Latest Estimates of Incidence and Prevalence of Canavan Disease Globally

Prevalence in Jewish Populations

The most recent data from a 2022 study indicates that Canavan disease affects one in 6,400 to 13,500 people in the Jewish population. This disease has a higher prevalence among children of Jewish extraction, particularly those of Ashkenazi Jewish descent.

In the Ashkenazi Jewish population, the carrier frequency among healthy Jews is 1:37-58. Three specific mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin, with the glu285→ala mutation being predominant (82.9%). This high prevalence makes the Ashkenazi Jewish population at increased risk for Canavan disease, alongside several other recessively inherited disorders.

A study of 5,685 Ashkenazi Jewish exomes documented that Canavan disease (ASPA, p.Glu285Ala) shows 12-fold enrichment in Ashkenazi Jewish populations compared to non-AJ populations.

Prevalence in Other Populations

While Canavan disease is most commonly associated with Ashkenazi Jewish descent, it has been diagnosed in many diverse ethnic groups. The disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA).

In India, a 2022 study reported 12 children diagnosed with Canavan disease, with 83.3% (10 children) born out of consanguineous parentage, suggesting potential higher risk in populations with consanguineous marriages. However, the prevalence and presentation of the disease in India and many other regions is largely unknown.

In Saudi Arabia, researchers have identified one novel and one known large deletion and two previously known mutations (IVS4 + 1G>T and G27R) associated with Canavan disease.

Genetic Variations

The genetic profile of Canavan disease varies significantly between Jewish and non-Jewish populations. Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In a study of 22 unrelated non-Jewish patients with Canavan disease, 24 different mutations were found, of which 14 were novel.

Global Prevalence

Recent advances in understanding the biochemical defect have led to increased awareness and diagnosis, revealing that the disease is not as rare as initially thought. However, the global prevalence outside specific ethnic groups remains poorly documented in the available literature.

It's worth noting that Canavan disease occurs more frequently outside Ashkenazi Jewish communities than previously reported, though specific global incidence rates beyond the Jewish population statistics are not well established.

Recent Studies for Canavan Disease

2024 LC-MS/MS Screening Test Study

Intervention: Development of a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots. Efficacy Outcomes: Successfully distinguished Canavan patients from controls with clear separation - patients showed levels of 5.7; 1.6-13.6 μmol/L compared to controls at 0.44; 0.24-0.99 μmol/L. The test meets general requirements of newborn screening and can be multiplexed with other screening approaches.

2023 Dual-Function Vector Combination Therapy

Intervention: Gene therapy combining ASPA gene replacement with lowering NAT8L expression using intracranial adeno-associated virus-mediated gene delivery. Efficacy Outcomes: Demonstrated significant knockdown of neuronal Nat8l paired with robust ectopic aspartoacylase expression. Treatment decreased brain vacuoles and reversed pathological hallmarks including loss of body weight, locomotor impairments, elevated N-acetyl-L-aspartate levels, astrogliosis, and demyelination. Shows potential to permanently alleviate Canavan disease symptoms and expand the therapeutic window for adult subjects.

Open-Label Expanded-Access Trial

Intervention: Simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA with prophylactic immunomodulation. Safety Outcomes: Immunomodulation successfully prevented anti-transgene immune response and enabled repeat dosing. Efficacy Outcomes: Two years post-treatment, the patient showed increased white matter myelination, improved motor function, and remained free of typical severe epilepsy. N-acetylaspartate (NAA) level was reduced at 3 months and remained stable up to 4 years post-treatment.

2015 Dietary Intervention Study

Intervention: Triheptanoin dietary treatment in the nur7 mouse model. Efficacy Outcomes: Treatment reduced oxidative stress, promoted long-term oligodendrocyte survival, increased myelin in the brain, achieved highly significant reduction in spongiform degeneration, and improved motor function. Results indicated a window of therapeutic intervention that corresponds with developmental myelination.

2014 Intravenous rAAV Gene Therapy Study

Intervention: Single intravenous (IV) injections of primate-derived recombinant adeno-associated viruses (rAAVs) with microRNA (miRNA)-mediated post-transcriptional detargeting. Efficacy Outcomes: Treatment completely rescued early lethality in mice when administered as late as postnatal day 20. Extended survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years. Treatment globally improved CNS myelination, although some abnormalities persisted.

2011 Enzyme Replacement Therapy Study

Intervention: PEGylated aspartoacylase enzyme replacement therapy. Efficacy Outcomes: Demonstrated statistically significant increases in brain enzyme activity levels in a mouse model and decreases in elevated substrate levels that mimic those found in Canavan disease patients. The modified enzyme gained access to the brain and functioned to correct the metabolic defect.