Canavan disease
General description
Canavan disease is a rare autosomal recessive leukodystrophy characterized by spongiform degeneration of the brain white matter. It is caused by mutations in the ASPA gene, encoding aspartoacylase enzyme. This enzyme normally catalyzes the hydrolysis of N-acetylaspartate (NAA) into aspartate and acetate, a critical step in brain metabolism. In Canavan disease, deficient aspartoacylase activity leads to NAA accumulation in the brain and increased excretion in urine.
The disease is inherited in an autosomal recessive pattern, requiring one defective ASPA gene copy from each parent to develop the condition. While affecting all ethnic backgrounds, Canavan disease has a higher prevalence in the Ashkenazi Jewish population.
Canavan disease is a genetic disorder with two main clinical forms that differ in severity and age of onset. The most common and severe form, known as the infantile or neonatal form, usually appears within the first few months of life. Affected infants may initially seem normal but soon develop symptoms such as poor head control, muscle weakness, enlarged head, and serious developmental delays. They often cannot reach major motor milestones like sitting or walking, and may have visual problems, feeding difficulties, seizures, and increasing muscle stiffness over time. Most children with this form experience significant intellectual disability and have a shortened lifespan, although supportive care can sometimes extend survival.
A milder, less common juvenile form appears later in childhood, typically around five years of age. In these cases, developmental delays are less severe, and children may be able to sit or walk. Symptoms can be subtle and may go unrecognized. People with this form often live into late adolescence or adulthood. The severity of the disease is linked to the amount of remaining enzyme activity, with more severe cases having very low levels and milder cases retaining more.
Magnetic resonance spectroscopy
Magnetic resonance spectroscopy (MRS) reveals specific patterns that aid in diagnosing Canavan disease. In affected brain regions, there is a notable increase in NAA peaks, along with an elevated NAA to choline ratio. Despite these changes, choline and creatinine levels generally remain within normal physiological ranges. These distinctive spectroscopic features are highly specific to Canavan disease and assist in distinguishing it from other types of leukodystrophies.
References
- Bhat, Maya Dattatraya, et al. "Cribriform appearance of white matter in Canavan disease associated with novel mutations of ASPA gene." Journal of Pediatric Genetics 11.04 (2022): 267-271.
- Rahimian, Elham, et al. "The full spectrum of MRI findings in 18 patients with Canavan disease: new insights into the areas of selective susceptibility." Neuroradiology 66.10 (2024): 1829-1835.
White matter lesion
-
CerebrumCerebral white matterSubcortical white matter
The cerebral white matter shows bilateral, symmetric, and widespread abnormalities, which appear as hyperintensities on T2-weighted images and hypointensities on T1-weighted images. These changes are especially notable in the subcortical white matter, including the U-fibers. Additionally, cystic formations may sometimes develop at the junction between gray and white matter.
Gray matter lesion
-
Globus pallidus
-
Thalamus
-
Internal capsule
-
Corpus callosum
-
Dentate nucleus
MRI typically reveals hyperintensity on T2-weighted and FLAIR images in the globus pallidus, a finding commonly seen in most cases. There is a distinctive sparing of other deep brain structures, including the putamen, caudate nucleus, and claustrum. The dentate nucleus may also be involved. The lateral thalamus is often affected, while the pulvinar region remains characteristically spared. As the disease advances, signal abnormalities may appear in the internal capsule, and involvement of the corpus callosum has also been reported in later stages.