ASPA DEFICIENCY
SPONGY DEGENERATION OF CENTRAL NERVOUS SYSTEM
ASP DEFICIENCY
CANAVAN-VAN BOGAERT-BERTRAND DISEASE
aspartoacylase deficiency
aminoacylase 2 deficiency
acy2 deficiency
Spongy degeneration of the brain
Kaul et al. (1993) stated that they had diagnosed 145 patients with Canavan disease at their center alone, suggesting that the disorder is more prevalent than previously thought. They noted that prenatal diagnosis by enzymatic activity is difficult ... Kaul et al. (1993) stated that they had diagnosed 145 patients with Canavan disease at their center alone, suggesting that the disorder is more prevalent than previously thought. They noted that prenatal diagnosis by enzymatic activity is difficult because of the low or undetectable aspartoacylase activity in direct or cultured normal chorionic villi and in normal cultured amniocytes.
The salient clinical features of Canavan disease are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average. The ... The salient clinical features of Canavan disease are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average. The neurologic findings are due to demyelination and leukodystrophy. Neuropathologic changes include spongy degeneration and astrocytic swelling with normal neurons (Matalon et al., 1988 and Matalon et al., 1989). Morphologic abnormality of the mitochondria of astrocytes was emphasized by Adornato et al. (1972). In 3 patients from 2 families of Ashkenazi descent with the diagnosis of cerebral spongy degeneration, or Canavan disease, Matalon et al. (1988) found increased amounts of N-acetylaspartic acid (NAA) in the urine and plasma. Aspartoacylase was assayed in cultured skin fibroblasts from 1 patient of each family, and a profound deficiency of the enzyme was found. Although the function of N-acetylaspartic acid was not understood, it was known to occur in high concentration in human brain. In an addendum, Matalon et al. (1988) reported finding aspartoacylase deficiency in a case of Canavan disease in a third family from Australia. Matalon et al. (1989) reported studies of 21 patients with Canavan disease. The diagnosis of spongy degeneration was confirmed by brain biopsy in 14. All patients had excessive urinary NAA excretion almost 200 times the amounts found in normal age-matched individuals or obligate carriers. One sample of cerebrospinal fluid from a patient with Canavan disease contained 232 micromoles/liter of NAA, whereas in a control sample NAA was undetectable. Deficiency of aspartoacylase was found in all 21 patients. The levels of aspartoacylase in obligate carriers were less than 50% of control values. Matalon et al. (1989) also showed that NAA was not elevated in the urine in other forms of leukodystrophy such as Alexander disease (203450), in which megalencephaly similar to that in patients with Canavan disease occurs, metachromatic leukodystrophy (250100), Krabbe disease (245200), and adrenoleukodystrophy (300100). Matalon et al. (1989) indicated that congenital, infantile, and late-onset forms of Canavan disease had been reported. Pathologic studies show spongy degeneration of the brain white matter, which is a nonspecific morphologic change and occurs in a number of situations. For example, spongy degeneration rather closely resembling that of Canavan disease was observed in a case of homocystinuria (236200) (Chou and Waisman, 1965). Feigelman et al. (1991) described prolonged survival in a 33-year-old Ashkenazi Jewish woman with Canavan disease. At the age of 2 years, mental retardation and extrapyramidal cerebral palsy had been diagnosed. At age 5 years, she was blind, but both pupils reacted to light, and she showed decerebrate posturing elicited by acute extension of the neck. Hyperreflexia with an extensor plantar response was observed. Generalized seizures first occurred at age 8 years. By age 20, she showed bilateral optic atrophy. By the time of report at age 33.5 years, she had deteriorated to a 'persistent vegetative state.' A younger sister was also mentally retarded with delayed development and died following aspiration at the age of 9 years. In 2 sibs with Canavan disease from a consanguineous marriage, Ishiyama et al. (2003) examined the temporal bone and found bilateral absence of the organ of Corti as well as absence of supporting cells and hair cells. There was mild secondary atrophy of the spiral ganglia neurons, but the auditory nerves and vestibular end organs and nerves were normal. The authors suggested a role for ASPA in the neurodevelopment of the organ of Corti.
Janson et al. (2006) reported 2 sisters with a mild form of Canavan disease confirmed by the finding of compound heterozygous mutations in the ASPA gene (A305E, 608034.0003; and R71H, 608034.0012). They presented at ages 50 and 19 ... Janson et al. (2006) reported 2 sisters with a mild form of Canavan disease confirmed by the finding of compound heterozygous mutations in the ASPA gene (A305E, 608034.0003; and R71H, 608034.0012). They presented at ages 50 and 19 months, respectively, with developmental delay, but without macrocephaly, hypotonia, spasticity, or seizures. The older child had mild cognitive and social impairment, whereas the infant showed age-appropriate language and behavior. In vitro studies showed severely deficient ASPA enzyme activity, but cerebral NAA levels in both patients were significantly less than expected for classic Canavan disease. Janson et al. (2006) noted that other patients had been reported with a milder, protracted course of Canavan disease (Toft et al., 1993; Zafeiriou et al., 1999), which did not seem to correlate with enzyme activity. Velinov et al. (2008) reported a 28-month-old girl with a mild form of Canavan disease associated with homozygosity for the R71H mutation. The parents were not related and originated from Ecuador. The child showed mild motor and speech delay at age 9 months and developed symmetric hyperintensities in the basal ganglia at age 18 months. She walked at age 19 months and spoke about 20 words at 25 months. She did not have macrocephaly or seizures. NAA levels were about 15 times greater than normal, but lower than observed in classic cases of Canavan disease. Velinov et al. (2008) concluded that the R71H mutation is associated with a milder form of the disorder.
In affected members of 3 pedigrees with Canavan disease, Kaul et al. (1993) identified a point mutation in the ASPA gene (E285A; 608034.0001). The same mutation was found in 85% of 34 Canavan alleles tested from Ashkenazi Jewish ... In affected members of 3 pedigrees with Canavan disease, Kaul et al. (1993) identified a point mutation in the ASPA gene (E285A; 608034.0001). The same mutation was found in 85% of 34 Canavan alleles tested from Ashkenazi Jewish patients. In 64 probands with Canavan disease, Kaul et al. (1994) identified several mutations in the ASPA gene (see, e.g., A305E, 608034.0003 and Y231X, 608034.0005). In 19 non-Jewish patients with Canavan disease, Shaag et al. (1995) identified 9 different mutations: 4 point mutations, 4 deletion mutations, and 1 exon skip. One mutation (A305E) accounted for 39.5% of the mutated alleles and was pan-European (i.e., identified in patients of Greek, Polish, Danish, French, Spanish, Italian, and British origin) and probably the most ancient mutation. As summarized by Sistermans et al. (2000), 2 mutations account for about 98% of the alleles of Ashkenazi Jewish patients, in which population the disease is highly prevalent: E285A and Y231X. In non-Jewish patients of European origin, the A305E mutation accounts for 50% of alleles. Zeng et al. (2002) studied the ASPA gene in 22 unrelated non-Jewish patients with Canavan disease and identified 24 different mutations, of which 14 were novel. The E24G gene mutation (608034.0010) resulted in substitution of an invariable amino acid (glu) in the first esterase catalytic domain consensus sequence. Patients with the novel D249V mutation (608034.0011) manifested clinically at birth and died early.
In the U.S., Canavan disease has been observed in infants of Jewish extraction whose ancestors lived in Vilna (Banker et al., 1964).
Matalon (1990) stated that of the more than 70 patients he has studied biochemically, ... In the U.S., Canavan disease has been observed in infants of Jewish extraction whose ancestors lived in Vilna (Banker et al., 1964). Matalon (1990) stated that of the more than 70 patients he has studied biochemically, only about 5 are non-Jewish. The Jewish cases could be traced to a particular area of Eastern Europe. He had information on about 35 cases that had been identified in Saudi Arabia. In an Iranian family with first-cousin parents, Mahloudji et al. (1970) described 4 affected sibs out of 9. Ozand et al. (1990) found deficient aspartoacylase activity in the fibroblasts cultured from 12 patients with Canavan disease in Saudi Arabia, where the disorder is apparently unusually frequent. Feigenbaum et al. (2004) screened 1,423 Ashkenazi Jews in Toronto for the 3 most common mutations causing Canavan disease in that population (E285A, Y231X, and A305E) and found 25 carriers, yielding a carrier rate of 1:57. The authors noted that in all E285A carriers the 854C mutation was in disequilibrium with a T polymorphism at the site of the 693C-A mutation (Y231X), indicating a founder chromosome for the 854A-C mutation in the Ashkenazi Jewish population.
The triad of hypotonia, macrocephaly, and head lag in an infant after age three to five months raises suspicion of neonatal/infantile (severe) Canavan disease. Neuroimaging studies reveal leukodystrophy. ...
DiagnosisClinical DiagnosisThe triad of hypotonia, macrocephaly, and head lag in an infant after age three to five months raises suspicion of neonatal/infantile (severe) Canavan disease. Neuroimaging studies reveal leukodystrophy. In individuals with mild/juvenile Canavan disease, neuroimaging may not be helpful.TestingN-Acetylaspartic acid (NAA)Urine. The concentration of NAA in the urine can be measured using gas chromatography-mass spectrometry (GC-MS) [Michals & Matalon 2011]. Control values in one series (n=48) were 23.5±16.1 µmol/mmol creatinine.In neonatal/infantile (severe) Canavan disease the mean concentration of NAA (n=117) was 1440.5±873.3 µmol/mmol creatinine. In mild/juvenile Canavan disease, mild elevation of NAA may be found, (n=2) 106 µmol/mmol creatinine. Note: Although NAA concentration is also elevated in the blood and CSF of children with neonatal/infantile (severe) Canavan disease, the number of affected individuals evaluated to date is small [Michals & Matalon 2011]. Amniotic fluid. The concentration of NAA can be measured in the amniotic fluid by stable-isotope dilution and GC-MS or by liquid chromatography tandem mass spectrometry [Bennett et al 1993, Al Dirbashi et al 2009]. NAA concentration in amniotic fluid was 0.30-2.55 µmol/L in controls and 8.68 µmol/L in an affected pregnancy [Bennett et al 1993].Aspartoacylase enzyme activitySkin fibroblasts. Although aspartoacylase enzyme activity can be assayed in cultured skin fibroblasts, it may not be reliable because the activity varies with culture conditions. Individuals with severe Canavan disease often have unmeasurable enzyme activity. Carriers of alleles associated with severe Canavan disease have about one-half normal enzyme activity [Matalon et al 1993]. White blood cells and thrombocytes. Aspartoacylase enzyme activity is not detectable in white blood cells or platelets.Amniocytes/CVS. Aspartoacylase enzyme activity is extremely low in normal amniocytes and chorionic villus sampling (CVS). Enzyme activity cannot be relied upon for prenatal testing [Bennett et al 1993]. Molecular Genetic TestingGene. ASPA is the only gene in which mutations are known to cause with Canavan disease.Clinical testingTargeted mutation analysisTwo mutations, p.Glu285Ala and p.Tyr231X, account for 98% of disease-causing alleles in the Ashkenazi Jewish population and 3% of alleles in non-Ashkenazi Jewish populations [Michals & Matalon 2011].One mutation, p.Ala305Glu, accounts for 30%-60% of disease-causing alleles in non- Ashkenazi Jewish populations and approximately 1% of alleles in the Ashkenazi Jewish populations [Kaul et al 1994b, Elpeleg & Shaag 1999]. Sequence analysis of the ASPA coding region is possible for individuals in whom mutations were not identified by targeted mutation analysis. Note: (1) The c.433-2A>G splice site mutation found in a single Ashkenazi Jewish family should not be considered a typical Ashkenazi Jewish mutation. (2) More than 50 other mutations have been reported in non- Ashkenazi Jewish populations [Kaul et al 1994b, Elpeleg & Shaag 1999, Olsen et al 2002, Zeng et al 2002, Michals & Matalon 2011].Deletion/duplication analysis. Deletions and duplications are not detectable by sequence analysis; other methods need to be used. Deleted segments of various sizes of cDNA have been reported [Zeng et al 2006, Kaya et al 2008]. The authors encountered two individuals with complete deletion of ASPA and two with partial deletions [Matalon, unpublished data]. Table 1. Summary of Molecular Genetic Testing Used in Canavan DiseaseView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAshkenazi JewishNon-Ashkenazi JewishASPATargeted mutation analysisPanel 2p.Glu285Ala, p.Tyr231X98%3%Clinical p.Ala305Glu1%30%-60%Sequence analysisSequence variants 3NA87%Deletion / duplication analysis 4Large genomic deletions/duplications comprising one or more exonsNAUnknown (<10%)NA = not applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. All laboratories use at least a two-allele panel for the Ashkenazi Jewish mutations; many laboratories use a three-allele panel, and a few use a four-allele panel.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband with:Neonatal/infantile (severe) Canavan diseaseWhite matter disease on neuroimaging suggests neonatal/infantile (severe) Canavan disease.Diagnosis relies on measurement of the concentration of N-acetylaspartic acid (NAA) in the urine using gas chromatography-mass spectrometry (GC-MS). Note: (1) Although NAA concentration is also elevated in the blood and cerebrospinal fluid (CSF) of children with neonatal/infantile (severe) Canavan disease, elevated urine concentration of NAA is sufficient for diagnosis of affected individuals [Michals & Matalon 2011]. (2) Aspartoacylase enzyme activity may not be reliable in the diagnosis of Canavan disease because enzyme activity fluctuates with culture conditions; therefore, measurement of the urinary concentration of NAA is the preferred diagnostic method [Matalon et al 1993].Molecular genetic testing can be used for confirmation of the diagnosis. In individuals of Ashkenazi Jewish ancestry: 1. Perform targeted mutation analysis for the two or three common ASPA mutations (p.Glu285Ala, p.Tyr231X, and p.Ala305Glu). 2. If neither or only one mutation in ASPA is identified, perform sequence analysis. 3. If neither or only one mutation in ASPA is identified on sequence analysis, consider deletion/duplication analysis. In individuals of non-Ashkenazi Jewish ancestry: 1. Perform targeted mutation analysis for the p.Ala305Glu mutation. 2. If neither or only one mutation in ASPA is identified, perform sequence analysis. 3. If neither or only one mutation in ASPA is identified on sequence analysis, consider deletion/duplication analysis.Mild/juvenile Canavan diseaseNeuroimaging usually does not indicate leukodystrophy. Concentration of NAA in the urine is slightly elevated. Diagnosis must be confirmed by ASPA molecular genetic testing in the order described above. Carrier testing Testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Population screening for Ashkenazi Jewish individuals of reproductive age is recommended [ACOG Committee on Genetics 2009] and typically includes evaluation for the two mutations common in the Ashkenazi Jewish population. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Note: When the family-specific mutations are not known, prenatal diagnosis of Canavan disease can be accomplished by measuring the concentration of NAA in amniotic fluid.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in ASPA.
Most individuals with Canavan disease have the neonatal/infantile form. Although these infants appear normal early in life, by age three to five months macrocephaly, lack of head control, and developmental delays become apparent. Developmental delay becomes more obvious with increasing age. Children with neonatal/infantile (severe) Canavan disease are especially delayed in their motor skills and are not able to sit, stand, walk, or talk. They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position. They are sometimes irritable. As they get older, hypotonia gives way to spasticity. ...
Natural HistoryNeonatal/Infantile (Severe) Canavan DiseaseMost individuals with Canavan disease have the neonatal/infantile form. Although these infants appear normal early in life, by age three to five months macrocephaly, lack of head control, and developmental delays become apparent. Developmental delay becomes more obvious with increasing age. Children with neonatal/infantile (severe) Canavan disease are especially delayed in their motor skills and are not able to sit, stand, walk, or talk. They learn to interact socially, laugh and smile, reach for objects, and raise their heads in the prone position. They are sometimes irritable. As they get older, hypotonia gives way to spasticity. Optic atrophy is present in many children with neonatal/infantile (severe) Canavan disease. However, they are still able to visually track objects. Hearing is usually not impaired. As they get older, children with neonatal/infantile (severe) Canavan disease may experience sleep disturbance, seizures, and feeding difficulties. They may require assisted feeding through a nasogastric tube or by a permanent gastrostomy. The life expectancy is variable; some children die in the first few years of life, while others survive into their teens or beyond, depending on the clinical course of their disease as well as on the medical and nursing care provided.Mild/Juvenile Canavan DiseaseChildren with mild/juvenile Canavan disease may have normal or mildly delayed speech or motor development early in life. If they have a diagnostic work-up for these delays, slightly elevated urinary NAA may be identified and indicate the diagnosis. Generally, these children attend regular school and may benefit from speech therapy or tutoring as needed. Neuroimaging Neonatal/infantile (severe) Canavan disease. CT or MRI performed in infancy may be interpreted as normal [Matalon & Michals-Matalon 2000]. Diffuse, symmetric white matter changes are observed in the subcortical areas and in the cerebral cortex; involvement of the cerebellum and brain stem is less marked [Matalon et al 1995]. Ultrasonography shows white matter echogenicity that differs from that of normal brain [Breitbach-Faller et al 2003].Mild/juvenile Canavan disease. Brain MRI does not show general white matter disease. Brain MRI on many children with Canavan disease demonstrates increased signal intensities in the basal ganglia [Surendran et al 2003, Yalcinkaya et al 2005, Michals & Matalon 2011]. Similar changes are observed on MRI of the brain of individuals with mitochondrial diseases [Surendran et al 2003, Tacke et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011]. NeuropathologyIn neonatal / infantile Canavan disease subcortical spongy degeneration is observed. Electron microscopy (EM) reveals swollen astrocytes and distorted mitochondria.
Strong genotype-phenotype correlations in Canavan disease have emerged since the measurement of N-acetylaspartic acid (NAA) in the urine and molecular genetic testing of ASPA have become routine....
Genotype-Phenotype CorrelationsStrong genotype-phenotype correlations in Canavan disease have emerged since the measurement of N-acetylaspartic acid (NAA) in the urine and molecular genetic testing of ASPA have become routine.Neonatal/Infantile (Severe) Canavan Disease Individuals homozygous for the p.Tyr231X mutation (who have no enzyme activity) cannot be clinically distinguished from individuals homozygous for the p.Glu285Ala mutation (who have some residual enzyme activity).The clinical phenotype in individuals homozygous for the p.Ala305Glu mutation, most commonly observed in non-Jews (who have no residual enzyme activity), is similar to that observed in individuals homozygous for one of the two mutations commonly found in the Ashkenazi Jewish population [Matalon & Michals-Matalon 1998]. The clinical phenotype in individuals homozygous or compound heterozygous for a large (i.e., multiexonic or whole-gene) deletion is severe.Deletion of both ASPA alleles causes a severe phenotype [Matalon unpublished data]. An individual homozygous for a 92-kb deletion had a severe phenotype [Zeng et al 2006]. Three individuals who were compound heterozygotes for a large deletion (a whole-gene 92-kb deletion, a multiexonic 56-kb deletion, and a multiexonic 12.3-kb deletion respectively) and a point mutation had severe phenotypes [Zeng et al 2006]. Mild/Juvenile Canavan DiseaseMild/juvenile Canavan disease is associated with at least one “mild” mutation (p.Tyr288Cys, p.Arg71His, or p.Pro257Arg) with residual ASPA enzyme activity. Individuals are usually heterozygous with one mild mutation and one severe mutation [Surendran et al 2003, Yalcinkaya et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].“Mild” mutations are now more readily recognized by their manifestations of slight increase of NAA in the urine, atypical MRI findings, and associated minor learning difficulties [Surendran et al 2003, Tacke et al 2005, Kurczynski & Victorio 2011, Michals & Matalon 2011].
Other neurodegenerative disorders of infancy that are associated with a normal or large head size include Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaricacidemia type 1 (see Organic Acidemias Overview). Laboratory testing or molecular genetic testing can be used to distinguish neonatal/infantile (severe) Canavan disease from these disorders....
Differential DiagnosisOther neurodegenerative disorders of infancy that are associated with a normal or large head size include Alexander disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaricacidemia type 1 (see Organic Acidemias Overview). Laboratory testing or molecular genetic testing can be used to distinguish neonatal/infantile (severe) Canavan disease from these disorders.Spongy degeneration of the brain can be found in viral infections, in mitochondrial disorders, particularly Leigh syndrome (see also Mitochondrial Disorders Overview), and in metabolic disorders such as glycine encephalopathy (nonketotic hyperglycinemia).Mild/juvenile Canavan disease may be misdiagnosed as a mitochondrial disorder (see Mitochondrial Disorders Overview).Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with neonatal/infantile (severe) Canavan disease, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with neonatal/infantile (severe) Canavan disease, the following evaluations are recommended:Brain MRI Developmental assessmentNutritional assessmentTreatment of ManifestationsNeonatal/infantile Canavan diseaseTreatment is supportive and directed to providing adequate nutrition and hydration, managing infectious diseases, and protecting the airway.Children benefit from physical therapy to minimize contractures and to maximize abilities and seating posture, from other therapies to enhance communication skills (especially in those with a more gradual clinical course), and from early intervention and special education programs.Seizures may be treated with antiepileptic drugs (AEDs).A feeding gastrostomy may be required to maintain adequate intake and hydration in the presence of swallowing difficulties.Diamox® seems to reduce intracranial pressure.Botox® injections may be used to relieve spasticity. Mild/juvenile Canavan disease. These individuals may require speech therapy or tutoring but require no special medical care.Prevention of Secondary ComplicationsNeonatal/infantile Canavan diseaseContractures and decubiti need to be prevented by exercise and position changes. Feeding difficulties and seizures increase the risk of aspiration, which can be reduced with use of a G-tube for feeding.SurveillanceNeonatal/infantile Canavan disease. Follow up at six-month intervals to evaluate developmental status and evidence of any new problems is suggested. Mild/juvenile Canavan disease. Annual routine follow up is indicated.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationHumans Gene transfer to the brains of two children with Canavan disease using a nonviral vector was well tolerated [Leone et al 2000, Janson et al 2002]. Some biochemical, radiologic, and clinical changes may have occurred; however, the children continued to follow the course of those with untreated Canavan disease. In ten children with Canavan disease, multisite injection with AAV2 as the vector for ASPA was well tolerated [McPhee et al 2006]. Three developed AAV2 neutralizing antibodies. No children improved. Lithium citrate may reduce N-acetylaspartic acid (NAA) concentration in the brain. Six persons with Canavan disease given lithium citrate for 60 days were reported to have reduced NAA in the basal ganglia and mild improvement in frontal white matter [Assadi et al 2010]. The clinical significance of use of lithium citrate is not known. The enzyme defect in Canavan disease leads to decreased levels of acetate in the brain. In a clinical trial with glycerol triacetate in two persons with Canavan disease the compound was well tolerated; however, there was no clinical improvement [Madhavarao et al 2009]. It is speculated that higher doses of glycerol triacetate may be needed. Animal models A knock-out mouse has been created, with a phenotype similar to that of human Canavan disease [Matalon et al 2000]. This model is being used to investigate pathophysiology [Surendran et al 2004] gene therapy and other modes of treatment [Matalon et al 2003]. Gene therapy with AAV2 was given to knock-out Canavan disease mice: localized improvement did not spread to the entire brain [Matalon et al 2003].Stem cell therapy in knock-out Canavan disease mice was done in collaboration with Genzyme Corporation: The stem cells produced some oligodendrocytes but not enough to make myelin [Surendran et al 2004].Enzyme replacement therapy using native ASPA and pegylated ASPA (i.e., ASPA in which covalent attachment of polyethylene glycol polymer chains masks the enzyme from the host allowing for longer circulation and less renal clearance) were injected into the peritoneum of Canavan disease mice. Preliminary results show that the enzyme passed the blood brain barrier and there was a decrease of NAA in the brain. These experiments were short term; longitudinal studies are being planned [Zano et al 2011].A mouse that seems to have a Canavan disease phenotype was produced by using the mutagen ethylenenitrosourea (ENU) to change the residue Gln193 to a termination codon in exon 4 (577C>T) [Traka et al 2008]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Canavan Disease: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDASPA17p13.2AspartoacylaseASPA @ LOVDASPAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Canavan Disease (View All in OMIM) View in own window 271900CANAVAN DISEASE 608034ASPARTOACYLASE; ASPANormal allelic variants. The gene comprises 29 kb with six exons and five introns. The exons vary in size from 94 bp (exon 3) to 514 bp (exon 6).Pathologic allelic variants. See Table 2. The major disease-causing allelic variants are p.Glu285Ala, p.Tyr231X, and p.Ala305Glu. (For more information, see Table A.)Table 2. Selected ASPA Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences c.433-2A>G--NM_000049.2 NP_000040.1c.693C>Ap.Tyr231Xc.854A>Cp.Glu285Alac.863A>Gp.Tyr288Cysc.914C>Ap.Ala305GluSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Normal gene product. Aspartoacylase is a protein of 313 amino acids, suggesting a molecular weight of 36 kd [Kaul et al 1993]. The 93% homology of the amino acid and nucleotide sequence of human and bovine aspartoacylase suggest a high degree of conservation of this enzyme in mammals [Kaul et al 1994a]. The protein is observed in most tissues.Recent studies have shown that ASPA is a dimer with zinc at the catalytic site analogous to other carboxypeptidases. Mutations caused conformational changes that affect the activity of the enzyme [Bitto et al 2007]. Abnormal gene product. Aspartoacylase is responsible for hydrolyzing N-acetylaspartic acid (NAA) into aspartic acid and acetate. The abnormal alleles include null mutations, which make no aspartoacylase, and missense mutations, which make less active forms of aspartoacylase. Although aspartoacylase is expressed widely throughout the body, its absence in the CNS leads to the specific build-up of NAA in the brain that causes demyelinization and other signs of the disease.