Canavan Disease
Canavan disease is a rare inherited neurological disorder belonging to the leukodystrophies, characterized by the breakdown of protective myelin sheaths in the brain and resulting in severe developmental impairments.
Overview
Canavan disease is a rare inherited condition that damages the ability of nerve cells in the brain to send and receive messages. It is classified as one of a group of genetic disorders known as leukodystrophies. These conditions disrupt the growth or maintenance of the myelin sheath, which serves as the protective covering for nerves and facilitates the efficient transmission of nerve impulses.
Forms and Symptoms
The condition presents in two primary forms, differing significantly in severity and progression:
Neonatal/Infantile Canavan Disease
This is the most common and severe form of the disorder. While affected infants appear normal during their first few months, developmental delays become apparent between 3 and 5 months of age. Typical characteristics include:
- Failure to develop motor skills, including rolling over, head control, and sitting without support
- Weak muscle tone (hypotonia)
- An unusually large head size
- Persistent irritability
- Feeding and swallowing difficulties
- Seizures
- Sleep disturbances
Most individuals with this severe infantile form survive only into childhood, though some may live into adolescence or beyond.
Mild/Juvenile Canavan Disease
The mild or juvenile form is much less common. Characteristics include:
- Mildly delayed development of speech and motor skills emerging in childhood
- Subtle and nonspecific delays that may not be recognized as signs of the condition
Individuals affected by the mild form generally do not experience a shortened lifespan.
Causes
Canavan disease is caused by mutations in the ASPA gene, which provides instructions for producing an enzyme called aspartoacylase. This enzyme is responsible for breaking down N-acetyl-L-aspartic acid (NAA), a compound concentrated in brain neurons.
When mutations impair aspartoacylase activity, NAA is not properly processed:
- Severe mutations drastically reduce enzyme function, causing rapid and extensive accumulation of NAA in the brain, characteristic of the neonatal/infantile form.
- Milder mutations allow partial enzyme function, resulting in less accumulation and a milder clinical course.
Excessive accumulation of NAA alters brain chemistry, disrupting the formation of new myelin sheaths during nervous system development and causing progressive destruction of existing myelin. Consequently, unprotected nerves malfunction, severely disrupting brain function.
Inheritance
Canavan disease is inherited in an autosomal recessive pattern. This means an affected individual must inherit two mutated copies of the ASPA gene, one from each parent. Parents typically carry one copy of the mutated gene and do not exhibit symptoms of the disorder.
Frequency
Canavan disease affects individuals of all ethnic backgrounds but occurs most frequently among people of Ashkenazi Jewish heritage, where it is estimated to affect 1 in 6,400 to 13,500 individuals. Its incidence in other populations remains unknown.
Other Names
- ACY2 deficiency
- Aminoacylase 2 deficiency
- Aspa deficiency
- Aspartoacylase deficiency
- Canavan's disease