Edit concept Question Editor Create issue ticket

Canavan Disease

Aspartoacylase Deficiency

Canavan disease is a rare autosomal recessive genetic disease which is caused by mutation in the aspartoacylase enzyme gene. A lack of enzyme leads to build-up of N-acetylaspartic acid and in turn damages the nerve's myelin sheath. It most commonly presents by the age of 3 to 5 months with macrocephaly, hypotonia and development delay.


The key features of Canavan disease are macrocephaly (larger-than-normal head size), hypotonia and development delays, most commonly presenting at the age of 3 to 5 months after birth. Such presentation constitutes the severe, or neonatal/infantile form, which is the most common one. In severe cases of hypotonia the affected child may require assistance in everyday activities such as independent sitting, standing and walking. Hypotonia may cause the child to appear "floppy", apathetic or lethargic and often leads to particularly noticeable difficulties with controlled movement of the head and neck. Assisted feeding with nasogastric tube or permanent gastrotomy may be required as affected children are unable to feed themselves and swallow properly. Further in course hypotonia evolves into spasticity with involuntary muscle spasms and movements. Affected patients may even experience decerebrate rigidity (uncontrolled rigid spasms and extensions of the muscles of arms, fingers and toes) or spastic paralysis. Leg movements become slow and stiff. As the child gets older, delays in development appear more clearly. Although social interaction remains intact and most of the patients learn to smile and laugh, progressive loss of coordination of mental and motor reactions emerge more and more with aging. Mental retardation is also frequently manifesting.

Additional possible complications include insomnia, dysphagia (which further contributes to feeding problems), speech difficulties, seizures, esophageal reflux of stomach acid (in some cases with vomiting) and atrophy of optic nerve. Optic atrophy is quite common among children with Canavan disease and may reduce visual reactivity, however, patients are usually still able to visually track and follow objects. Hearing loss is a rare complication.

Canavan disease frequently progresses to severe life-threatening complications, although the course of the disease is variable, hugely relying on the adequate management. Life expectancy may go up to the teen age [10] or beyond, however, many patients develop severe fatal complications and die early in infancy.

The mild/juvenile form of Canavan disease, which also has ASPA gene mutations and only mild amount of NAA in the urine, has been reported in recent years. It is characterized by minor development delay with ability to successfully study in schools. Head circumference may be slightly enlarged, but usually goes unnoticed. Patients don't have the typical pathological white matter changes of the severe form. Prognosis of the mild/juvenile form of Canavan disease is much more positive.

  • A deletion of exon4, which until now had only been described once, was revealed in all five alleles of Turkish origin tested, indicating that this is a founder effect in the Turkish population.[ncbi.nlm.nih.gov]
  • 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.[web.peacelink.it]
  • Glucose Transporter Type 1 (Glut1) Deficiency A four year old female presented with infantile-onset epilepsy, truncal hypotonia, dystonia, spasticity, intellectual disability and intermittent hypoglycemia associated with fatigue.[ncbi.nlm.nih.gov]
  • In contrast, the loss of van der Waals contacts in the F295S mutant and the loss of hydrophobic and hydrogen bonding interactions in the Y231C mutant lead to a local collapse of the hydrophobic core structure in the carboxyl-terminal domain, contributing[ncbi.nlm.nih.gov]
  • Dentists aware of CD can assist in the treatment of infants and children afflicted with this disorder. Early dental treatment may support parents and siblings in caring for the child with CD and help create good family dynamics.[ncbi.nlm.nih.gov]
  • CD presents pathophysiological dysfunctions similar to diseases caused by myelin gene mutations, such as Pelizaeus-Merzbacher disease (PMD) and several animal models, such as myelin deficient rat (md), jimpy (jp), shiverer (sh), and quaking (qk viable[ncbi.nlm.nih.gov]
Mild Clinical Course
  • Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics. 2005; 36 :252–5. [ PubMed : 16138249 ] Yalcinkaya C, Benbir G, Salomons GS, Karaarslan E, Rolland MO, Jakobs C, van der Knaap MS.[ncbi.nlm.nih.gov]
  • Possible genotype-phenotype correlations in children with mild clinical course of Canavan disease. Neuropediatrics. 2005 Aug;36(4):252-5.[ghr.nlm.nih.gov]
Failure to Thrive
  • […] to thrive Seizures : The brain controls how the body moves by sending electrical signals.[ulf.org]
  • […] to thrive due to difficulty in feeding and swallowing Nasal regurgitation of food Irregular stance of flexed arms and straight legs Atypical muscle tone such as floppiness or stiffness especially in the neck muscle Visual responsiveness is diminished[healthool.com]
  • Initial Symptoms presented: • Delayed psychomotor development • Lethargy and poor head and neck control Later Symptoms Presented: • Movement Disorders • Seizures • Blindness • Failure to Thrive • Gastrointestinal reflux Type III: Juvenile Form Onset after[mazornet.com]
  • Others megencephaly /- increased ICP seizures 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 1.[web.peacelink.it]
  • […] by Jon Merz, who was also present at the meetings, says the offered sum was 20,000 per year, with the further condition that the Consortium members not publicly criticize the MCH. 22 The Consortium welcomed the financial help but did not agree to the gag[doi.org]
Hearing Impairment
  • SPG7) Genetic analysis None Arginase Deficiency ARG1 Spastic diplegia, GDD/ID, hyperammonemia None; occasional cerebral atrophy Plasma arginine level, genetic analysis None RNASET2-Deficiency RNASET2 Microcephaly, GDD/ID, seizures, hearing impairment[ncbi.nlm.nih.gov]
  • Clinical manifestation is being noted for diagnosing such as presentation of joint stiffness and hyperreflexia including as well the presence of optic atrophy.[healthool.com]
  • After that, hypotonia progresses to spasticity, hyperreflexia, extensor plantar responses, and tonic extensor spasms. The extensor spasms may occur in response to noise.[ncbi.nlm.nih.gov]
  • Hyperreflexia with an extensor plantar response was observed. Generalized seizures first occurred at age 8 years. By age 20, she showed bilateral optic atrophy.[web.peacelink.it]
  • Neurologic examination was notable for a lack of visual tracking, central hypotonia, limb hyperreflexia, and choreiform limb movements.[ojrd.biomedcentral.com]
Progressive Macrocephaly
  • We report on a non-Jewish female infant who presented at age 6 months with progressive macrocephaly and developmental delay.[ncbi.nlm.nih.gov]
Spastic Paralysis
  • Affected patients may even experience decerebrate rigidity (uncontrolled rigid spasms and extensions of the muscles of arms, fingers and toes) or spastic paralysis. Leg movements become slow and stiff.[symptoma.com]
  • Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania.[ncbi.nlm.nih.gov]
Progressive Macrocephaly
  • We report on a non-Jewish female infant who presented at age 6 months with progressive macrocephaly and developmental delay.[ncbi.nlm.nih.gov]
  • At 4 years of age, he was normocephalic, with mild clumsiness, speech delay, and seizures.[ncbi.nlm.nih.gov]


The measuring of N-acetylaspartic acid concentration in the urine is diagnostic for Canavan disease. High concentration of the acid is characteristic for the disease, particularly in the neonatal/infantile form. The mild/juvenile form may show only slightly increased NAA in the urine, and the diagnosis should be based on the testing of ASPA gene on molecular level.

The diagnosis may be made prenatally by amniocentesis at 16-18 weeks of gestation or by chorionic villus sampling (CVS) at 10-12 weeks of gestation. The CVS testing is recommended for parents each of whom is confirmed to have ASPA gene mutations. 

The magnetic resonance imaging (MRI) is recommended for patients with Canavan disease to evaluate the extent of the disease. On the MRI Canavan disease would manifest as macrocephaly, tissue swelling and homogenous low intensity of white matter signal on T1-weighted images and high intensity of the signal on T2-weighted images [11] [12]. Subcortical-periventricular white matter would appear dysmyelinated. Subcortical arcuate fibers are particularly affected in Canavan disease, which helps to differentiate it with other leukodystrophies. As the disease progresses, cortex atrophy would become more prominent.

Magnetic resonance spectroscopy (MRS) is a useful diagnostic modality and will show N-acetylaspartic acid accumulation in the brain even before it would appear in urine.

Canavan disease can be suspected in patients with characteristic clinical findings such as macrocephaly, hypotony and development delays and associated risk factors, such as being part of an ethnicity of a certain origin. A diagnosis should then be confirmed by detailed patient history as well as genetic evaluation. Specific tests for Canavan disease include gas chromatography-mass spectrometry, which detects high levels of NAA in the urine as well as blood and cerebrospinal fluid. Enzyme aspartoacylase activity decrease may be detected in cultured fibroblasts and white blood cells.


Treatment is mostly supportive. Proper nutrition and hydration, infection prophylaxis and treatment of occurring complications are the key points. Physical therapy may be used to compensate muscular impairment and improve motor skills and posture to some extent. Nasogastric feeding tubes or gastrotomy may be required to ensure sufficient nutrition and hydration if dysphagia is making the unassisted feeding difficult. Seizures are treated with antiepileptic drugs (AEDs). Patients with social deficits and mental retardation may benefit from early intervention and special education programs to maximize their communication skills and intelligence potential.

Recent studies suggest that gene therapy could be a possible deal-breaker in the treatment of genetic disorders such as Canavan disease in the future. In the meantime, genetic counseling and carrier testing may benefit affected families.


The prognosis is variable. Patients suffering from the neonatal/infantile form tend to only live up to early childhood or pass away in the first few years of life due to the frequent onset of severe life-threatening complications, although some survive into adolescence and beyond. The mild/juvenile form has much better prognosis with most of the patients having normal life expectancy as well as better social functioning and unaffected intelligence and mental functions. The expected lifespan also relies on the adequate medical and nursing care given to the patients presenting the severe form, as proper nutrition, hydration and treatment of occurring complications is crucial for their survival.


Canavan disease is a genetic disorder with mutation occurring in the gene encoding for aspartoacylase (ASPA) enzyme. The mode of inheritance is autosomal recessive. The gene is located on the short arm of chromosome 17. There is association with more than 54 loss-of-function mutations on the ASPA gene and the disease [3] [4] [5]. Aspartoacylase enzyme breaks down N-acetylaspartic acid to aspartate and acetate in brain and other tissues. The deficiency of enzyme leads to N-acetylaspartate build-up and in turn to the damage of nervous system. The myelin sheath is particularly affected, leading to demyelination of nerve fibers. 


The overall incidence of Canavan disease in the general population has not been estimated. As this disease is inherited in autosomal recessive way it is mostly prevalent in isolated populations such as Ashkenazi Jews (population of Eastern and Central Europe). In this population the disease affects 1 in 6400 to 13500 people. People of Ashkenazi heritage have carrier state as frequent as 1 in 40-58 people. Although the disease may affect any ethnic group, its frequency in general population is suspected to be much lower. 

Canavan disease has no gender preference, with both males and females affected equally. 

Sex distribution
Age distribution


Canavan disease is a genetic disorder resulting in aspartoacylase enzyme deficiency. The enzyme mediates the conversion of N-acetylaspartate to acetate and aspartate. The ASPA deficiency leads to build-up of N-acetylaspartate in the white brain matter, which interferes with the natural development process of the brain [6] [7] [8]. The exact pathophysiology is not yet clear but the result is extensive dysmyelination, vacuolation of the central nervous system (CNS) white matter and intramyelinic edema leading to hydrocephalus [9]. Myelin breakdown is hypothesized to be the main cause of the occurring pathological processes.

Canavan disease is classified as a leukodystrophy. The leukodystrophies are a group of disorders affecting the nervous system, both central and peripheral. All the leukodystrophies are advancing metabolic rare genetic disorders. Approximately 10 different neurochemicals of the white brain matter are thought to be involved in the pathophysiology of leukodystrophies. The white brain matter is a neural tissue containing high amounts of neural fibers, which are covered in lipid sheath known as myelin. Myelin is a natural insulator and increases the speed of transmission in nerves. Leukodystrophies disrupt myelin coverage resulting into dysfunction of nerves.


As the disease is of genetic origin, no guaranteed prevention methods are available. Prevention can be achieved by genetic counseling of affected families in populations at risk. Prenatal diagnosis is possible by measuring N-acetylaspartic acid levels in amniotic fluid via amniocentesis, however, DNA analysis is the method of choice.


Canavan disease is a genetic disease inherited by autosomal recessive way. Causative mutations are occurring in the gene encoding aspartoacylase enzyme located on the short arm of chromosome 17. The aspartoacylase enzyme promotes the breakdown of N-acetylaspartic acid into aspartate and acetate and its deficiency leads to build-up of N-acetylaspartic acid (NAA) in the tissues. The exact pathophysiological mechanism is unknown, but the accumulation of NAA in the white brain matter results in global demyelination of nerve fibers [1]. The degenerative changes may lead to sponginess of the gross appearance of the brain. Canavan disease is quite severe in its most common neonatal/infantile form and is usually fatal early in life due to serious life-threatening complications [2]. However, some patients survive into the teen age and even further. The less severe mild/juvenile form has been reported in recent years. Canavan disease is extremely rare among the general population, mainly occurring in the isolated populations such as Ashkenazi Jews with a prevalence of 1 in 6400 to 13500 people and carrier state as frequent as 1 in 40-58 people.

Affected newborns may appear normal at birth, but usually manifest with a presentation of macrocephaly, hypotony and development delay by the age of 3 to 6 months. Hypotony may be severe enough to cause head movement difficulties, complete "floppiness" of the baby and inability to sit and ambulate independently. The course of the disease may be accompanied by complications such as speech difficulties, esophageal reflux, dysphagia, optic atrophy and mental retardation.

Diagnosis is made by detecting high levels of N-acetylaspartic acid in the urine. Also, prenatal options for the diagnosis exist. Imaging studies may be used to assess the extent of the disease. Genetic counseling is suggested for all affected families.

Treatment is mainly supportive and includes proper nutrition and hydration, infection control, airway protection, assisted feeding with nasogastral tube or gastrotomy. Physical therapy helps to compensate motor impairment. Special education may be required as affected children often develop mental retardation. Patients may benefit from genetic therapy in the future.

Patient Information

Canavan disease is a very rare genetic disorder, causing deficiency in the aspartoacylase enzyme. This enzyme breaks down certain chemicals in the brain and other organs. When the enzyme is not produced, the chemicals build-up and cause damage to nerve fibers, particularly the myelin (protective layer of lipids covering the nerve). The nerve damage results in vast malfunctioning of the nervous system.

The disease is inherited via autosomal recessive way, meaning that in order to actually obtain the disease, two copies of defective genes must be passed to the child, one from each parent. When only one copy of the defective gene is inherited, the disease does not develop, however, it can be passed to offsprings of that person.

Affected children usually show no symptoms at birth, but by the age of 3 to 5 months they usually develop serious problems. The head of these children is often enlarged, they may fail to reach developmental milestones as other kids of their age do, i.e. sitting, crawling, standing or talking. Affected children have reduced muscle tone, called hypotonia, meaning that all their muscles become weak. Further into disease course they may develop seizures, paralysis, blindness and trouble swallowing. Most of the children do not live past age 10. However, there is a milder form of disease with little to none symptoms and much better prognosis, but unfortunately it is less common than the severe form.

In order to diagnose the disease, doctors test the child's urine. Images of the brain with magnetic resonance imaging (MRI) may also be taken to evaluate the extent of the damage. The disease can also be diagnosed before birth by taking a small amount of liquid surrounding the fetus with a needle.

Currently there is no treatment for Canavan disease. However, to ensure prolonged survival of the affected children adequate care must be provided. This includes proper nutrition, hydration, treatment of infections and occurring complications. A thin tube may be put through the child's nose into the stomach to facilitate nutrition if swallowing difficulties develop. A special operation on the child's stomach to insert the tube directly is also available. Seizures are treated with antiepileptic drugs. Physical therapy may help with movement problems and special education may be required to help the child socialize.



  1. Matalon R, Rady PL, Platt KA, et al. Knock-out mouse for Canavan disease: A model for gene transfer to the central nervous system J Gene Med 2000;2:165–175.
  2. 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 Feb;29(2):463-71.
  3. Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003 Jun;21(6):577-81.
  4. Matalon R, Kaul R, Gao GP et al. Prenatal diagnosis for Canavan disease: the use of DNA markers. J Inherit Metab Dis. 1995;18(2):215-7.
  5. Kaul R, Gao GP, Balamurugan K, Matalon R. Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease. Nat Genet. 1993 Oct;5(2):118-23.
  6. Ishiyama G, Lopez I, Baloh RW, Ishiyama A. Canavan's leukodystrophy is associated with defects in cochlear neurodevelopment and deafness. Neurology. 2003 May 27;60(10):1702-4.
  7. Janson CG, Kolodny EH, Zeng BJ, et al. Mild-onset presentation of Canavan's disease associated with novel G212A point mutation in aspartoacylase gene. Ann Neurol. 2006 Feb;59(2):428-31.
  8. Kaul R, Gao GP, Aloya M, Balamurugan K, Petrosky A, Michals K, Matalon R. Canavan disease: mutations among Jewish and non-Jewish patients. Am J Hum Genet. 1994 Jul;55(1):34-41.
  9. Matalon R, Michals-Matalon K. Molecular basis of Canavan disease. Eur J Paediatr Neurol. 1998;2(2):69-76.
  10. Matalon R, Michals-Matalon K. Canavan Disease. 1999 Sep 16 [Updated 2011 Aug 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1234/ 
  11. Osborn AG. Inherited metabolic, white matter, and degenerative diseases of the brain, in Diagnostic Neuroradiology. St. Louis, MO, Mosby-Year Book, Inc., 1994.
  12. Barkovich AJ. Toxic and metabolic brain disorders, in Pediatric Neuroimaging. Philadelphia, Lippincott Willams & Wilkins; 2000.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 21:53