Canavan disease

Canavan disease typically presents with developmental delay, macrocephaly and seizures. It has the highest prevalence in Ashkenazi Jewish populations.

Canavan disease can occur in infancy (infantile type) or early childhood (juvenile type). The more common infantile type is more severe; most affected individuals do not survive into adolescence. The less common and milder juvenile type causes motor and speech delay; individuals appear to have a normal life expectancy. Clinical features of each type are listed below.

Infantile (onset around 3–5 months)

• Hypotonia and head lag.
• Developmental delay and regression of skills.
• Feeding difficulties.
• Macrocephaly (from around six months).
• Progressive visual impairment.
• Seizures
• Irritability and sleep disturbance.
• Increasing spasticity (presentation is similar to cerebral palsy).
• Life limiting, with most not surviving childhood.

Juvenile

• Mild speech and/or motor delay.
• No regression and normocephalic.
• Retinitis pigmentosa and seizures (though this is rare).
• Usually normal life expectancy.

Canavan disease occurs due to pathogenic variants in both copies of the aspartoacylase (ASPA) gene, located on the short arm of chromosome 17. The gene encodes aspartoacylase, an enzyme which metabolises N-acetylaspartic acid (NAA).

Pathogenic variants in ASPA that severely impair the enzyme’s function cause the (more severe) infantile form of Canavan disease due to the build of of high levels of NAA in the brain. Pathogenic variants in ASPA that only slightly reduce the enzyme’s function cause the milder juvenile form of the disease.

Canavan disease is most common in people with Ashkenazi Jewish ancestry. Two founder variants account for 98% of cases in Ashkenazi Jewish populations.

Canavan disease can be diagnosed through a combination of clinical findings, biochemical testing (NAA levels in blood or urine) and genomic testing.

For information about genomic testing, see: Presentation: Child with macrocephaly or Presentation: Child with developmental delay or intellectual disability.

Canavan disease is an autosomal recessive condition.

If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:

• 1 in 4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
• 1 in 2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
• 1 in 4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.

The parents of individuals affected with Canavan disease are likely to be carriers of the condition and therefore have a 25% (one-in-four) chance of having another affected child. Genomic counselling is particularly important so that any future pregnancies can be managed appropriately. Options include preimplantation genomic testing for monogenic conditions (PGT-M) and prenatal testing. For more information, see Pregnancy at risk of an autosomal recessive condition.

The carrier frequency for Canavan disease in the Ashkenazi Jewish population is over 1 in 40. For this reason, where one partner is either affected with or a known carrier of the disorder, the couple may be eligible for: R246 Carrier testing at population risk for partners of known carriers of nationally agreed autosomal recessive disorders.

Management of children with Canavan disease is complex and should be delivered via a multidisciplinary team, with detailed suggested approaches published by several authors (see our resources list).

Experimental research into developing gene therapy is ongoing.

For clinicians

• Alex, the Leukodystrophy Charity (Alex TLC): What is leukodystrophy?
• Alex TLC: A-Z of leukodystrophy
• GeneReviews: Canavan disease
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Institute of Neurological Disorders and Stroke: Canavan disease
• NHS England: National Genomic Test Directory
• OMIM: 271900 Canavan disease
• US National Library of Medicine: ClinicalTrials.gov (database)

References:

• Bley A, Denecke J, Kohlschütter A and others. ‘The natural history of Canavan disease: 23 new cases and comparison with patients from literature’. Orphanet Journal of Rare Diseases 2021: volume 16, issue 1, article number 227. DOI: 10.1186/s13023-020-01659-3

For patients

• Alex, the Leukodystrophy Charity (Alex TLC)
• Alex TLC: What is leukodystrophy?
• Canavan Foundation: Resources and support