Alternative titles; symbols
SNOMEDCT: 80544005; ICD10CM: E75.28; ORPHA: 141, 314911, 314918; DO: 3613;
| 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 |
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.
Canavan disease is a severe progressive autosomal recessive neurodegenerative disorder characterized by vacuolar degeneration of the lower layers of the brain cortex and the subcortical white matter. Clinical signs usually begin during the first few months after birth, manifested by poor head control and marked developmental delay, and progress to macrocephaly, optic atrophy, seizures, and hypertonia, with death in early childhood. Although most patients with Canavan disease are of Ashkenazi Jewish ancestry, this disorder has also been found in many other ethnic groups (summary by Zeng et al., 2002).
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.
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 transmission pattern of Canavan disease in the families reported by Kaul et al. (1993) was consistent with autosomal recessive inheritance.
In affected members of 3 pedigrees with Canavan disease, Kaul et al. (1993) identified a homozygous 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 biallelic 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.
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 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.
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.
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