Leucodistrofie/CANAVAN'S DISEASE

a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)

iii) MORBO DI CANAVAN
(CANAVAN'S DISEASE)

DEFINITION:

A neurodegenerative disorder characterized by degeneration of CNS white matter and specific CNS pathological findings.

EPIDEMIOLOGY:

   incidence: rare 
   age of onset: 
      newborn to childhood (depends on the Form) 
   risk factors: 
      familial - autosomal recessive (Type I) 
         chrom.#: ? 
         gene: ? aspartoacylase 
      Ashkenazi Jews (Type I) 
      sporadic (Type II)

PATHOGENESIS:

PATHOLOGY:

TYPES:

CLINICAL FEATURES:

Type I - Neonatal Form
onset: at birth
death within the first few weeks of life
Type II - Infantile Form
onset: first few months of life
most common form
death by 3-4 years of age
Type III - Juvenile Form
onset: over 5 years of age
death in adolescence
1. Neurological Manifestations

INVESTIGATIONS:

1. Diagnosis

abnormal amounts of N-acetylaspartic acid in urine (300x normal), blood, and CSF (urine and serum for amino acids) deficiency of aspartoacylase (less than 40% of normal) in cultured skin fibroblasts

2. Imaging Studies

MANAGEMENT:

DESCRIPTION ANC CLINICAL HISTORY

Salient clinical features are onset in early infancy, atonia of neck muscles, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average.
Matalon et al. (1989) indicated that congenital, infantile, and late-onset forms of Canavan disease have been reported. Pathologic studies show spongy degeneration of the white matter.
Spongy degeneration is a nonspecific morphologic change, which occurs in a number of situations. Spongy degeneration rather closely resembling that of Canavan-Van Bogaert-Bertrand disease was observed in a case of homocystinuria (Chou and Waisman, 1965).
Feigelman et al. (1991) described Canavan disease in a 33-year-old woman of Ashkenazi Jewish ancestry.
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 the U.S., Canavan disease has been observed in infants of Jewish extraction whose ancestors lived in Vilna (Banker et al., 1964).
In an Iranian family with first-cousin parents, Mahloudji et al. (1970) described 4 affected sibs out of 9. 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. Morphologic abnormality of the mitochondria of astrocytes was emphasized by Adornato et al. (1972).
Hagenfeldt et al. (1967) and Kvittingen et al. (1986) probably reported cases of N-acetylaspartic aciduria, and Divry et al. (1988) reported affected brother and sister. In the case of Kvittingen et al. (1986), aspartoacylase was normal, while in the case of Hagenfeldt et al. (1967), aspartoacylase was deficient.
Enzyme data were not available in the case of Divry et al. (1988). In 3 patients from 2 families with the diagnosis of cerebral spongy degeneration, 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 is not understood, it is 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.
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.
(Aspartoacylase (EC 3.5.1.15 ) is also called aminoacylase-2. Aminoacylase-1 (EC 3.5.1.14 ) cleaves acylated L-amino acids, except L-aspartate, into L-amino acids and an acyl group; see ACY1, 104620.) 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, while 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, in which megalencephaly similar to that in patients with CD occurs, metachromatic leukodystrophy, Krabbe disease and adrenoleukodystrophy.

Kaul et al. (1993) cloned the human aspartoacylase cDNA (which they symbolized ASP) which spanned 1,435 basepairs. They showed that the isolated cDNA expresses aspartoacylase activity in bacteria.
In 85% of 34 Canavan alleles tested, they found an A-to-C transversion at nucleotide 854 resulting in a missense glu285-to-ala mutation predicted to be part of the catalytic domain of aspartoacylase.
Canavan disease is the only known genetic disorder caused by a defect in the metabolism of a small metabolite, N-acetyl-L-aspartic acid, synthesized exclusively in the brain in a cell-specific manner.
Aspartoacylase catalyzes hydrolysis of this molecule to aspartate and acetate.
Kaul et al. (1993) stated that they had diagnosed 145 patients with this disorder at their center alone, suggesting that the disorder is more prevalent than previously thought.
DNA methods for prenatal diagnosis are desirable because enzymatic diagnosis is rendered difficult by the low or undetectable aspartoacylase activity in direct or cultured, normal chorionic villi and in normal cultured amniocytes.

Kaul et al. (1994) cloned the human ASPA gene and found it to span 29 kb of the genome. Human aspartoacylase is coded by 6 exons intervened by 5 introns. The exons vary from 94 (exon 3) to 514 (exon 6) bases.
The exon/intron splice junction sites follow the gt/ag consensus sequence rule. By Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines, Kaul et al. (1994) localized the ASPA gene to human chromosome 17.
The localization was refined to 17pter-p13 by fluorescence in situ hybridization.

Kaul et al. (1994) reported mutation analysis of the ASPA gene in 64 probands with Canavan disease.
Of the 128 unrelated Canavan chromosomes analyzed, 88 were from probands of Ashkenazi Jewish descent. The glu285-to-ala mutation accounted for 82.9% of chromosomes in this population, followed by the tyr231-to-ter (14.8%) and the 433,G-to-A,-2 (1.1%) mutations.
The 3 mutations accounted for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin. An ala305-to-glu mutation (271900.0003) was found exclusively in non-Jewish probands of European descent and constituted 60% of the 40 mutant chromosomes from this population.
The predominant occurrence of certain mutations suggested a founder effect. It is curious, however, that more than one mutation is relatively common in the Ashkenazi Jewish population as is the case also with Tay-Sachs disease and Gaucher disease.

Shaag et al. (1995) found a variety of mutations in the ACY2 gene in non-Jewish patients with Canavan disease. In 19 non-Jewish patients they found 4 point mutations, 4 deletion mutations, and 1 exon skip.
The ala305-to-glu mutation 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.
In contrast, the gly274-to-arg and the deletion of exon 4 (designated 527del108 by them) were found only in patients of Turkish origin, and the cys218-to-ter mutation was identified only in patients of Gypsy origin.
Homozygosity for the A305E mutation was identified in patients with both the severe and the mild forms of Canavan disease.
The mutation was identified in 31 of the 38 alleles in the 19 non-Jewish patients, representing an overall detection rate of 81.6%. All 9 mutations identified in non-Jewish patients resided in exons 4-6 of the ACY2 gene.

ALLELIC VARIANTS

.0001 CANAVAN DISEASE [ASPA, GLU285ALA]

In 29 of 34 alleles from a sample of 17 unrelated pedigrees of Ashkenazi Jewish descent, Kaul et al. (1993) found a missense glu285-to-ala mutation. Of the 17 probands, 12 were found to be homozygous for the mutation and 5 were compound heterozygotes, the mutation on the second Canavan allele remaining to be determined.
Elpeleg et al. (1994) found that the A-to-C transition at nucleotide 854 of the cDNA was present in homozygous state in all 18 patients with Canavan disease observed in Israel. All were Israeli Ashkenazi Jews. Among 879 healthy Israeli Ashkenazi Jews, 15 heterozygotes were found, representing a carrier rate of 1:59 and suggesting that a screening for the mutation is warranted among couples of particular ethnic background.

.0002 CANAVAN DISEASE [ASPA, CYS152ARG]

In an Arab child with Canavan disease, Kaul et al. (1995) identified a T-to-C transition at nucleotide 454 resulting in a cys152-to-arg aminoacid substitution.
This was the second missense mutation and the fifth mutation of any type to be described for the ASPA gene.

.0003 CANAVAN DISEASE [ASPA, ALA305GLU]

Shaag et al. (1995) found the A305E mutation due to a GCA-to-GAA transversion in 15 out of38 mutant alleles in 19 non-Jewish patients. This distribution was pan-European,suggesting that it is the most ancient mutation.

.0004 CANAVAN DISEASE [ASPA, CYS218TER]

In 3 Gypsy patients with Canavan disease, Shaag et al. (1995) found homozygosity for a C218X mutation caused by a TGC-to-TGA transversion.

SEE ALSO :

Aduchi and Aronson (1967) ; Banker and Victor (1979) ; Hogan and Richardson (1965) ; Kaul et al. (1994) ; Morcaldi et al. (1969) ; Schmidt et al. (1978); Ungar and Goodman (1983); van Bogaert (1963) ; ZuRhein et al. (1960)

REFERENCES

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 ofaffected twins.
Neurology 22: 202-210, 1972.
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.
Banker, B. Q.; Robertson, J. T.; Victor, M. :
Spongy degeneration of the central nervous system in infancy.
Neurology 14: 981-1001, 1964.
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.
. Chou, S. M.; Waisman, H. A. :
Spongy degeneration of the central nervous system: case of homocystinuria.
Arch. Path. 79:357-363, 1965.
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 neurologicalsyndrome associating macrocephaly and leucodystrophy.
J. Inherit. Metab. Dis. 11: 307-308, 1988.
Elpeleg, O. N.; Anikster, Y.; Barash, V.; Branski, D.; Shaag, A. :
The frequency of the C854 mutation in the aspartoacylase gene in Ashkenazi Jews in Israel.
Am. J. Hum. Genet. 55: 287-288, 1994.
Feigelman, T.; Shih, V. E.; Buyse, M. L. :
Prolonged survival in Canavan disease.
Dysmorph. Clin. Genet. 5: 107-110, 1991.
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, 1967.
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.
Kaul, R.; Balamurugan, K.; Gao, G. P.; Matalon, R. :
Canavan disease: genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution.
Genomics 21: 364-370, 1994.
Kaul, R.; Gao, G.P.; Aloya, M.; Balamurugan, K.; Petrosky, A.; Michals, K.; Matalon, R.:
Canavan disease: mutations among Jewish and non-Jewish patients.
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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.
Kaul, R.; Gao, G.P.; Michals, K.; Whelan, D.T.; Levin, S.; Matalon, R. :
Novel (cys152-to-arg) missense mutation in an Arab patient with Canavan disease.
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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.
Mahloudji, M.; Daneshbod, K.; Karjoo, M. :
Familial spongy degeneration of the brain.
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Matalon, R. : Personal Communication. Miami, Fla., 11/3/1990.
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.
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.
Morcaldi, L.; Salvati, G.; Giordano, G. G.; Guazzi, G. C. :
Congenital van Bogaert-Bertrand disease in a non-Jewish family.
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Ozand, P. T.; Gascon, G. G.; Dhalla, M. :
Aspartoacylase deficiency and Canavan disease in Saudi Arabia.
Am. J. Hum. Genet. 35: 266-268, 1990.
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.
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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.
Ungar, M.; Goodman, R. M. :
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van Bogaert, L. :
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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.