Guidelines on Hereditary Leukodystrophies
Canavan disease (OMIM #271900)
Disease description: Canavan disease is an autosomal recessive inherited progressive cerebral leukodystrophy caused by a mutation in the gene encoding aspartoacylase. It is classified into three types by onset timing: congenital, infantile, and juvenile. Patients typically exhibit hypotonia, irritability, and lack of control over head movements in early infancy, with macrocephaly, delayed psychomotor development, spastic palsy, and optic atrophy gradually becoming apparent. Test results characteristically show highly elevated levels of urinary N-acetylasparitic acid (NAA). The prognosis is poor, with most patients dying before age 10.
Treatment: Treatments including lithium, lipoic acid, and glyceryl triacetate have been used to limit NAA accumulation in the central nervous system. Although there is currently no cure, gene therapy using virus vectors has been attempted.
1. Overview
C.Q1 What is Canavan disease?
Definition
First described by Canavan in 1931, this syndrome was subsequently established as a disease by Bertrand and Bogaert in 1949 (1, 2). Canavan disease is an autosomal recessive inherited cerebral leukodystrophy characterized neuropathologically by edema and spongiform degeneration of the cerebral white matter. Genetic screening has since shown that it is mainly caused by a mutation in the ASPA gene encoding aspartoacylase (ASPA), an enzyme that hydrolyzes the N-acetylasparitic acid (NAA) generated in the tricarboxylic acid cycle into acetic acid and aspartate, and a decrease in its enzymatic activity causes NAA to accumulate in the central nervous system, resulting in neurological symptoms (3).
Epidemiology
Only one case has been reported in Japan, and questionnaire surveys have not identified any other patients with a confirmed diagnosis, making this an extremely rare disease (4). Most reported cases have occurred within the Ashkenazi Jewish community (3).
Etiology and pathophysiology
High levels of ASPA are normally expressed in oligodendrocytes in the brain, and NAA is hydrolyzed to acetic acid and aspartate in these cells. If ASPA enzymatic activity is reduced by a mutation in the ASPA gene, NAA accumulates and the supply of acetic acid, a myelin substrate, is reduced, causing spongiform degeneration (5, 6).
Clinical symptoms
In the congenital type, which is the most serious, symptoms start to appear within a few weeks after birth. In the infantile type, which is the most common, they appear by 6 months of age; in the mildest juvenile type, they appear by age 4–5 years. Irritability and hypotonia typically become apparent in the early stages of the disease, with motor development delayed from the point at which infants are usually able to hold up their own heads. Symptoms including macrocephaly, poor ocular pursuit, ataxia, dysphagia, and seizures become more obvious. Optic atrophy and spastic palsy are progressive, and most patients die before reaching puberty (5,7,8).
Imaging and other investigations
The characteristic test result is highly elevated urinary NAA excretion. In affected individuals, it is several tens of times higher than the amount normally excreted (9). General blood count and biochemical test results are unremarkable. Cranial magnetic resonance imaging reveals diffuse white-matter lesions with mild edema of the subcortical white matter. The central white matter in the periventricular margins and internal capsule is generally spared at first, but as symptoms progress, this too becomes affected and shows signs of atrophy. The globus pallidus and thalamus are also involved, but the putamen and caudate nucleus are spared (10). Magnetic resonance spectroscopy exhibits an abnormal NAA peak and an elevated NAA/choline ratio (11).
Genetic diagnosis
For patients with suspected Canavan disease on the basis of urinalysis, the diagnosis is confirmed by ASPA gene screening. The human ASPA gene, located on the short arm of chromosome 17, was identified by Kaul et al. in 1991. It is 30 kb long and consists of 6 exons and 5 introns (12). In over 96% of Ashkenazi Jewish patients, the cause is a missense mutation of codon 285 (Glu285Ala) or a nonsense mutation of codon 231 (Tyr231X), but other mutations have been found in non-Jewish patients, including the Japanese case.
2. Treatment and care
At this point there is no cure for Canavan disease; therefore, symptomatic therapy is provided.
a. Delayed psychomotor development
Because motor disability is present alongside intellectual disability, in practice many children receive the same special needs care and education as that provided for children with cerebral palsy, the most common similar condition. They are referred by a public health center or the hospital where they are diagnosed to an institution for children with special needs or a hospital rehabilitation department. They are provided with the necessary care to maintain body posture and prevent joint contracture. Clinically, Canavan disease is unlike cerebral palsy in terms of the occurrence of developmental regression.
b. Epilepsy
Although there has been no statistical study of the proportion of Canavan disease patients with epilepsy, depending on the type of seizure, partial seizures are treated with carbamazepine or lamotrigine, while full seizures are treated with valproic acid or zonisamide.
c. Respiratory disturbance and dysphagia
Laryngopharyngeal dysfunction may make patients prone to aspiration pneumonia. Patients who have difficulty ingesting food by mouth may be fed via a nasogastric tube or a gastrostoma; if gastroesophageal reflux is present due to muscle hypertonia, then fundoplication is also performed.
3. Diet and nutrition
No particular diet or type of nutrition is recommended. A nutritionally balanced diet is desirable.
4. Prognosis
There has been no survey of the natural history of Canavan disease, but in individuals with the infantile type, death is believed to occur before puberty.
5. Differential diagnosis
Other neurodegenerative diseases that cause macrocephaly include Alexander disease and Tay-Sachs disease. 3-Hydroxy-3-methylglutaric acidemia is another possibility. Diseases causing spongiform cerebral degeneration include mitochondrial disease and other congenital metabolic disorders as well as viral encephalitis.
6. Recent topics
Many aspects of the etiology of the central nervous system symptoms of Canavan disease remain unclear, but targeted treatments attempting to alleviate the osmotic edema caused by NAA accumulation, supplement the substrates for NAA-derived myelin structural lipids, or reduce oxidative stress have been attempted (13). Gene therapy is also being investigated, but this remains at the experimental level.
a. Lithium
Lithium administration may help alleviate NAA accumulation in the central nervous system. One study found that the administration of lithium chloride 45 mg/kg/day partially improved neurological symptoms with no major side effects, reducing the concentration of NAA in the central nervous system and encouraging myelination (14).
b. Glyceryl triacetate
Treatment to provide the necessary substrate for myelin formation is being tried, with the aim of preventing the dysmyelination and degeneration associated with the inadequate supply of acetic acid when the hydrolysis of NAA is blocked. One study found that glyceryl triacetate safely increased the concentration of acetic acid in the cerebrospinal fluid but did not improve neurological symptoms, whereas another claimed to observe improvements in spongiform cavitation and motor function at high doses (15) (16).
c. Gene therapy
Leone et al. performed ASPA gene therapy using a viral vector in 13 patients with Canavan disease and reported that the NAA concentration in the central nervous system decreased, seizure frequency stabilized, and atrophy progression slowed with no side effects (17).
References (Unless otherwise noted at the end, all are evidence level 6.)
- Canavan WP. Reaction of the contents of Trichinella spiralis cysts. Science 1931; 74: 71.
- Bertrand I, Van Bogaert L. [Demyelinizing diseases in man and animals: Remarks and conclusions]. Acta Neurol Psychiatr Belg 1954; 54: 682-691.
- 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 1988; 29: 463-471.
- Hoshino H, Kubota M. Canavan disease: Clinical features and recent advances in research.
Peds Intl 2014; 56: 477-483. - Adachi M, Schneck L, Cara J, Volk BW. Spongy degeneration of the central nervous system (van Bogaert and Bertrand type; Canavan’s disease). A review. Hum Pathol 1973; 4: 331-347.
- Moffett JR, Namboodiri AM. Preface: A brief review of N-acetylaspartate. Adv Exp Med Biol 2006; 576: vii-xiii.
- Gascon GG, Ozand PT, Mahdi A et al. Infantile CNS spongy degeneration – 14 cases: clinical update. Neurology 1990; 40: 1876-1882.
- Matalon RM, Michals-Matalon K. Spongy degeneration of the brain, Canavan disease: Biochemical and molecular findings. Front Biosci 2000; 5: D307-311.
- Inoue Y, Kuhara T. Rapid and sensitive screening for and chemical diagnosis of Canavan disease by gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 806: 33-39.
- van der Knaap MS. Canavan Disease, Magnetic Resonance of Myelination and Myelin Disorders, 3rd edn. Springer, Berlin, 2005; 326-333.
- Wittsack HJ, Kugel H, Roth B, Heindel W. Quantitative measurements with localized 1H MR spectroscopy in children with Canavan’s disease. J Magn Reson Imaging 1996; 6: 889-893.
- Kaul R, Balamurugan K, Gao GP, Matalon R. Canavan disease: Genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution. Genomics 1994; 21: 364-370.
- Rebecca B, Christina E, Apostolos Z, George S. Non-genetic therapeutic approaches to Canavan disease. J Neuro Sci 2016; 366: 116-124.
- Janson CG, Assadi M, Francis J, Bilaniuk L, Shera D, Leone P. Lithium citrate for Canavan disease. Pediatr Neurol 2005; 33: 235-243.(5)
- Madhavarao CN, Arun P, Anikster Y, Mog SR, Staretz-Chacham O, Moffett JR, Grunberg NE, Gahl WA, Namboodiri AM. Glyceryl triacetate for Canavan disease: a low-dose trial in infants and evaluation of a higher dose for toxicity in the tremor rat model. J Inherit Metab Dis 2009; 32: 640-650.(5)
- Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MA. Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain. J Pharmacol Exp Ther 2005; 315: 297-303.(5)
- Leone P, Shera D, McPhee SW et al. Long-term follow-up after gene therapy for Canavan disease. Sci Transl Med 2012; 4: 165ra63.(5)
Literature search
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