a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)
iii) MORBO DI CANAVAN
A neurodegenerative disorder characterized by degeneration of CNS white
matter and specific CNS pathological findings.
age of onset:
newborn to childhood (depends on the Form)
familial - autosomal recessive (Type I)
gene: ? aspartoacylase
Ashkenazi Jews (Type I)
sporadic (Type II)
a genetic defect affecting aspartoacylase (normally cleaves the
N-acetyl group from N-acetylaspartic acid) -> accumulation of
N-acetylaspartic acid throughout the white matter (specifically in
1. Spongy Vacuolization/Degeneration
accumulation of N-acetylaspartic acid leads to vacuolization of the
white matter with astrocyte swelling -> spongy degeneration of myelin
fibres required for definite diagnosis but not pathognomonic as spongy
vacuolization is seen in other disorders, i.e., Maple Syrup Urine
Type I: Neonatal Form
Type II: Infantile Form
Type III: Juvenile Form
- Type I - Neonatal Form
onset: at birth
death within the first few weeks of life
1. Neurological Manifestations
hypotonia, lethargy, decreased spontaneous movements
difficulty sucking, swallowing, and feeding
- Type II - Infantile Form
onset: first few months of life
most common form
death by 3-4 years of age
1. Neurologic Manifestations
plateauing then delayed psychomotor development
infantile hypotonia, lethargy, poor head & neck control
1. Movement Disorders
hypotonia -> spasticity with decorticate and decerebrate
megencephaly +/- increased ICP
nystagmus, optic atrophy, and blindness
failure to thrive with gastroesophageal reflux
- Type III - Juvenile Form
onset: over 5 years of age
death in adolescence
1. Neurological Manifestations
ataxia, tremor, mental deterioration, ptosis
dementia, dysarthria, progressive cerebellar syndrome
spasticity optic atrophy, abnormal retinal pigmentation
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
2. Imaging Studies
progressive leukodystrophy with diffuse white matter degeneration
diffuse attenuation of white matter
later cerebral atrophy with ventricular dilatation
no treatment available
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.
treat movement disorders, seizures, and feeding problems
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
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.
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 22.214.171.124 ) is also called aminoacylase-2. Aminoacylase-1
(EC 126.96.36.199 ) 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
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
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.
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
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
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.
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.
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.
.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
.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
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)
- 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-
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.
- . 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.
Am. J. Hum. Genet. 55: 34-41, 1994.
- 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
Hum. Mutat. 5: 269-271, 1995.
- 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.
Arch. Neurol. 22: 294-298, 1970.
- 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
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.
Acta Genet. Med. Gemellol. 18: 142-157, 1969.
- 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
Klin. Paediat. 190: 580-585, 1978.
- 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. :
Spongy degeneration of the brain in Israel: a retrospective study.
Clin. Genet. 23: 23-29, 1983.
- van Bogaert, L. :
Familial spongy degeneration of the brain. (Complementary study of the
Acta Psychiat. Neurol. Scand. 39: 107-113, 1963.
- 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.