Canavan disease is caused by biallelic pathogenic variants in the ASPA gene, which encodes aspartoacylase — the enzyme responsible for breaking down N-acetylaspartic acid (NAA) in the brain and nervous system. Loss of aspartoacylase activity leads to toxic accumulation of NAA in the central nervous system, progressive destruction of white matter, and the characteristic leukodystrophy. ASPA is the sole gene definitively associated with Canavan disease per ClinGen classification.

Per expert review, the severity of the phenotype correlates closely with the degree of residual aspartoacylase enzyme activity. Two common pathogenic variants in the Ashkenazi Jewish population cause complete loss of enzyme activity and are associated with typical Canavan disease. In non-Ashkenazi European populations, a separate common pathogenic variant is associated with very low aspartoacylase activity and has been identified in both typical and atypical presentations. Pathogenic variants with higher residual enzyme activity — whether in the homozygous or compound heterozygous state — are associated with atypical Canavan disease.

The condition follows autosomal recessive inheritance: an individual must inherit pathogenic ASPA variants from both parents to be affected. Carrier parents are asymptomatic and are not at risk of developing the disorder.

Per expert review, no consensus clinical diagnostic criteria for Canavan disease have been published. Diagnosis is established through a combination of clinical evaluation, biochemical testing, neuroimaging, and molecular genetic testing.

Suggestive clinical features in infancy include the triad of hypotonia, head lag, and progressive macrocephaly appearing after ages three to five months, accompanied by poor visual tracking, nystagmus, and feeding difficulties. Seizures and developmental delays that become more evident within the first months of life also raise clinical suspicion.

Neuroimaging with brain MRI typically reveals generalized leukodystrophy with diffuse, symmetric white matter changes, including involvement of the globus pallidus with relative sparing of the caudate nucleus and putamen. Brain magnetic resonance spectroscopy (MRS) detects elevated NAA levels and serves as a key diagnostic tool, even in infants with initially normal brain MRI. Biochemical confirmation of elevated NAA in urine is performed using gas chromatography-mass spectrometry (GC-MS).

Molecular genetic testing identifying biallelic pathogenic variants in ASPA confirms the diagnosis. Family history consistent with autosomal recessive inheritance supports clinical suspicion but is not required for diagnosis, as most new cases occur in families without a known history of the condition.

Canavan disease is included in expanded newborn screening research programs; inclusion in standard newborn screening panels varies by jurisdiction.

Per expert review, there is no cure for Canavan disease, and no FDA-approved disease-specific therapies are currently available. Management is supportive, with goals of maintaining adequate nutrition and hydration, managing seizures, addressing spasticity, and protecting the airway.

A multidisciplinary care team — encompassing pediatric neurology, ophthalmology, gastroenterology, physical medicine and rehabilitation, physical therapy, occupational therapy, and speech-language pathology — provides comprehensive supportive care. Anti-seizure medications are used for seizure management, though no specific anti-seizure medication has been demonstrated to be uniquely effective in Canavan disease. Spasticity may be addressed through physical therapy and, in some cases, botulinum toxin injections. Gastrostomy tube placement may be required when swallowing difficulties and aspiration risk progress. Physical and occupational therapy aim to minimize contractures and optimize motor function and activities of daily living.

Per expert review, Canavan disease is associated with a significantly reduced life expectancy. In the typical form, 73% of affected individuals survive to age ten years, as reported in a cohort encompassing both typical and atypical Canavan disease. Most children with typical disease die in the first two decades of life, though survival has improved compared to historical reports, likely reflecting advances in supportive and nursing care. Children with typical Canavan disease generally do not achieve developmental milestones beyond a six-month level and experience progressive loss of previously acquired skills over time.

The atypical form carries a more variable and generally less severe prognosis. Developmental regression in atypical Canavan disease typically occurs later — in childhood or adolescence — and the overall clinical trajectory is wider in scope.

Canavan disease is an active area of gene therapy investigation. Per expert review, early-phase clinical trials are evaluating AAV9-based gene therapy approaches aimed at restoring ASPA gene function in affected individuals. Preliminary data from ongoing studies have demonstrated sustained reductions in NAA levels in urine, cerebrospinal fluid, and brain; improved myelination on brain MRI; and early positive trends in motor outcome measures. Additional research efforts include expanded newborn screening programs to enable earlier identification of affected infants and biorepository projects to advance understanding of myelin disorders. Active clinical trials for this condition are listed on ClinicalTrials.gov.