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Canavan Disease

Updated : May 14, 2024





Background

Canavan disease is a rare genetic disorder that affects the central nervous system, particularly the white matter of the brain. It is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown and metabolism of a substance called N-acetyl-L-aspartic acid (NAA).

Without enough aspartoacylase, NAA accumulates in the brain, leading to the destruction of the myelin sheath that surrounds and protects nerve cells. Canavan disease is an autosomal recessive disorder, which means that a child must inherit two copies of the mutated gene (one from each parent) to develop the disease.

It is more common in certain ethnic groups, particularly Ashkenazi Jews, but can occur in any population. Symptoms typically appear in the first few months of life and can include developmental delays, hypotonia (poor muscle tone), feeding difficulties, seizures, and vision and hearing impairment. There is currently no cure for Canavan disease, and treatment is supportive and focused on managing symptoms.

Epidemiology

Canavan disease is a rare disorder, with an estimated incidence of 1 in 40,000 to 60,000 live births. The disorder is more common in certain populations, particularly in individuals of Ashkenazi Jewish descent, where the carrier frequency is estimated to be 1 in 40.

The Canavan disease occurs with equal frequency in males and females and is found in all ethnic and racial groups. However, its prevalence varies among different populations due to genetic and environmental factors.

Anatomy

Pathophysiology

Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown and metabolism of a substance called N-acetyl-L-aspartic acid (NAA). Without enough aspartoacylase, NAA accumulates in the brain, leading to the destruction of the myelin sheath that surrounds and protects nerve cells. Myelin is a fatty substance that insulates nerve fibers and facilitates the rapid transmission of nerve impulses.

In individuals with Canavan disease, the lack of myelin disrupts communication between nerve cells, leading to the symptoms of the disorder. The destruction of myelin is most pronounced in the white matter of the brain, which is responsible for transmitting signals between different areas of the brain and the rest of the body. The loss of myelin in this area of the brain leads to a decrease in the volume of white matter and an increase in the amount of fluid in the brain (hydrocephalus).

The accumulation of fluid can lead to an increase in intracranial pressure, which can cause symptoms such as headaches, vomiting, and irritability. The exact mechanisms by which the accumulation of NAA leads to the destruction of myelin in Canavan disease are not fully understood. However, it is thought that the accumulation of NAA disrupts the normal functioning of oligodendrocytes, the cells that produce myelin in the brain. The oligodendrocytes are unable to properly synthesize and maintain myelin in the presence of high levels of NAA, leading to its breakdown and the characteristic symptoms of Canavan disease.

Etiology

Canavan disease is caused by mutations in the ASPA gene, which provides instructions for making the enzyme aspartoacylase. The mutations that cause Canavan disease are autosomal recessive, which means that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder.

The ASPA gene is located on chromosome 17, and over 70 different mutations in this gene have been identified that can cause Canavan disease. The most common mutation is a deletion of a single nucleotide (a building block of DNA) in the ASPA gene, which results in the production of a nonfunctional version of the aspartoacylase enzyme.

This enzyme is essential for the breakdown of a substance called N-acetyl-L-aspartic acid (NAA), and the accumulation of NAA in the brain is believed to be responsible for the symptoms of Canavan disease. Other mutations in the ASPA gene can also lead to the production of a nonfunctional enzyme or decreased levels of enzyme activity, resulting in a similar accumulation of NAA in the brain.

Genetics

Prognostic Factors

The prognosis for individuals with Canavan disease is variable and depends on the severity of the condition. Most infants with the classic form of Canavan disease do not survive beyond childhood, while individuals with the milder form of the disease may have a longer life expectancy.

Some factors that can affect the prognosis include:

  • Age of onset: Infants with early-onset Canavan disease typically have a more severe form of the condition and a poorer prognosis.
  • Disease severity: The severity of the symptoms can vary widely among individuals with Canavan disease, with some having a more rapidly progressive course than others.
  • Genetics: The specific mutations in the ASPA gene can also affect the severity of the disease and the prognosis.
  • Treatment: Early diagnosis and management of symptoms can improve the quality of life and extend survival.

Unfortunately, there is no cure for Canavan disease, and the condition can be fatal. However, supportive care and symptom management can improve the quality of life for affected individuals and their families. Genetic counseling and prenatal testing may be recommended for families with a history of Canavan disease to help them make informed decisions about family planning.

Clinical History

Clinical history

Canavan disease is typically diagnosed in infants or young children, usually by the age of 6 months. The following are some of the clinical features that may be present in individuals with Canavan disease:

  • Delayed development: Affected infants may not be able to lift their heads, sit up, or crawl at the expected ages. Developmental milestones are often delayed.
  • Hypotonia: Infants with Canavan disease may have poor muscle tone and may feel floppy or limp when held.
  • Seizures: Seizures may occur in some individuals with Canavan disease.
  • Macrocephaly: The head size may be larger than normal, which is known as microcephaly.
  • Feeding difficulties: Infants with Canavan disease may have difficulty feeding, which can lead to poor weight gain.
  • Irritability: Infants may be irritable, and crying may be prolonged.
  • Vision and hearing problems: Some individuals with Canavan disease may have a vision or hearing problems.
  • Sleep disturbances: Some individuals may have trouble sleeping or may sleep excessively.
  • Respiratory problems: Some individuals with Canavan disease may have difficulty breathing, which can lead to respiratory infections.

It is important to note that the severity of symptoms can vary widely among individuals with Canavan disease, and some individuals may have only mild symptoms.

Physical Examination

Physical examination

Physical examination of individuals with Canavan disease may reveal the following:

  • Macrocephaly: The head circumference may be larger than expected for the age and sex of the individual.
  • Hypotonia: Infants may have poor muscle tone and may feel floppy or limp when held.
  • Absent or weak reflexes: The deep tendon reflexes may be absent or weak.
  • Developmental delay: Infants may not be able to lift their heads, sit up, or crawl at the expected ages.
  • Seizures: Some individuals with Canavan disease may have seizures.
  • Vision and hearing problems: Individuals may have a vision or hearing problems.
  • Respiratory problems: Some individuals with Canavan disease may have difficulty breathing, which can lead to respiratory infections.

It is important to note that the physical examination findings can be variable and may not be present in all individuals with Canavan disease. Additionally, the findings may overlap with those of other conditions, so a definitive diagnosis typically requires additional testing, such as genetic testing or imaging studies.

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Differential diagnosis

The symptoms of Canavan disease can overlap with those of other conditions, so a proper diagnosis is important.

Differential diagnoses may include:

  • Leukodystrophies: There are various types of leukodystrophies, and some of them can present with symptoms similar to Canavan disease. These conditions involve the destruction of the white matter of the brain. Some examples include metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy.
  • Cerebral palsy: This is a group of motor disorders that occur due to damage to the brain during development. Some of the symptoms of cerebral palsies, such as spasticity and delayed development, can resemble those of Canavan disease.
  • Hydrocephalus: This is a condition characterized by the buildup of fluid in the brain. Hydrocephalus can cause symptoms such as headaches, vomiting, and irritability, which can also occur in Canavan disease.
  • Alexander disease: This is a rare genetic disorder that affects the white matter of the brain. Some of the symptoms of Alexander’s disease can overlap with those of Canavan disease, such as developmental delay and seizures.
  • Mitochondrial disorders: These are a group of genetic disorders that affect the way energy is produced in cells. Some mitochondrial disorders can present with symptoms similar to Canavan diseases, such as developmental delay and seizures.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Currently, there is no cure for Canavan disease, and treatment is mainly supportive and focused on managing the symptoms.

Some of the interventions that may be recommended for individuals with Canavan disease include:

  • Symptomatic treatment: Medications may be prescribed to manage symptoms such as seizures, muscle spasms, or sleep disturbances.
  • Physical therapy: Physical therapy may be recommended to help improve muscle strength and mobility.
  • Nutritional support: Infants with feeding difficulties may require nutritional support, such as a feeding tube or specialized formula.
  • Respiratory support: Some individuals with Canavan disease may require respiratory support, such as oxygen therapy or assisted ventilation.
  • Palliative care: For individuals with severe symptoms, palliative care may be recommended to help manage pain and improve quality of life.
  • Gene therapy: Researchers are currently exploring gene therapy as a potential treatment for Canavan disease. Gene therapy involves introducing a healthy copy of the ASPA gene into the body to replace the defective gene responsible for the condition. However, this treatment is still in the experimental stages and is not yet widely available.

It is important to note that the management of Canavan disease is often complex and requires a multidisciplinary team approach involving various healthcare professionals, including neurologists, genetic counselors, nutritionists, and palliative care specialists.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

Media Gallary

References

https://www.ncbi.nlm.nih.gov/books/NBK430816/

Canavan Disease

Updated : May 14, 2024




Canavan disease is a rare genetic disorder that affects the central nervous system, particularly the white matter of the brain. It is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown and metabolism of a substance called N-acetyl-L-aspartic acid (NAA).

Without enough aspartoacylase, NAA accumulates in the brain, leading to the destruction of the myelin sheath that surrounds and protects nerve cells. Canavan disease is an autosomal recessive disorder, which means that a child must inherit two copies of the mutated gene (one from each parent) to develop the disease.

It is more common in certain ethnic groups, particularly Ashkenazi Jews, but can occur in any population. Symptoms typically appear in the first few months of life and can include developmental delays, hypotonia (poor muscle tone), feeding difficulties, seizures, and vision and hearing impairment. There is currently no cure for Canavan disease, and treatment is supportive and focused on managing symptoms.

Canavan disease is a rare disorder, with an estimated incidence of 1 in 40,000 to 60,000 live births. The disorder is more common in certain populations, particularly in individuals of Ashkenazi Jewish descent, where the carrier frequency is estimated to be 1 in 40.

The Canavan disease occurs with equal frequency in males and females and is found in all ethnic and racial groups. However, its prevalence varies among different populations due to genetic and environmental factors.

Canavan disease is caused by a deficiency of the enzyme aspartoacylase, which is necessary for the breakdown and metabolism of a substance called N-acetyl-L-aspartic acid (NAA). Without enough aspartoacylase, NAA accumulates in the brain, leading to the destruction of the myelin sheath that surrounds and protects nerve cells. Myelin is a fatty substance that insulates nerve fibers and facilitates the rapid transmission of nerve impulses.

In individuals with Canavan disease, the lack of myelin disrupts communication between nerve cells, leading to the symptoms of the disorder. The destruction of myelin is most pronounced in the white matter of the brain, which is responsible for transmitting signals between different areas of the brain and the rest of the body. The loss of myelin in this area of the brain leads to a decrease in the volume of white matter and an increase in the amount of fluid in the brain (hydrocephalus).

The accumulation of fluid can lead to an increase in intracranial pressure, which can cause symptoms such as headaches, vomiting, and irritability. The exact mechanisms by which the accumulation of NAA leads to the destruction of myelin in Canavan disease are not fully understood. However, it is thought that the accumulation of NAA disrupts the normal functioning of oligodendrocytes, the cells that produce myelin in the brain. The oligodendrocytes are unable to properly synthesize and maintain myelin in the presence of high levels of NAA, leading to its breakdown and the characteristic symptoms of Canavan disease.

Canavan disease is caused by mutations in the ASPA gene, which provides instructions for making the enzyme aspartoacylase. The mutations that cause Canavan disease are autosomal recessive, which means that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder.

The ASPA gene is located on chromosome 17, and over 70 different mutations in this gene have been identified that can cause Canavan disease. The most common mutation is a deletion of a single nucleotide (a building block of DNA) in the ASPA gene, which results in the production of a nonfunctional version of the aspartoacylase enzyme.

This enzyme is essential for the breakdown of a substance called N-acetyl-L-aspartic acid (NAA), and the accumulation of NAA in the brain is believed to be responsible for the symptoms of Canavan disease. Other mutations in the ASPA gene can also lead to the production of a nonfunctional enzyme or decreased levels of enzyme activity, resulting in a similar accumulation of NAA in the brain.

The prognosis for individuals with Canavan disease is variable and depends on the severity of the condition. Most infants with the classic form of Canavan disease do not survive beyond childhood, while individuals with the milder form of the disease may have a longer life expectancy.

Some factors that can affect the prognosis include:

  • Age of onset: Infants with early-onset Canavan disease typically have a more severe form of the condition and a poorer prognosis.
  • Disease severity: The severity of the symptoms can vary widely among individuals with Canavan disease, with some having a more rapidly progressive course than others.
  • Genetics: The specific mutations in the ASPA gene can also affect the severity of the disease and the prognosis.
  • Treatment: Early diagnosis and management of symptoms can improve the quality of life and extend survival.

Unfortunately, there is no cure for Canavan disease, and the condition can be fatal. However, supportive care and symptom management can improve the quality of life for affected individuals and their families. Genetic counseling and prenatal testing may be recommended for families with a history of Canavan disease to help them make informed decisions about family planning.

Clinical history

Canavan disease is typically diagnosed in infants or young children, usually by the age of 6 months. The following are some of the clinical features that may be present in individuals with Canavan disease:

  • Delayed development: Affected infants may not be able to lift their heads, sit up, or crawl at the expected ages. Developmental milestones are often delayed.
  • Hypotonia: Infants with Canavan disease may have poor muscle tone and may feel floppy or limp when held.
  • Seizures: Seizures may occur in some individuals with Canavan disease.
  • Macrocephaly: The head size may be larger than normal, which is known as microcephaly.
  • Feeding difficulties: Infants with Canavan disease may have difficulty feeding, which can lead to poor weight gain.
  • Irritability: Infants may be irritable, and crying may be prolonged.
  • Vision and hearing problems: Some individuals with Canavan disease may have a vision or hearing problems.
  • Sleep disturbances: Some individuals may have trouble sleeping or may sleep excessively.
  • Respiratory problems: Some individuals with Canavan disease may have difficulty breathing, which can lead to respiratory infections.

It is important to note that the severity of symptoms can vary widely among individuals with Canavan disease, and some individuals may have only mild symptoms.

Physical examination

Physical examination of individuals with Canavan disease may reveal the following:

  • Macrocephaly: The head circumference may be larger than expected for the age and sex of the individual.
  • Hypotonia: Infants may have poor muscle tone and may feel floppy or limp when held.
  • Absent or weak reflexes: The deep tendon reflexes may be absent or weak.
  • Developmental delay: Infants may not be able to lift their heads, sit up, or crawl at the expected ages.
  • Seizures: Some individuals with Canavan disease may have seizures.
  • Vision and hearing problems: Individuals may have a vision or hearing problems.
  • Respiratory problems: Some individuals with Canavan disease may have difficulty breathing, which can lead to respiratory infections.

It is important to note that the physical examination findings can be variable and may not be present in all individuals with Canavan disease. Additionally, the findings may overlap with those of other conditions, so a definitive diagnosis typically requires additional testing, such as genetic testing or imaging studies.

Differential diagnosis

The symptoms of Canavan disease can overlap with those of other conditions, so a proper diagnosis is important.

Differential diagnoses may include:

  • Leukodystrophies: There are various types of leukodystrophies, and some of them can present with symptoms similar to Canavan disease. These conditions involve the destruction of the white matter of the brain. Some examples include metachromatic leukodystrophy, Krabbe disease, and adrenoleukodystrophy.
  • Cerebral palsy: This is a group of motor disorders that occur due to damage to the brain during development. Some of the symptoms of cerebral palsies, such as spasticity and delayed development, can resemble those of Canavan disease.
  • Hydrocephalus: This is a condition characterized by the buildup of fluid in the brain. Hydrocephalus can cause symptoms such as headaches, vomiting, and irritability, which can also occur in Canavan disease.
  • Alexander disease: This is a rare genetic disorder that affects the white matter of the brain. Some of the symptoms of Alexander’s disease can overlap with those of Canavan disease, such as developmental delay and seizures.
  • Mitochondrial disorders: These are a group of genetic disorders that affect the way energy is produced in cells. Some mitochondrial disorders can present with symptoms similar to Canavan diseases, such as developmental delay and seizures.

Currently, there is no cure for Canavan disease, and treatment is mainly supportive and focused on managing the symptoms.

Some of the interventions that may be recommended for individuals with Canavan disease include:

  • Symptomatic treatment: Medications may be prescribed to manage symptoms such as seizures, muscle spasms, or sleep disturbances.
  • Physical therapy: Physical therapy may be recommended to help improve muscle strength and mobility.
  • Nutritional support: Infants with feeding difficulties may require nutritional support, such as a feeding tube or specialized formula.
  • Respiratory support: Some individuals with Canavan disease may require respiratory support, such as oxygen therapy or assisted ventilation.
  • Palliative care: For individuals with severe symptoms, palliative care may be recommended to help manage pain and improve quality of life.
  • Gene therapy: Researchers are currently exploring gene therapy as a potential treatment for Canavan disease. Gene therapy involves introducing a healthy copy of the ASPA gene into the body to replace the defective gene responsible for the condition. However, this treatment is still in the experimental stages and is not yet widely available.

It is important to note that the management of Canavan disease is often complex and requires a multidisciplinary team approach involving various healthcare professionals, including neurologists, genetic counselors, nutritionists, and palliative care specialists.

https://www.ncbi.nlm.nih.gov/books/NBK430816/