# 271900

CANAVAN DISEASE


Alternative titles; symbols

CANAVAN-VAN BOGAERT-BERTRAND DISEASE
SPONGY DEGENERATION OF CENTRAL NERVOUS SYSTEM
ASPARTOACYLASE DEFICIENCY
ASPA DEFICIENCY
ASP DEFICIENCY
AMINOACYLASE 2 DEFICIENCY
ACY2 DEFICIENCY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17p13.2 Canavan disease 271900 AR 3 ASPA 608034
Clinical Synopsis
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Head
- Increased head circumference
- Delayed closure of anterior fontanel
Ears
- Deafness
Eyes
- Optic atrophy
- Nystagmus
- Blindness
NEUROLOGIC
Central Nervous System
- Initial hypotonia, followed by spasticity
- Generalized seizures
- Opisthotonus
- Loss of very early milestones
- Decerebrate or decorticate posturing late
- Demyelination with white matter disease in internal capsule, external capsule, genu of corpus callosum, subcortical white matter, and posterior fossa
- Brain atrophy
LABORATORY ABNORMALITIES
- Spongy degeneration of brain on histology
- Increased N-acetyl-L-aspartic acid (NAA) in urine, CSF, and blood
- Reduced aspartoacylase activity in cultured skin fibroblasts
MISCELLANEOUS
- Normal first month
- Onset of symptoms at 2-4 months
- Prevalent in Ashkenazi Jews
- Death within first decade
MOLECULAR BASIS
- Caused by mutation in the aspartoacylase gene (ASPA, 608034.0001)

TEXT

A number sign (#) is used with this entry because Canavan disease is caused by homozygous or compound heterozygous mutation in the gene encoding aspartoacylase (ASPA; 608034) on chromosome 17p13.


Clinical Features

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.


Diagnosis

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.


Molecular Genetics

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.


Genotype/Phenotype Correlations

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.


Population Genetics

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.


History

Hagenfeldt et al. (1987) and Kvittingen et al. (1986) reported cases of N-acetylaspartic aciduria in patients with leukodystrophy and progressive cerebral atrophy, respectively. In the case of Kvittingen et al. (1986), aspartoacylase activity was normal, whereas in the case of Hagenfeldt et al. (1987), aspartoacylase activity was deficient. However, neither of these reports linked the findings to Canavan disease. Divry et al. (1988) reported a brother and sister with N-acetylaspartic aciduria and a neurologic syndrome associated with macrocephaly and leukodystrophy. Enzyme data were not available.


REFERENCES

  1. Adornato, B. T., O'Brien, J. S., Lampert, P. W., Roe, T. F., Neustein, H. B. Cerebral spongy degeneration of infancy: a biochemical and ultrastructural study of affected twins. Neurology 22: 202-210, 1972. [PubMed: 4333033, related citations] [Full Text]

  2. Aduchi, M., Aronson, S. M. Studies on spongy degeneration of the central nervous system (van Bogaert-Bertrand type). In: Aronson, S. M.; Volk, B. W.: Inborn Disorders of Sphingolipid Metabolism. Oxford: Pergamon Press (pub.) 1967. Pp. 129-147.

  3. Banker, B. Q., Robertson, J. T., Victor, M. Spongy degeneration of the central nervous system in infancy. Neurology 14: 981-1001, 1964. [PubMed: 14239091, related citations] [Full Text]

  4. Banker, B. Q., Victor, M. Spongy degeneration of infancy. In: Goodman, R. E.; Motulsky, A. G.: Genetic Diseases Among Ashkenazi Jews. New York: Raven Press (pub.) 1979. Pp. 201-216.

  5. Chou, S. M., Waisman, H. A. Spongy degeneration of the central nervous system: case of homocystinuria. Arch. Path. 79: 357-363, 1965. [PubMed: 14254905, related citations]

  6. Divry, P., Vianey-Liaud, C., Gay, C., Macabeo, V., Rapin, F., Echenne, B. N-acetylaspartic aciduria: report of three new cases in children with a neurological syndrome associating macrocephaly and leucodystrophy. J. Inherit. Metab. Dis. 11: 307-308, 1988. [PubMed: 3148075, related citations] [Full Text]

  7. Feigelman, T., Shih, V. E., Buyse, M. L. Prolonged survival in Canavan disease. Dysmorph. Clin. Genet. 5: 107-110, 1991.

  8. Feigenbaum, A., Moore, R., Clarke, J., Hewson, S., Chitayat, D., Ray, P. N., Stockley, T. L. Canavan disease: carrier-frequency determination in the Ashkenazi Jewish population and development of a novel molecular diagnostic assay. Am. J. Med. Genet. 124A: 142-147, 2004. [PubMed: 14699612, related citations] [Full Text]

  9. Hagenfeldt, L., Bollgren, I., Venizelos, N. N-acetylaspartic aciduria due to aspartoacylase deficiency--a new etiology of childhood leukodystrophy. J. Inherit. Metab. Dis. 10: 135-141, 1987. [PubMed: 3116332, related citations] [Full Text]

  10. Hogan, G. R., Richardson, E. P., Jr. Spongy degeneration of the nervous system (Canavan's disease): report of a case in an Irish-American family. Pediatrics 35: 284-294, 1965. [PubMed: 14261965, related citations]

  11. Ishiyama, G., Lopez, I., Baloh, R. W., Ishiyama, A. Canavan's leukodystrophy is associated with defects in cochlear neurodevelopment and deafness. Neurology 60: 1702-1704, 2003. [PubMed: 12771274, related citations] [Full Text]

  12. Janson, C. G., Kolodny, E. H., Zeng, B.-J., Raghavan, S., Pastores, G., Torres, P., Assadi, M., McPhee, S., Goldfarb, O., Saslow, B., Freese, A., Wang, D. J., Bilaniuk, L., Shera, D., Leone, P. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Ann. Neurol. 59: 428-431, 2006. [PubMed: 16437572, related citations] [Full Text]

  13. Kaul, R., Gao, G. P., Aloya, M., Balamurugan, K., Petrosky, A., Michals, K., Matalon, R. Canavan disease: mutations among Jewish and non-Jewish patients. Am. J. Hum. Genet. 55: 34-41, 1994. [PubMed: 8023850, related citations]

  14. Kaul, R., Gao, G. P., Balamurugan, K., Matalon, R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nature Genet. 5: 118-123, 1993. [PubMed: 8252036, related citations] [Full Text]

  15. Kvittingen, E. A., Guldal, G., Borsting, S., Skalpe, I. O., Stokke, O., Jellum, E. N-acetylaspartic aciduria in a child with a progressive cerebral atrophy. Clin. Chim. Acta 158: 217-227, 1986. [PubMed: 3769199, related citations] [Full Text]

  16. Mahloudji, M., Daneshbod, K., Karjoo, M. Familial spongy degeneration of the brain. Arch. Neurol. 22: 294-298, 1970. [PubMed: 5417637, related citations] [Full Text]

  17. Matalon, R., Kaul, R., Casanova, J., Michals, K., Johnson, A., Rapin, I., Gashkoff, P., Deanching, M. Aspartoacylase deficiency: the enzyme defect in Canavan disease. J. Inherit. Metab. Dis. 12 (suppl. 2): 329-331, 1989. [PubMed: 2512436, related citations] [Full Text]

  18. Matalon, R., Michals, K., Sebesta, D., Deanching, M., Gashkoff, P., Casanova, J. Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. Am. J. Med. Genet. 29: 463-471, 1988. [PubMed: 3354621, related citations] [Full Text]

  19. Matalon, R. Personal Communication. Miami, Fla. 11/3/1990.

  20. Morcaldi, L., Salvati, G., Giordano, G. G., Guazzi, G. C. Congenital van Bogaert-Bertrand disease in a non-Jewish family. Acta Genet. Med. Gemellol. 18: 142-157, 1969. [PubMed: 5369099, related citations] [Full Text]

  21. Ozand, P. T., Gascon, G. G., Dhalla, M. Aspartoacylase deficiency and Canavan disease in Saudi Arabia. Am. J. Med. Genet. 35: 266-268, 1990. [PubMed: 2309767, related citations] [Full Text]

  22. Schmidt, H., Rott, H.-D., Neuhauser, G., Neumann, W. Spongiose Hirndystrophie im fruhen Kindesalter (Typ Canavan-van Bogaert-Bertrand): Erkrankung von 3 Geschwistern einer nichtjudischen Familie aus Oberfranken. Klin. Padiatr. 190: 580-585, 1978. [PubMed: 568685, related citations]

  23. Shaag, A., Anikster, Y., Christensen, E., Glustein, J. Z., Fois, A., Michelakakis, H., Nigro, F., Pronicka, E., Ribes, A., Zabot, M. T., Elpeleg, O. N. The molecular basis of Canavan (aspartoacylase deficiency) disease in European non-Jewish patients. Am. J. Hum. Genet. 57: 572-580, 1995. [PubMed: 7668285, related citations]

  24. Sistermans, E. A., de Coo, R. F. M., van Beerendonk, H. M., Poll-The, B. T., Kleijer, W. J., van Oost, B. A. Mutation detection in the aspartoacylase gene in 17 patients with Canavan disease: four new mutations in the non-Jewish population. Europ. J. Hum. Genet. 8: 557-560, 2000. [PubMed: 10909858, related citations] [Full Text]

  25. Toft, P. B., Geiss-Holtorff, R., Rolland, M. O., Pryds, O., Muller-Forell, W., Christensen, E., Lehnert, W., Lou, H. C., Ott, D., Hennig, J., Henriksen, O. Magnetic resonance imaging in juvenile Canavan disease. Europ. J. Pediat. 152: 750-753, 1993. [PubMed: 8223809, related citations] [Full Text]

  26. Ungar, M., Goodman, R. M. Spongy degeneration of the brain in Israel: a retrospective study. Clin. Genet. 23: 23-29, 1983. [PubMed: 6831759, related citations] [Full Text]

  27. van Bogaert, L. Familial spongy degeneration of the brain. (Complementary study of the family R). Acta Psychiat. Neurol. Scand. 39: 107-113, 1963.

  28. Velinov, M., Zellers, N., Styles, J., Wisniewski, K. Homozygosity for mutation G212A of the gene for aspartoacylase is associated with atypical form of Canavan's disease. (Letter) Clin. Genet. 73: 288-289, 2008. [PubMed: 18070137, related citations] [Full Text]

  29. Zafeiriou, D. I., Kleijer, W. J., Maroupoulos, G., Anastasiou, A. L., Augoustidou-Savvopoulou, P., Papadopoulou, F., Kontopoulos, E. E., Fagan, E., Payne, S. Protracted course of N-acetylaspartic aciduria in two non-Jewish siblings: identical clinical and magnetic resonance imaging findings. Brain Dev. 21: 205-208, 1999. [PubMed: 10372908, related citations]

  30. Zeng, B. J., Wang, Z. H., Ribeiro, L. A., Leone, P., De Gasperi, R., Kim, S. J., Raghavan, S., Ong, E., Pastores, G. M., Kolodny, E. H. Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. J. Inherit. Metab. Dis. 25: 557-570, 2002. [PubMed: 12638939, related citations] [Full Text]

  31. ZuRhein, G. M., Eichman, P. L., Puletti, F. Familial idiocy with spongy degeneration of the central nervous system of van Bogaert-Bertrand type. Neurology 10: 998-1006, 1960. [PubMed: 13788842, related citations] [Full Text]


Cassandra L. Kniffin - updated : 5/6/2008
Cassandra L. Kniffin - updated : 4/13/2006
Marla J. F. O'Neill - updated : 6/23/2004
Ada Hamosh - updated : 9/23/2003
Cassandra L. Kniffin - reorganized : 8/15/2003
Cassandra L. Kniffin - updated : 8/13/2003
Victor A. McKusick - updated : 3/15/2001
Victor A. McKusick - updated : 12/6/1999
Victor A. McKusick - updated : 3/17/1999
Victor A. McKusick - updated : 3/13/1998
Creation Date:
Victor A. McKusick : 6/4/1986
carol : 01/09/2018
carol : 01/08/2018
alopez : 10/25/2012
wwang : 5/13/2008
ckniffin : 5/6/2008
terry : 8/24/2006
wwang : 5/4/2006
wwang : 4/19/2006
wwang : 4/19/2006
wwang : 4/18/2006
ckniffin : 4/13/2006
carol : 6/30/2004
terry : 6/23/2004
alopez : 9/23/2003
carol : 8/15/2003
carol : 8/15/2003
ckniffin : 8/13/2003
mcapotos : 3/27/2001
mcapotos : 3/22/2001
terry : 3/15/2001
carol : 12/8/1999
carol : 12/8/1999
terry : 12/6/1999
carol : 3/30/1999
terry : 3/17/1999
dkim : 7/17/1998
alopez : 3/13/1998
terry : 3/10/1998
terry : 3/10/1998
mark : 9/10/1995
terry : 4/19/1995
carol : 9/1/1994
jason : 6/9/1994
mimadm : 3/12/1994
carol : 12/16/1993

# 271900

CANAVAN DISEASE


Alternative titles; symbols

CANAVAN-VAN BOGAERT-BERTRAND DISEASE
SPONGY DEGENERATION OF CENTRAL NERVOUS SYSTEM
ASPARTOACYLASE DEFICIENCY
ASPA DEFICIENCY
ASP DEFICIENCY
AMINOACYLASE 2 DEFICIENCY
ACY2 DEFICIENCY


SNOMEDCT: 80544005;   ICD10CM: E75.28;   ORPHA: 141, 314911, 314918;   DO: 3613;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17p13.2 Canavan disease 271900 Autosomal recessive 3 ASPA 608034

TEXT

A number sign (#) is used with this entry because Canavan disease is caused by homozygous or compound heterozygous mutation in the gene encoding aspartoacylase (ASPA; 608034) on chromosome 17p13.


Clinical Features

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.


Diagnosis

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.


Molecular Genetics

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.


Genotype/Phenotype Correlations

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.


Population Genetics

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.


History

Hagenfeldt et al. (1987) and Kvittingen et al. (1986) reported cases of N-acetylaspartic aciduria in patients with leukodystrophy and progressive cerebral atrophy, respectively. In the case of Kvittingen et al. (1986), aspartoacylase activity was normal, whereas in the case of Hagenfeldt et al. (1987), aspartoacylase activity was deficient. However, neither of these reports linked the findings to Canavan disease. Divry et al. (1988) reported a brother and sister with N-acetylaspartic aciduria and a neurologic syndrome associated with macrocephaly and leukodystrophy. Enzyme data were not available.


See Also:

Aduchi and Aronson (1967); Banker and Victor (1979); Hogan and Richardson (1965); Morcaldi et al. (1969); Schmidt et al. (1978); Ungar and Goodman (1983); van Bogaert (1963); ZuRhein et al. (1960)

REFERENCES

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Contributors:
Cassandra L. Kniffin - updated : 5/6/2008
Cassandra L. Kniffin - updated : 4/13/2006
Marla J. F. O'Neill - updated : 6/23/2004
Ada Hamosh - updated : 9/23/2003
Cassandra L. Kniffin - reorganized : 8/15/2003
Cassandra L. Kniffin - updated : 8/13/2003
Victor A. McKusick - updated : 3/15/2001
Victor A. McKusick - updated : 12/6/1999
Victor A. McKusick - updated : 3/17/1999
Victor A. McKusick - updated : 3/13/1998

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
carol : 01/09/2018
carol : 01/08/2018
alopez : 10/25/2012
wwang : 5/13/2008
ckniffin : 5/6/2008
terry : 8/24/2006
wwang : 5/4/2006
wwang : 4/19/2006
wwang : 4/19/2006
wwang : 4/18/2006
ckniffin : 4/13/2006
carol : 6/30/2004
terry : 6/23/2004
alopez : 9/23/2003
carol : 8/15/2003
carol : 8/15/2003
ckniffin : 8/13/2003
mcapotos : 3/27/2001
mcapotos : 3/22/2001
terry : 3/15/2001
carol : 12/8/1999
carol : 12/8/1999
terry : 12/6/1999
carol : 3/30/1999
terry : 3/17/1999
dkim : 7/17/1998
alopez : 3/13/1998
terry : 3/10/1998
terry : 3/10/1998
mark : 9/10/1995
terry : 4/19/1995
carol : 9/1/1994
jason : 6/9/1994
mimadm : 3/12/1994
carol : 12/16/1993