• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Canavan Disease

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Last updated: 9/24/2024
Years published: 1986, 1990, 1994, 1995, 1996, 1998, 2003, 2008, 2012, 2015, 2024


Acknowledgment

NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders and Reuben Matalon, MD, PhD (deceased) for assistance in the preparation of this report.


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Disease Overview

Summary

Canavan disease is a rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain.

Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in “floppiness” and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age.

Canavan disease is caused by changes (variants) in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.

There is no cure yet. Treatment depends on the specific symptoms that the affected person has.

Introduction

Canavan disease belongs to a group of disorders known as leukodystrophies. Leukodystrophies are a group of rare, progressive, metabolic, genetic disorders that can affect the brain, spinal cord and often the nerves outside the central nervous system (peripheral nerves). Each type of leukodystrophy is caused by variants affecting a specific gene that results in abnormal development of one of at least 10 different chemicals that make up the white matter of the brain. The white matter is tissue composed of nerve fibers. Many of these nerve fibers are covered by a collection of fats (lipids) and proteins known as myelin. Myelin, which collectively may be referred to as the myelin sheath, protects the nerve fibers, acts as an insulator and increases the speed of transmission of nerve signals. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of different neurological problems.

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Synonyms

  • ASPA deficiency
  • aspartoacylase deficiency
  • Canavan's leukodystrophy
  • Canavan-Van Bogaert-Bertrand disease
  • spongy degeneration of the central nervous system
  • Van Bogaert-Bertrand syndrome
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Signs & Symptoms

Canavan disease is a leukodystrophy characterized by delays in development, abnormal muscle tone and an unusually large head (macrocephaly). The symptoms and progression of Canavan disease varies from person to person.

The disease exists in two forms: typical Canavan disease which is more severe and atypical Canavan disease which is milder. Each form has its own set of symptoms and progression. 

Typical Canavan Disease

Symptoms appear usually between 3 to 5 months of age and may include:

  • Motor and developmental delays:
    • Weak muscle tone or floppiness (hypotonia), an early sign, leading to poor head control and inability to support the head
    • Progressive growth of the head (head size is normal at birth) resulting in macrocephaly, typically between 4 and 18 months
    • Developmental delays, where most children cannot sit, stand, walk, or talk (some may develop a social smile and can laugh, while a few may use their hands purposefully)
  • Progressive loss of abilities requiring the coordination of mental and muscular activity (psychomotor regression)
  • Intellectual disability, becoming apparent during infancy (babies and children younger than 5 years of age
  • Seizures (common) of many types such as tonic spasms, generalized tonic-clonic seizures and infantile spasms
    • Seizures usually begin in the first year of life and become more frequent over time
  • Vision problems that may include:
    • Trouble focusing and tracking objects, often due to cerebral visual impairment (in many patients)
    • Damage to the optic nerve (optic atrophy), leading to reduced vision
    • Nystagmus (rapid, involuntary eye movements) which often develops in infancy
  • Hearing problems, in very rare cases
  • Feeding difficulties and swallowing problems (dysphagia) sometimes requiring a gastrostomy tube for feeding
  • Muscle tone changes that are first characterized by low muscle tone (hypotonia) that may progress into spasticity (stiff, uncontrolled muscle movements), leading to further motor challenges
  • Unresponsiveness, apathy, lethargy, irritability and sleep disturbances as the disease progresses.

Most children with typical Canavan disease live into their first two decades, though a small number survive beyond this due to improved care. 

Atypical Canavan Disease

Atypical Canavan disease appears often later than in typical Canavan disease, with developmental delays becoming apparent in early childhood or adolescence.

  • Motor and developmental delays: Children with atypical Canavan disease may have mild delays in speech and movement. Some can learn to sit, stand, walk and even attend school with specialized educational support
  • Progressive growth of the head size (macrocephaly) in some children
  • Coordination difficulties (ataxia), gait disturbances, and problems with balance
  • Other symptoms such as seizures and retinitis pigmentosa (a progressive eye disease affecting vision) may occur in some patients

Children with atypical Canavan disease often make slow developmental progress without regression until later in life. They may have significant language impairment or intellectual disability, but some are able to walk and attend school.

While the lifespan of individuals with atypical Canavan disease is not well defined, many survive into adulthood. 

Milder Form of Canavan Disease

Children with this form of the disease may have only slight developmental delays. They can learn, attend school, and their life expectancy is much better than those with typical Canavan disease.

  • Some children may have an enlarged head, but the typical white matter changes seen in Canavan disease may be absent.

This form is much milder, with better outcomes and longer survival. 

Additional symptoms may include: 

  • Feeding problems, where babies and young children may have trouble swallowing (dysphagia), leading to feeding difficulties and nasal regurgitation
  • Acid from the stomach backing up into the esophagus (reflux) and vomiting
  • Vision problems such as optic atrophy leading to decreased vision
  • Hearing loss in very rare cases
  • Muscle tone changes, where, as children age, hypotonia develop into spasticity Some may eventually have uncontrolled stiffening of the limbs (decerebrate rigidity) or paralysis
  • Sleep disorders in many affected children

Canavan disease can lead to severe, life-threatening complications at different stages of life, though the severity and progression vary between affected people.

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Causes

Canavan disease is caused by changes (variants) in the aspartoacylase (ASPA) gene.

The ASPA gene contains instructions for developing (encoding) aspartoacylase, an enzyme that breaks down (metabolizes) N-acetylaspartic acid (NAA). NAA is a compound that researchers think plays a vital role in maintaining the brain’s white matter. Deficient or inactive aspartoacylase results in the accumulation of NAA in brain tissue. The symptoms of Canavan disease result from damage to the white matter from the abnormally high levels of NAA.

Milder symptoms are associated with specific variants in the ASPA gene and with only a slight increase in NAA in the urine.

Canavan disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Canavan disease affects males and females in equal numbers. It affects all ethnic groups but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-82 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown.

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Diagnosis

Doctors may first suspect Canavan disease if an infant shows certain signs, including:

  • Poor head control
  • Enlarged head (macrocephaly)
  • Delayed developmental milestones

If these symptoms are present, further testing is needed to confirm the diagnosis.

The main tests that can confirm the diagnosis include:

  • Biochemical testing: The main biochemical test for Canavan disease looks for high levels of a substance called N-acetylaspartic acid (NAA) in the body. The doctors check for elevated NAA using the following test:
    • Urine test: A device called gas chromatography-mass spectrometry (GC-MS) is used to detect high NAA levels in the urine.
    • Brain scan: A special brain scan, proton magnetic resonance spectroscopy, can detect high NAA levels in the brain.
    • Blood and spinal fluid: High NAA levels can also be found in blood and cerebrospinal fluid (CSF), and testing blood samples may become more common in the future with the development of new techniques.
  • Molecular genetic testing can confirm the diagnosis by identifying the ASPA gene variants that can cause Canavan disease. If a child has two disease-causing variants in this gene, the diagnosis is confirmed.
  • Enzyme activity testing in skin cells or white blood cells to check for a lack of an enzyme called aspartoacylase, which is crucial for breaking down NAA can strongly suggest the diagnosis if this enzyme is missing.

If both parents carry an ASPA gene variant, they may choose to have prenatal testing for an unborn baby:

  • Amniocentesis: Performed at 16-18 weeks of pregnancy, this test measures the NAA levels in the amniotic fluid surrounding the baby.
  • Chorionic Villus Sampling (CVS): Performed at 10-12 weeks of pregnancy, this test checks placental cells for ASPA gene variants.
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Standard Therapies

Treatment

Canavan disease is a genetic disorder that affects the brain, and while there is currently no cure, treatment focuses on managing symptoms and improving the quality of life.

Treatment for Canavan disease is tailored to the person’s specific symptoms. This approach involves addressing different aspects of the disease:

  • Early intervention with physical therapy can help improve posture, movement and reduce muscle tightness (spasticity).
  • Therapy aimed at enhancing communication skills can be beneficial, especially in young children.
  • Swallowing difficulties may require using a feeding tube (gastrostomy tube) to ensure the person gets enough nutrition and stays hydrated and it also helps prevent food from accidentally entering the lungs (aspiration).
  • Seizure control, typically managed with anti-seizure medications (antiepileptic drugs)
  • Botulinum toxin Injections, which can help reduce muscle stiffness or spasticity

Managing Canavan disease requires a team of specialists to ensure all aspects of the individual’s health are addressed:

  • Neurology: A neurologist helps manage issues like seizures and spasticity.
  • Orthopedics and physical therapy: Orthopedic doctors and physical therapists work together to minimize joint contractures (stiffness) and improve the ability to sit and move.
  • Feeding therapy: Specialists ensure that the patient receives enough nutrition, monitors weight gain and reduces the risk of choking or aspiration.
  • A gastrostomy tube (also known as a G-tube) is often used to ensure the person receives enough nutrition and hydration if swallowing becomes difficult. This can help prevent serious issues like aspiration (inhaling food or liquids into the lungs) which can lead to infections like pneumonia.
  • Occupational therapy: This therapy focuses on helping individuals with everyday tasks and improving their seating posture and movement abilities.
  • Education and special programs: Special education programs are available to support learning and developmental needs. Interventions may be designed to help with communication and cognitive development.
  • Genetic Counseling: Families may benefit from genetic counseling to better understand the condition, assess the risk of passing the disease to future children, and explore carrier testing.

Regular follow-up visits with the healthcare team are essential to monitor the person’s health and adjust treatments as needed. These visits often include evaluations of:

  • Growth and nutrition: Ensuring the affected child is growing properly and getting the nutrition they need.
  • Respiratory health: Checking lung function and ensuring there are no breathing issues.
  • Seizure control: Making sure seizures are under control with medication.
  • Developmental progress: Assessing how the child is developing, especially in terms of mobility, communication and self-help skills.
  • Mobility and contracture prevention: Watching for any issues with movement or joint stiffness (contractures).
  • Social services: The healthcare team may also connect families with services such as palliative care (focused on comfort) or respite care (temporary relief for caregivers).

News related to Canavan disease treatment and other aspects of care can be seen at the Canavan Foundation website: https://www.canavanfoundation.org/news

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
van Passel-Clark L, Pearl PL. Leukodystrophy (Canavan Disease). NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 550-1.

JOURNAL ARTICLES
Janson CG, McPhee SW, Francis J, et al., Natural history of Canavan disease revealed by proton magnetic resonance spectroscopy (1H-MRS) and diffusion-weighted MRI. Neuropediatrics. 2006;37:209-21.

Surendran S, Michals-Matalon K, Quast MJ, et al. Canavan disease: a monogenic trait with complex genomic interaction. Mol Genet Metab. 2003;80:74-80.

Olsen TR, Tranebjaerg L, Kvittingen EA, et al., Two novel aspartoacylase gene (ASPA) missense mutations specific to Norwegian and Swedish patients with Canavan disease. J Med Genet. 2002;39:55-8.

Janson C, McPhee S, Bilaniuk L, et al. Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther. 2002;20:1391-412.

Matalon R, Matalon KM. Canavan disease prenatal diagnosis and genetic counseling. Obstet Gynecol Clin North Am. 2002:29:297-304.

Sugarman EA Allitto BA. Carrier testing for seven diseases common in the ashkenazi jewish population: implications for counseling and testing. Obstet Gynecol. 2001;97:S38-S39.

Gordon N. Canavan disease:a review of recent developments Eur J Paediatr Neurol. 2001;5:65-69.

Leone P, Janson CG, Bilaniuk L, et al. Aspartoacyclase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol. 2000;48-9-10.

Traeger EC, Rapin I. The clinical course of Canavan disease. Pediatr Neurol. 1998;18:207-12.

Matalon R. Canavan disease: diagnosis and molecular analysis. Genet Test. 1997;1:21-25.

Kaul R, Gao GP, Balamurugan K, et al. Spectrum of Canavan mutations among Jewish and non-Jewish patients. Am J Hum Genet. 1994;55:A212.

INTERNET
Nagy A, Bley AE, Eichler F. Canavan Disease. 1999 Sep 16 [Updated 2023 Dec 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1234/ Accessed Sept 23, 2024.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Canavan Disease. Entry No: 271900. Last Edit Date: 04/04/2024. Available at: https://omim.org/entry/271900 Accessed Sept 23, 2024.

Bokhari MR, Samanta D, Bokhari SRA. Canavan Disease. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430816/ Accessed Sept 23, 2024.

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Programs & Resources

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RareCare® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Patient Organizations


More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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