Clinical characteristics: Canavan disease is a leukodystrophy characterized by neurodevelopmental delays, macrocephaly, and tone abnormalities. The phenotypic spectrum ranges from the more severe typical Canavan disease (85%-90% of individuals) to the less severe atypical Canavan disease (10%-15%). Typical Canavan disease is characterized by neurodevelopmental impairment evident by ages three to five months, followed by neurodegeneration and developmental regression. The clinical course of atypical Canavan disease is more variable, with neurodevelopmental delay usually becoming evident in the first years of life and frequently followed by developmental regression later in childhood or adolescence. All individuals with Canavan disease have reduced life expectancy, with the majority surviving to age ten years and the minority living to adulthood.
Diagnosis/testing: The diagnosis of Canavan disease is established in a proband with suggestive findings either by biochemical testing or by molecular genetic testing. The biochemical diagnosis is established in an individual with suggestive clinical findings and elevated N-acetylaspartic acid (NAA) in urine (using gas chromatography-mass spectrometry) or in the brain by proton magnetic resonance spectroscopy. The molecular diagnosis is established in an individual with suggestive clinical findings and biallelic ASPA pathogenic variants identified by molecular genetic testing. Frequently, both types of testing are performed; turnaround time, which varies among laboratories, should be considered when determining the order of testing.
Management: Treatment of manifestations: Multidisciplinary care by specialists in neurology (to manage spasticity and seizures if present); orthopedics, physical medicine and rehabilitation, physical therapy, and occupational therapy (to minimize contractures, optimize abilities and seating posture); feeding therapy (to assure adequate nutrition and weight gain, minimize risk of aspiration); and education (to support appropriate learning goals).
Surveillance: Regularly scheduled evaluations of growth, nutrition, and safety of oral intake; respiratory function; seizure control and neurologic findings; developmental progress and educational needs; assessment of mobility and self-help skills; and need for social services such as palliative/respite care.
Genetic counseling: Canavan disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ASPA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the ASPA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
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