Introduction

Canavan disease is one of the most common disorders affecting the nervous system in infants and children. It is characterised by defects in development, as well as an abnormal head size and muscle tone.¹ 73% of those affected with Canavan disease live until 10 years of age, with a low number of individuals reaching adulthood.^1,2 Canavan disease has a known genetic basis and most of the affected individuals come from the Ashkenazi Jewish descent.¹

Canavan disease is a neurodevelopmental disorder that belongs to a group of disorders called leukodystrophies.¹ This refers to a genetic condition where the white matter in the brain is affected.³ This includes the myelin sheath of neurons, which is the insulative layer surrounding the axons of neurons. This means that signaling, or communication, between neurons is interrupted.³ 

Canavan disease is categorised into two types: Infantile onset (typical) and Juvenile onset (atypical). This is because life expectancy of people with Canavan disease is around 10 years.¹

This article aims to cover the two different forms of Canavan disease in terms of their frequency, clinical onset, along with underlying causes and diagnosis. The available treatments will also be addressed. 

Key points:

• Canavan disease is a rare genetic leukodystrophy that affects the white matter of the brain and causes delays in the development of the nervous system
• It is caused by a deficiency of the aspartoacylase enzyme
• Infantile onset is more common and severe, with symptoms beginning in very early infancy
• Juvenile onset is more rare and has milder symptoms that begin during the first few years of life

What causes Canavan disease?

Canavan disease is caused by the lack of aspartoacylase, an enzyme necessary for the proper functioning of the nervous system. Its absence results in the decrease of white matter in the brain, causing problems with signaling between neurons.¹ This is due to the presence of a mutation in the gene encoding for aspartoacylase (i.e. ASPA gene), leading to the complete loss or reduced levels of this enzyme in the brain.¹ Aspartoacylase has the role of breaking down N-acetylaspartic acid (NAA) in the brain.⁴ The loss of aspartoacylase function interferes with the production of myelin in the brain, a component of the neuronal axon necessary for fast and efficient nerve conduction. These defects with neuronal signaling result in developmental delays and regressions observed in Canavan disease, leading to defects in motor and brain function as seen in babies and children.^1,4

Infantile onset Canavan disease

Infantile onset, also known as typical Canavan disease, is seen in around 90% of cases and is the more severe type.¹ Its presence can be seen in babies that are between 3 to 5 months old, where the development of the nervous system starts showing impairments along with regression and degeneration. Early symptoms include hypotonia, defined as the inability to support the head, along with an unusual head size. Later on, problems with normal development start becoming visible, where basic activities like walking and speaking become impaired.¹ During the first years of life, seizures can be seen in around 50% of the cases. seizures may increase over time and can be difficult to treat with medication.^1,4 Difficulties in feeding, swallowing, seeing and visually tracking objects can also present major issues.^1,4 In most cases, the first symptoms are seen between 2 to 4 months of age.² The affected children stop developing when they are around three to six months old. The enlargement of the head usually starts at the seventh to eighth month and stops growth by 18 months of age.²

Juvenile onset Canavan disease

Juvenile onset, also known as atypical Canavan disease, is seen in around 10% of cases and follows a more variable path.¹ Neurodevelopmental issues present during the first years of life, and developmental regression can be observed throughout childhood and teenage years. 

Symptoms may include speech, vision and movement impairments due to defects during development; however, the progression of these defects is slower than seen with infantile onset.¹ Juvenile onset has also been suggested to occur after five years of age. Due to the nonspecific symptoms, developmental delays (e.g., problems with motor and speaking abilities) can go unnoticed. The frequency of seizures increases with age, and almost all patients experience seizures by the age of 10.² In adults, the symptoms of this disease is similar to those seen with multiple sclerosis.⁴

Therapeutic approaches 

Currently, there is no available therapy that can cure or cease the progression of Canavan disease. The therapeutic approaches aim to minimise seizures as well as to sustain the feeding and nutrition of patients with Canavan disease.⁴ It has been suggested that intervening within the first year of life, before the patient is 12 months of age, may be the most effective strategy in slowing the progression of the disease.⁵ Current therapeutic approaches may include:^4,6

• Anti-epileptic drugs for controlling the onset of seizures
• Physical therapy for improving posture and minimising injuries
• Inserting a gastrostomy tube for feeding and hydration
• Prescribing dietary supplements (i.e. lithium citrate, acetate, glyceryl triacetate, or triheptanoin), which can decrease NAA levels in the brain and boost motor activity

Summary

Canavan disease is a rare genetic disorder that causes damage to the white matter of the brain due to mutations in the gene coding for the aspartoacylase enzyme. It can be present as the infantile onset form, which is more severe with rapid progression, and the juvenile onset form, which is milder with slower progression. Diagnostic tests for Canavan disease may show differences for the two forms, and involve checking for certain clinical signs such as difficulties in feeding, defects in motor skills, and high NAA levels in the urine and brain. Currently, therapeutic interventions aim to treat symptoms and are unable to cure the disease.