The packet lists ASPA, on chromosome 17, as the associated gene, with ClinGen gene-disease validity rated definitive. Inheritance is autosomal recessive.

Per GeneReviews, parents of an affected child are presumed to be heterozygous for an ASPA pathogenic variant, and carriers are described as asymptomatic. When both parents are known carriers, each sibling 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. When a variant is found in only one parent, GeneReviews describes de novo or parental mosaic variants, or uniparental isodisomy, as possibilities.

GeneReviews describes genotype-phenotype correlations tied to residual aspartoacylase activity. The two common ASPA variants in the Ashkenazi Jewish population cause complete loss of activity and are associated with typical disease. A common variant in non-Ashkenazi European individuals has very low activity and has been found in typical and atypical disease. Variants with higher residual activity are associated with atypical disease.

GeneReviews states that no consensus clinical diagnostic criteria have been published. Suggestive findings for typical disease include hypotonia, head lag, and macrocephaly after age three to five months, poor visual tracking, nystagmus, feeding difficulty, seizures, and developmental delay with regression. For atypical disease they include developmental delay in the first years of life, nystagmus or vision impairment, and ataxia.

Brain CT or MRI in early infancy may be interpreted as normal; later changes are described as diffuse leukodystrophy with involvement of the globus pallidus and sparing of the caudate nucleus and putamen. Magnetic resonance spectroscopy detecting N-acetylaspartic acid is reported as a diagnostic method in infants. GeneReviews states the diagnosis is established by biochemical testing (elevated N-acetylaspartic acid in urine or brain) or by molecular genetic testing showing biallelic pathogenic or likely pathogenic ASPA variants, and that both are frequently performed. Absence of a known family history is noted not to preclude the diagnosis.

The GeneReviews differential diagnosis lists other infant neurodegenerative disorders, including nonketotic hyperglycinemia, megalencephalic leukoencephalopathy with subcortical cysts, metachromatic leukodystrophy, Krabbe disease, Alexander disease, and Leigh syndrome.

The packet lists no FDA-approved therapies for Canavan disease, and GeneReviews states that there is no cure and that no clinical practice guidelines have been published; its management content is based on the authors' personal experience. Two orphan drug designations are listed: an oligodendrocyte-targeted AAV gene therapy (rAAV-Olig001-ASPA, Myrtelle, Inc.) and a self-complementary AAV9 vector expressing human aspartoacylase (Aspa Therapeutics, Inc.). Designation is not approval.

Supportive care. GeneReviews describes supportive treatment directed at nutrition and hydration, infection risk, and airway protection. By manifestation, it describes Botox injections for spasticity; anti-seizure medications under an experienced neurologist, noting none has been demonstrated specifically effective for this disorder; physical and occupational therapy with durable medical equipment; and feeding therapy, with gastrostomy tube placement described as sometimes required. For developmental delay it describes early intervention programs (ages 0-3) and individualized education plans (ages 3-5) in the United States, along with social work, respite, palliative care, and home nursing involvement.

Surveillance. GeneReviews lists ongoing assessments to follow existing manifestations and detect new ones: growth and nutrition every 3-6 months, seizure review every 3-6 months depending on control, developmental progress every 6 months, musculoskeletal assessment every 3-6 months, ophthalmology examination per the treating ophthalmologist, and family support needs at each visit. The evaluations described span neurology, orthopedics and rehabilitation, ophthalmology, gastroenterology and nutrition, and genetics.

Investigational. GeneReviews describes two early-phase gene therapy trials, BBP-812, an AAV9-based therapy (NCT04998396), and rAAV-Olig001-ASPA (NCT04833907), reporting preliminary reductions in N-acetylaspartic acid levels and improved myelination on MRI, with early positive trends in functional outcomes.

GeneReviews states that individuals with Canavan disease have a reduced life expectancy; in one reported cohort including typical and atypical disease, 73% survived to age ten years and a minority lived to adulthood. For typical disease, it states that most children die in the first two decades of life, with survival longer than previously reported and likely related to improved medical and nursing care. Atypical disease is described as having a more variable course. These figures come from published cohorts and do not describe any individual.

The packet lists active ClinicalTrials.gov records: NCT04998396, a phase 1 study of AAV9 gene therapy in participants with Canavan disease (CANaspire; Aspa Therapeutics; recruiting; 2021-09-08 to 2032-10-08); NCT03047369, the Myelin Disorders Biorepository Project (Children's Hospital of Philadelphia; recruiting; 2016-12-08 to 2030-12-08); and NCT03655223, Early Check expanded newborn screening (RTI International; active, not recruiting; 2018-10-15 to 2026-12-31). GeneReviews also describes the rAAV-Olig001-ASPA trial (NCT04833907) as active but not recruiting. Further studies are searchable on ClinicalTrials.gov.