit the hyperacusis noted in Tay-Sachs disease.
By age six months, neurologic abnormalities are invariant in those with the typical form of aspartoacylase deficiency. Little subsequent development is noted, although visual fixation may be acquired later only to be lost.
Blindness in association with optic atrophy occurs between 6 and 18 months. Seizures, usually generalized tonic-clonic, are noted in about 50 percent. Unlike most leukodystrophies, the cerebrospinal fluid protein is usually normal. Fair complexion has been described, but this is of dubious significance.
Pseudobulbar signs and decerebrate posturing dominate the end stage of aspartoacylase deficiency. Feeding is a major issue with prominent swallowing dysfunction and gastroesophageal reflux. Death may occur in childhood, although survival into the teens is typical as the result of enhanced medical management, particularly alternative feeding strategies.
Variant forms — The presence of variant forms of aspartoacylase deficiency is controversial. A suggested juvenile-onset form, beginning after age 5, is characterized by spasticity, cerebellar dysfunction, and blindness, with death occurring by the age of 15 years [57]. Onset in adults, clinically resembling multiple sclerosis, also has been reported.
Whether these variants represent aspartoacylase deficiency is unclear, as they were described prior to the availability of biochemical and molecular diagnosis [57]. At that time, the diagnosis was based upon the characteristic clinical features and demonstration of spongiform degeneration of the brain. However, this is a nonspecific pathology shared by a number of other unrelated conditions [58]. (See 'Differential diagnosis' below.)
Later studies have not found evidence supporting a distinct juvenile form of aspartoacylase deficiency. Rather, they suggest that the disease typically begins in infancy but progresses at a highly variable rate, with no correlation of genotype or residual enzyme activity to clinical presentation [59].
●One study reported 22 Ashkenazi infants with Canavan disease and typical onset in infancy [58]. There were 14 patients younger than age 6 who were clinically stable. Two patients died before the age of 5. Survival beyond age 5 was noted in six patients, with ages at death ranging from 6 to 17 years.
●Another series of 60 children, mainly Ashkenazi, with onset prior to 10 months of life demonstrated high variability in survival, including significantly different longevity in two siblings from two families [56].
The authors in both studies concluded that despite variable survival, these children did not represent variant forms of aspartoacylase deficiency. In subsequent reports, milder disease expression has been associated with specific ASPA gene mutations that may produce a relatively benign phenotype [60-62].
Neuroimaging — In patients with aspartoacylase deficiency, cranial imaging by computed tomography (CT) and magnetic resonance imaging (MRI) typically shows diffuse and symmetrical white matter involvement. CT shows marked reduction of white matter [63-67]. MRI demonstrates white matter that is hypointense on T1 and hyperintense on T2 (image 1 and image 2) [64-67]. On diffusion-weighted MRI sequences, restricted diffusion in deep white matter and brainstem corresponding to cytotoxic brain edema is frequently present early in Canavan disease [68]. In individuals with delayed onset and slower progression, brain MRI may show less prominent white matter changes and increased signal intensity in basal ganglia [59,69,70]. In a case report of a girl with incidentally discovered Canavan disease who had a benign clinical course, there were atypical MRI findings of diffuse T2 and fluid-attenuated inversion recovery (FLAIR) signal hyperintensity and restricted diffusion involving the cortex and sparing the white matter [71].
Magnetic resonance spectroscopy (MRS) typically shows markedly increased levels of N-acetylaspartic acid (NAA) (image 3) [66,67,72,73]. MRI without any white matter abnormalities but with elevated NAA peak on MRS was reported in a five-year-old child with the insidious onset of mild motor and speech delay [74].
MRS is also being studied to track the natural progression of metabolite changes and could serve as a measure for monitoring therapeutic interventions [75]. In some instances, NAA levels are normal, but other metabolites are reduced, yielding elevated ratios of NAA/choline and NAA/creatine [76].
Neuropathology — Brain weight is increased significantly in aspartoacylase deficiency, reflecting the prominent macrocephaly noted in early infancy [57]. However, by age 30 months, brain weight may be normal, reflecting the progressive white matter loss [57].
The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter. Grossly enlarged Alzheimer type II astrocytes are seen in gray matter.
Ultrastructural studies reveal disruption of mitochondria in astrocytes. Myelin is markedly reduced and may be virtually absent in some areas. Myelin lamellae within subcortical white matter are separated by vacuoles. With prolonged survival, white matter is depleted and vacuolization is present throughout the cortex.
Unlike galactosylceramide lipidosis (Krabbe disease) and sulfatide lipidosis (metachromatic leukodystrophy), peripheral nerves are generally uninvolved in aspartoacylase deficiency [57]. An early report, prior to biochemical or molecular diagnosis, did identify peripheral nerve changes including axonopathy and demyelination [77].
Pregnancy — As affected individuals are unlikely to reproduce, no information is available regarding pregnancy in patients with aspartoacylase deficiency.
Findings from the knockout mouse model suggest reduced reproductive health in the homozygous affected females and heightened fetal lethality (50 percent fewer pups/litter) [78].
DIAGNOSIS — The clinical diagnosis of aspartoacylase deficiency is relatively straightforward. In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis is supported by elevated levels of urine N-acetylaspartic acid (NAA) and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing [25].
Laboratory studies — In patients with clinical features and cranial imaging findings suggesting aspartoacylase deficiency, one should request measurement of NAA in urine using gas chromatography/mass spectrometry [79].
Urine levels of NAA are increased up to 200 times normal in aspartoacylase deficiency [24]. This measurement is determined by gas chromatography/mass spectrometry. Occasional patients with aspartoacylase deficiency have lower levels of urine NAA excretion, but the levels are still approximately five- to ten-fold higher than normal [80].
In affected infants, levels of NAA are also increased in plasma and in cerebrospinal fluid, but elevated urine NAA is sufficient to support the diagnosis [25].
Canavan disease may be suspected when the NAA peak is elevated in MR spectroscopy [72-76]. (See 'Neuroimaging' above.)
Aspartoacylase activity can be measured reliably in cultured skin fibroblasts [2,81,82]. This test is used to confirm the chemical diagnosis and to rule out false positives, particularly for patients who have an elevation of urine NAA that is lower than usual for aspartoacylase deficiency.
Molecular genetic testing — For patients diagnosed with aspartoacylase deficiency by elevated urine NAA levels, targeted molecular genetic testing of the patient and family members can be useful for purposes of genetic counseling, particularly in Ashkenazi children where the number of possible mutations is small, or in families with a previously affected sibling whose mutation is known. In non-Ashkenazi families with their first affected child and no previously identified mutation, complete molecular testing may be required in order to provide genetic counseling, especially when the family may wish to consider a future pregnancy.
Targeted mutation analysis can identify specific alleles that cause most cases of aspartoacylase deficiency [25]:
●In Ashkenazi Jewish cases, two mutations, p.Glu285Ala and p.Tyr231X, are found in approximately 98 percent of disease-causing alleles [12]. Two other mutations, p.Ala305Glu and c.433-2A>G, each account for approximately one percent of alleles [8].
●In non-Jewish patients of European origin, the p.Ala305Glu mutation accounts for 40 to 60 percent of disease-causing alleles [8,10].
Sequence analysis of the ASPA coding region can be performed first for individuals of non-Ashkenazi Jewish ancestry [25]. Complete or partial deletions of the entire ASPA gene in aspartoacylase deficiency are rare [14,83].
Prenatal diagnosis — Prenatal diagnosis is possible once pathogenic variants of ASPA have been identified in an affected member of the family [25].
For pregnancies at 25 percent risk (ie, the parents are each carriers of a pathogenic variant in the ASPA gene, or the pathogenic variant is known from a previously affected offspring), mutation analysis can be performed from cells obtained using chorionic villous sampling at approximately 10 to 12 weeks gestation or amniocentesis at approximately 15 to 38 weeks gestation [84,85]. Analysis of cell-free DNA in the mother's circulation is likely to become more available in the coming years [86].
Preimplantation diagnosis using single cell molecular methodologies has been accomplished successfully in one of two families evaluated [87].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly the following:
●Krabbe disease (galactosylceramide lipidosis) (see "Krabbe disease")
●Metachromatic leukodystrophy (sulfatide lipidosis) (see "Metachromatic leukodystrophy")
●Vanishing white matter disease (see "Vanishing white matter disease")
●Early-onset adrenoleukodystrophy (see "X-linked adrenoleukodystrophy and adrenomyeloneuropathy")
●Alexander disease which, like Canavan disease, is associated with macrocephaly (see "Alexander disease")
●Demyelinating disorders such as acute demyelinating encephalomyelitis and multiple sclerosis (see "Differential diagnosis of acute central nervous system demyelination in children")
Spongiform degeneration of the brain is a nonspecific pathology shared by a number of other unrelated conditions [58]. These include certain mitochondrial disorders (eg, Leigh syndrome), metabolic diseases (eg, glycine encephalopathy), and viral infections [25].
The subsequent clinical course, cranial imaging abnormalities, and biochemical studies should differentiate aspartoacylase deficiency from the others.
MANAGEMENT — No effective treatment is available for aspartoacylase deficiency. Management is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections [25]. Assessment of nutritional and developmental status is recommended to guide management.
●A feeding gastrostomy tube is typically needed to maintain adequate nutrition and hydration in the presence of dysphagia. A gastrostomy tube can also reduce the risk of aspiration. (See "Poor weight gain in children younger than two years in resource-abundant countries: Management", section on 'Estimation of energy requirements'.)
●Seizures are treated with standard antiseizure medications. (See "Seizures and epilepsy in children: Initial treatment and monitoring".)
●Exercise (physical therapy) and position changes are helpful to reduce the risk of contractures and decubitus ulcers, and to improve sitting posture.
●Special education programs and interventions to enhance communication skills may be helpful, particularly for those with a less severe clinical course.
●Botulinum toxin injections can be used to treat spasticity.
Investigational therapies — Gene transfer, enzyme replacement therapy, acetate supplementation, anaplerotic therapy, and lithium are being studied as possible treatments for aspartoacylase deficiency.
●A number of preliminary studies have evaluated gene transfer:
•The combined delivery of liposome enclosed enzyme and viral vector-mediated gene transduction was employed in two children [88,89]. While successful delivery could be demonstrated, the results did not demonstrate substantial efficacy.
•Adeno-associated viral vector mediated gene transfer of ASPA was studied in 10 children with aspartoacylase deficiency [90,91]. No significant adverse immune response was noted, and no statement on efficacy was available.
•A knock-out mouse model has been developed, paving the way for additional gene therapy studies [78,92-97], and a spontaneously arising rat model with aspartoacylase deficiency also has been developed [98]. Effective gene transfer using an adeno-associated viral vector has been demonstrated in each model [99-102]. Further, neural progenitor cells have been transplanted successfully in the mouse knockout model and have differentiated into myelin forming oligodendrocytes [103].
●Modified aspartoacylase has been shown to reach the central nervous system following intraperitoneal injection, resulting in a reduction of N-acetylaspartic acid (NAA) levels [104]. This finding suggests that enzyme replacement approaches may be examined in this model.
●Acetate supplementation has been proposed as potentially beneficial for myelin formation by oligodendrocytes based upon the presumption that aspartoacylase deficiency and resultant acetate deficiency in these cells could be responsible for abnormal myelination [45]. As noted earlier (see 'Pathogenesis' above), given the multiple metabolic sources of acetate, this hypothesis seems unlikely. Nonetheless, the acetate precursor glyceryl triacetate was evaluated in low doses (up to 25 mg/kg daily) in two children with aspartoacylase deficiency and in higher doses (up to 5.8 mg/kg daily) in an animal model [105]. No evidence of toxicity was noted with either dosing schedule. In addition, the two children demonstrated no further clinical deterioration, providing a rationale for evaluating a larger dose in affected children. In an earlier study, acetate supplementation in normal mice did increase acetate levels in brain [45].
●Anaplerotic therapy using triheptanoin shows promise based upon a study in an animal model [51]. (See 'Pathogenesis' above.)
●Intraperitoneal lithium chloride injection produced reduction, albeit modest, of brain NAA levels in the spontaneous rat model of aspartoacylase deficiency [106]. In a study of six children with Canavan disease, lithium citrate administration was associated with a small but statistically significant decline in brain NAA detected by magnetic resonance spectroscopy [107].
●Decreasing NAA by lowering its synthesis may be a useful approach [42,43].
SUMMARY
●Aspartoacylase deficiency (Canavan disease; MIM #271900) is an autosomal recessive spongiform leukodystrophy that is prevalent in the Ashkenazi Jewish population. The disease typically begins in infancy and is marked by relentless progression. (See 'Introduction and background' above.)
●Aspartoacylase deficiency is caused by mutations in the ASPA gene that encodes the enzyme aspartoacylase. The resulting deficiency of aspartoacylase leads to accumulation of N-acetylaspartic acid (NAA) in brain and to oligodendrocyte dysfunction, spongiform changes, and absence of myelin. However, the precise mechanisms causing to spongiform degeneration are uncertain. (See 'Etiology' above.)
●Aspartoacylase deficiency is highly prevalent among Ashkenazi Jewish individuals, but is much less common in other populations (see 'Epidemiology' above).
●Aspartoacylase deficiency typically presents at about age three months with lethargy and listlessness, weak cry and suck, poor head control, and hypotonia with a paucity of extremity movement. Macrocephaly becomes prominent by three to six months. Thereafter hypotonia progresses to spasticity and tonic extensor spasms. By age six months, neurologic abnormalities are invariant. Little subsequent development is noted. Blindness from optic atrophy occurs between 6 and 18 months. Seizures are noted in about 50 percent of patients. Pseudobulbar signs and decerebrate posturing dominate the end stage. (See 'Clinical features' above.)
●The presence of variant forms of aspartoacylase deficiency is controversial. (See 'Variant forms' above.)
●Brain imaging by computed tomography (CT) and magnetic resonance imaging (MRI) reveals diffuse and symmetrical white matter involvement. (See 'Neuroimaging' above.)
●The gross pathologic findings are dominated by spongy degeneration of deep cortex, subcortical white matter, and cerebellum. The spongiform changes reflect vacuolated astrocytes in deeper cortical layers and in adjacent subcortical white matter. (See 'Neuropathology' above.)
●In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis of aspartoacylase deficiency is supported by elevated levels of urine NAA and/or biallelic pathogenic variants in ASPA identified by molecular genetic testing. (See 'Diagnosis' above.)
●The differential diagnosis of aspartoacylase deficiency includes other progressive white matter diseases of infancy, particularly Krabbe disease, metachromatic leukodystrophy, early-onset adrenoleukodystrophy, Alexander disease, and demyelinating disorders. (See 'Differential diagnosis' above.)
●No effective treatment is available for aspartoacylase deficiency. Management is supportive and aimed at maintaining nutrition and hydration, protecting the airway, preventing seizures, minimizing contractures, and treating infections. Gene transfer, enzyme replacement therapy, acetate supplementation, anaplerotic therapy, reduction in NAA synthesis, and lithium are being studied as possible treatments for aspartoacylase deficiency. (See 'Management' above.)
ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge Alan K Percy, MD, and Raphael Schiffman, MD, MHSc, FAAN, who contributed to earlier versions of this topic review.
1 : N-acetylaspartic aciduria due to aspartoacylase deficiency--a new aetiology of childhood leukodystrophy.
2 : Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease.
3 : Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease.
4 : Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.
5 : Canavan disease: molecular basis of aspartoacylase deficiency.
6 : Biochemistry and molecular biology of Canavan disease.
7 : The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel.
8 : Canavan disease: mutations among Jewish and non-Jewish patients.
9 : The molecular basis of canavan (aspartoacylase deficiency) disease in European non-Jewish patients.
10 : The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients.
11 : Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease.
12 : Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population.
13 : Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease.
14 : Rapid detection of three large novel deletions of the aspartoacylase gene in non-Jewish patients with Canavan disease.
15 : Mutation analysis of the aspartoacylase gene in non-Jewish patients with Canavan disease.
16 : Missense mutation (I143T) in a Japanese patient with Canavan disease.
17 : Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease.
18 : N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation.
19 : N-acetylaspartate in the vertebrate brain: metabolism and function.
20 : Expression of aspartoacylase activity in cultured rat macroglial cells is limited to oligodendrocytes.
21 : Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease.
22 : Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase.
23 : Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination.
24 : Detection of increased urinary N-acetylaspartylglutamate in Canavan disease.
25 : Detection of increased urinary N-acetylaspartylglutamate in Canavan disease.
26 : Mutational analysis of aspartoacylase: implications for Canavan disease.
27 : Relationship between enzyme properties and disease progression in Canavan disease.
28 : Canavan disease: a white matter disorder.
29 : Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease.
30 : N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology.
31 : Canavan disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms.
32 : The effect of N-acetyl-aspartyl-glutamate and N-acetyl-aspartate on white matter oligodendrocytes.
33 : Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease.
34 : Canavan disease and the role of N-acetylaspartate in myelin synthesis.
35 : Defective myelin lipid synthesis as a pathogenic mechanism of Canavan disease.
36 : Does ASPA gene mutation in Canavan disease alter oligodendrocyte development? A tissue culture study of ASPA KO mice brain.
37 : In vivo quantitation of cerebral metabolite concentrations using natural abundance 13C MRS at 1.5 T.
38 : Aspartoacylase deficiency affects early postnatal development of oligodendrocytes and myelination.
39 : Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation.
40 : Are astrocytes the missing link between lack of brain aspartoacylase activity and the spongiform leukodystrophy in Canavan disease?
41 : Canavan disease, a rare early-onset human spongiform leukodystrophy: insights into its genesis and possible clinical interventions.
42 : N-Acetylaspartate Synthase Deficiency Corrects the Myelin Phenotype in a Canavan Disease Mouse Model But Does Not Affect Survival Time.
43 : Suppressing N-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy.
44 : N-acetylaspartylglutamate in Canavan disease: an adverse effector?
45 : Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain.
46 : Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease.
47 : Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS.
48 : N-acetylaspartic acid promotes oxidative stress in cerebral cortex of rats.
49 : Intracerebroventricular administration of N-acetylaspartic acid impairs antioxidant defenses and promotes protein oxidation in cerebral cortex of rats.
50 : Aspartoacylase supports oxidative energy metabolism during myelination.
51 : Dietary triheptanoin rescues oligodendrocyte loss, dysmyelination and motor function in the nur7 mouse model of Canavan disease.
52 : Pathophysiology and Treatment of Canavan Disease.
53 : Infantile CNS spongy degeneration--14 cases: clinical update.
54 : Prevalence of Canavan disease heterozygotes in the New York metropolitan Ashkenazi Jewish population.
55 : Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay.
56 : The clinical course of Canavan disease.
57 : Spongy degeneration of the central nervous system (van Bogaert and Bertrand type; Canavan's disease). A review.
58 : Protracted clinical course for patients with Canavan disease.
59 : Atypical clinical and radiological course of a patient with Canavan disease.
60 : Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings.
61 : Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease.
62 : Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene.
63 : Computed tomography in the diagnosis of Canavan's disease.
64 : CT and MR imaging of Canavan disease.
65 : Canavan disease: CT and MR imaging of the brain.
66 : Use of computed tomography, magnetic resonance imaging, and localized 1H magnetic resonance spectroscopy in Canavan's disease: a case report.
67 : Case 99: Canavan disease.
68 : Cytotoxic edema and diffusion restriction as an early pathoradiologic marker in canavan disease: case report and review of the literature.
69 : Magnetic resonance imaging in juvenile Canavan disease.
70 : Atypical MRI findings in Canavan disease: a patient with a mild course.
71 : Canavan disease - unusual imaging features in a child with mild clinical presentation.
72 : Quantitative measurements with localized 1H MR spectroscopy in children with Canavan's disease.
73 : [Brain magnetic resonance spectroscopy].
74 : Juvenile Canavan Disease: A Leukodystrophy without White Matter Changes.
75 : Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI.
76 : Proton NMR spectroscopy of Canavan's disease.
77 : Peripheral nerve lesion in spongy degeneration of the central nervous system.
78 : Aspartoacylase deficiency does not affect N-acetylaspartylglutamate level or glutamate carboxypeptidase II activity in the knockout mouse brain.
79 : Rapid and sensitive screening for and chemical diagnosis of Canavan disease by gas chromatography-mass spectrometry.
80 : Canavan disease: biochemical and molecular studies.
81 : SSIEM Award. Aspartoacylase deficiency: the enzyme defect in Canavan disease.
82 : Aspartoacylase deficiency and Canavan disease in Saudi Arabia.
83 : Genome-wide gene expression profiling and mutation analysis of Saudi patients with Canavan disease.
84 : Prenatal diagnosis for Canavan disease: the use of DNA markers.
85 : Prenatal detection of Canavan disease (aspartoacylase deficiency) by DNA analysis.
86 : Prenatal Diagnosis: Screening and Diagnostic Tools.
87 : Preimplantation genetic diagnosis of Canavan disease.
88 : Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease.
89 : Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease.
90 : Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.
91 : Immune responses to AAV in a phase I study for Canavan disease.
92 : Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system.
93 : Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease.
94 : Metabolic changes in the knockout mouse for Canavan's disease: implications for patients with Canavan's disease.
95 : Mental retardation and hypotonia seen in the knock out mouse for Canavan disease is not due to succinate semialdehyde dehydrogenase deficiency.
96 : Aspartoacylase gene knockout in the mouse: impact on reproduction.
97 : Canavan disease: studies on the knockout mouse.
98 : Accumulation of N-acetyl-L-aspartate in the brain of the tremor rat, a mutant exhibiting absence-like seizure and spongiform degeneration in the central nervous system.
99 : Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease.
100 : Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease.
101 : A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice.
102 : Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice.
103 : Mouse neural progenitor cells differentiate into oligodendrocytes in the brain of a knockout mouse model of Canavan disease.
104 : Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan disease.
105 : Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model.
106 : The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats.
107 : Lithium citrate reduces excessive intra-cerebral N-acetyl aspartate in Canavan disease.