Table of Contents
- ASPA deficiency
- aspartoacylase deficiency
- Canavan’s leukodystrophy
- Canavan-Van Bogaert-Bertrand disease
- spongy degeneration of the central nervous system
- Van Bogaert-Bertrand syndrome
- ACY2 deficiency
- Aminoacylase 2 deficiency
In vitro fertilization (IVF) and preimplantation genetic testing (PGT) are significant advancements in the realm of reproductive medicine and genetics, particularly for individuals at risk of transmitting genetic disorders like Canavan Disease. For couples with a known risk of passing on Canavan Disease to their offspring, IVF coupled with PGT offers a proactive approach. In this process, eggs are fertilized in a lab setting, and the resulting embryos are screened for the specific genetic mutations associated with Canavan Disease. This enables the selection of embryos without the disorder for implantation, significantly reducing the likelihood of the child inheriting Canavan Disease. Thus, IVF and PGT provide a powerful combination for family planning, particularly for those with a genetic predisposition to this condition, allowing them to minimize the risk of genetic transmission while achieving pregnancy.
Overview of Canavan Disease
Canavan disease is a rare genetic neurological disorder characterized by the progressive degeneration of the brain’s white matter. While affected infants may initially appear healthy at birth, symptoms typically emerge between the ages of 3 to 6 months. These symptoms include developmental delays such as the inability to perform basic motor skills like turning over, controlling head movements, and sitting unassisted. Other common features of Canavan disease encompass weak muscle tone (hypotonia), an enlarged head size (macrocephaly), and irritability. Additionally, feeding and swallowing difficulties, seizures, and disruptions in sleep patterns may develop.
The mild/juvenile form of Canavan disease is less prevalent. Individuals with this form experience mild delays in speech and motor skill development that commence in childhood. These delays may be so subtle that they often go unrecognized as being linked to Canavan disease.
Canavan disease is primarily caused by mutations in the aspartoacylase (ASPA) gene, which impacts the metabolism of N-acetylaspartic acid (NAA). It is inherited as an autosomal recessive condition.
This disorder belongs to a group of conditions known as leukodystrophies, which are rare genetic disorders characterized by the disruption of myelin sheath growth or maintenance in the brain, spinal cord, and peripheral nerves. The myelin sheath plays a vital role in protecting nerves and facilitating efficient nerve signal transmission. Various types of leukodystrophies arise due to abnormalities in specific genes associated with myelin sheath development, resulting in a range of neurological issues.
The prevalence of Canavan Disease is highest among individuals of Ashkenazi Jewish ancestry, with an estimated 1 in 40 Ashkenazi Jews being carriers of the Canavan gene. It is also present in other ethnic groups, albeit at a lower frequency. Today, many children born with Canavan disease have no known Jewish heritage.
Life expectancy varies among individuals with Canavan disease. Most people with the neonatal/infantile form do not survive beyond childhood, although some may reach adolescence or even longer. In contrast, individuals with the mild/juvenile form do not appear to have a shortened lifespan.
Canavan disease, also known as Canavan-Van Bogaert-Bertrand disease, is a rare and fatal hereditary neurological disorder that typically manifests in infancy. This condition falls under the category of leukodystrophies, a group of genetic diseases characterized by the disruption of white matter in the brain, leading to impaired nerve signal transmission.
The disease follows an autosomal recessive pattern and is associated with a gene locus on chromosome 17. It results from mutations in the ASPA gene, which encodes the aspartoacylase enzyme. These mutations lead to a deficiency of aspartoacylase, causing an accumulation of N-acetylaspartic acid (NAA) in the brain. NAA is believed to contribute to oligodendrocyte dysfunction, spongiform changes, and the degeneration of myelin within axon phospholipid layers.
Canavan disease presents in two forms:
- Neonatal (Infantile): This is the more common and severe form of the disease. Affected babies typically appear healthy initially but begin to exhibit developmental issues, as mentioned in the Symptoms section below, by 3 to 5 months of age.
- Juvenile: This form is less common and milder in its symptoms. Developmental problems are less severe compared to the neonatal form, and in some cases, symptoms are so subtle that Canavan disease remains undiagnosed.
Prevalence of Canavan Disease
Canavan disease affects individuals of all genders and ethnic backgrounds, but it is more frequently observed in people of Ashkenazi Jewish descent. In this particular population, the estimated carrier frequency is as high as one in 40 to 58 individuals. For Ashkenazi Jewish couples, the risk of having an affected child falls between 1 in 6,400 and 1 in 13,456.
In contrast, the carrier frequency in other ethnic groups is believed to be considerably lower. The overall incidence of Canavan disease in the general population remains uncertain.
Among the Ashkenazi Jewish community, carrier frequencies range from 1 in 37 to 1 in 57 individuals, resulting in approximate prevalence rates spanning from 1 in 6,000 to 1 in 14,000.
Symptoms of Canavan Disease
Canavan disease presents a range of symptoms, including:
– Abnormal posture characterized by flexed arms and straight legs.
– Food material flowing back into the nose.
– Feeding difficulties.
– An increase in head size.
– Poor muscle tone, particularly in the neck muscles.
– Inability to control the head when transitioning from a lying to a sitting position.
– Poor visual tracking or even blindness.
– Reflux with associated vomiting.
– Severe intellectual disability.
– Swallowing difficulties.
Canavan disease exhibits variability in symptoms and progression from one individual to another. Typically, the disorder becomes noticeable between 3 and 6 months of age. Initial symptoms often include severe issues with head control, an abnormally large head (macrocephaly), and significant muscle tone reduction (hypotonia), leading to floppy movements. Affected infants may appear apathetic, lethargic, or irritable.
Children with Canavan disease experience developmental delays, such as delayed sitting or standing unassisted. Most affected individuals never achieve independent walking. As infants age, they may learn to smile, laugh, raise their heads, and engage socially.
As the disease progresses, individuals with Canavan disease may develop additional symptoms, including seizures, sleep disturbances, feeding problems, nasal regurgitation, acid reflux leading to vomiting, and optic atrophy, which affects vision. Hearing loss can also occur.
Shift From Hypotonia to Spasticity
Hypotonia can evolve into spasticity, characterized by involuntary muscle spasms that result in slow, stiff movements of the legs. Some individuals may develop uncontrolled rigid extensions and rotations of the arms, legs, fingers, and toes (decerebrate rigidity) or even paralysis.
Canavan disease ultimately leads to life-threatening complications, but the severity and progression differ among individuals. Some experience life-threatening issues in infancy, while others survive into their teenage years.
In recent years, a milder form of Canavan disease has been recognized, characterized by specific ASPA gene mutations and only slightly elevated N-acetyl-L-aspartic acid (NAA) levels in urine. These children may have mild delays, attend school, and experience a better prognosis, although head enlargement and typical white matter changes might be absent.
Symptoms Similar to Other Disorders
Symptoms of Canavan disease can resemble those of other disorders, including leukodystrophies (a group of rare genetic diseases affecting the brain and spinal cord), metachromatic leukodystrophy (a specific leukodystrophy), Tay-Sachs disease, and certain mitochondrial disorders, like Leigh’s disease. These disorders can involve neurological problems and developmental delays.
Causes of Canavan Disease
Canavan disease is primarily caused by mutations in the ASPA gene. This gene contains instructions for producing an enzyme called aspartoacylase.
Normal Enzyme Function
Aspartoacylase, the enzyme created by the ASPA gene, plays a crucial role in breaking down a compound known as N-acetyl-L-aspartic acid (NAA). NAA is primarily found in the neurons of the brain. While the exact function of NAA remains unclear, earlier theories suggested its involvement in myelin sheath production. Recent research, however, indicates that NAA may not have this role and could instead be associated with the regulation of water molecules within neurons.
The Impact of ASPA Mutations
Mutations in the ASPA gene disrupt the normal function of aspartoacylase, hindering the breakdown of NAA. In cases of neonatal/infantile Canavan disease, these mutations severely impair the enzyme’s activity, resulting in the accumulation of high levels of NAA in the brain. In contrast, the mild/juvenile form of the disorder is associated with less pronounced effects on the enzyme’s activity, leading to a lower buildup of NAA.
Consequences of NAA Accumulation
The excessive presence of NAA in the brain contributes to the characteristic signs and symptoms of Canavan disease. Studies suggest that when NAA isn’t properly broken down, it disrupts the chemical balance, impeding the formation of myelin sheaths during the development of the nervous system. Additionally, the buildup of NAA progressively damages existing myelin sheaths, causing malfunctioning nerves and hindering normal brain development.
Figure 9 Comparision of NAA metabolic pathway in canvan disease and healthy pathway
Inheritance of Canavan Disease
Canavan disease follows an autosomal recessive inheritance pattern. This means that an affected individual inherits two mutated copies of the gene responsible for the condition, one from each parent. While the parents are typically carriers of one mutated gene copy, they do not exhibit signs or symptoms of Canavan disease.
To identify carriers of Canavan disease among at-risk relatives, it is essential to first identify the specific ASPA pathogenic variants within the family.
Challenges in Carrier Detection
Detecting carriers through biochemical assays is not a routine practice because it relies on complex enzyme assays conducted in cultured skin fibroblasts. Furthermore, enzyme activity levels may fluctuate depending on the culture conditions, making this method less reliable for carrier identification.
Complications Associated with Canavan Disease
Canavan disease can lead to significant and life-altering complications, including:
- Blindness: Impairment or complete loss of vision.
- Inability to Walk: Loss of the ability to walk or significant mobility challenges.
- Intellectual Disability: Reduced cognitive function and intellectual challenges.
- Lack of Motor Skills: Difficulty in performing basic motor skills and movements.
- Difficulty Feeding: Challenges related to eating and maintaining proper nutrition.
- Hypotonia: Reduced muscle tone and strength.
- Paralysis: Loss of muscle control and paralysis in severe cases.
- Seizures: Recurrent seizures or convulsions.
- Death: Canavan disease can ultimately lead to premature death due to its severe neurological impact.
Understanding these potential complications is essential for individuals and families affected by Canavan disease, as it guides them in providing appropriate care and support.
Diagnosis of Canavan Disease
The diagnosis of Canavan disease may be suspected in infants displaying characteristic features of the disorder, such as poor head control and macrocephaly (enlarged head). Confirming the diagnosis involves a comprehensive clinical evaluation, a detailed patient history, and a range of specialized tests.
A physical examination may reveal the following clinical signs:
– Exaggerated reflexes
– Joint stiffness
– Optic nerve tissue loss
Diagnostic tests for Canavan disease include:
– Blood chemistry analysis
– Cerebrospinal fluid (CSF) chemistry analysis
– Genetic testing specifically for mutations in the aspartoacylase gene
– CT scan of the head
– MRI scan of the head
– Urine or blood chemistry to detect elevated aspartic acid levels
– DNA analysis
Additionally, gas chromatography-mass spectrometry may be employed to detect increased levels of N-acetylaspartic acid (NAA) in urine. Elevated NAA levels can also be identified in the blood and cerebrospinal fluid (CSF). Examination of cultured fibroblasts, connective tissue cells from the skin, may reveal a deficiency of the enzyme aspartoacylase. Aspartoacylase activity is typically absent in white blood cells.
Prenatal diagnosis of Canavan disease is feasible through amniocentesis, where the level of NAA in the amniotic fluid surrounding the developing fetus is measured at 16-18 weeks of gestation. In cases where both parents have known ASPA gene mutations, chorionic villus sampling (CVS) can be utilized for mutation analysis. CVS involves sampling placental cells and is performed at 10-12 weeks of gestation.
Neuroimaging plays a crucial role in the diagnosis of Canavan disease. CT and MRI scans reveal distinctive features, including a characteristic low attenuation of white matter. These scans illustrate spongiform degeneration and edema of the white matter, with no post-contrast enhancement typically observed.
Molecular Genetic Testing
Molecular genetic testing methods for Canavan disease encompass gene-targeted testing (single-gene testing or multigene panels) and comprehensive genomic testing (such as exome sequencing or genome sequencing). The choice of testing approach depends on the patient’s clinical presentation. Infants displaying distinctive symptoms are more likely to be diagnosed with gene-targeted testing, while those with milder or juvenile forms of Canavan disease may benefit from genomic testing.
Evaluations Following Initial Diagnosis
After an initial diagnosis of Canavan disease, further evaluations are recommended to assess the extent of the disease. These evaluations vary depending on the form of the disease:
Neonatal/Infantile (Severe) Form:
– Brain MRI and MRI spectroscopy
– Neurologic evaluation
– Developmental assessment
– Ophthalmologic assessment
– Nutritional assessment
– Neurologic evaluation
– Developmental assessment
– Ophthalmologic assessment
It’s essential to consider other dysmyelinating diseases when diagnosing Canavan disease. Conditions that may present with similar symptoms include:
– Alexander disease
– Metachromatic leukodystrophy
– Pelizaeus-Merzbacher disease
Managing Canavan Disease and Providing Support
Treatment for Canavan disease focuses on addressing specific symptoms observed in each affected individual. Supportive care aims to alleviate discomfort and enhance the individual’s overall well-being.
- Physical Therapy: Early intervention with physical therapy can improve posture and motor skills, particularly in neonatal/infantile Canavan disease.
- Communication Enhancement: Early intervention services may include speech therapy and tutoring to enhance communication skills.
- Feeding Tube: In cases of swallowing difficulties, the use of feeding tubes ensures proper nutrition and hydration.
- Seizure Management: Seizures can be treated with anti-seizure (anti-convulsant) medications.
Genetic Counseling and Carrier Testing:
– Genetic counseling and carrier testing are crucial for families affected by Canavan disease, providing information and guidance for future pregnancies.
– Carrier testing is available, particularly for individuals of Ashkenazi Jewish heritage, to identify carriers of the disease.
Surveillance and Follow-Up:
– For neonatal/infantile Canavan disease, regular follow-up every six months is essential to assess developmental progress and identify any emerging issues.
– Mild/juvenile Canavan disease may necessitate annual routine follow-up with a pediatric neurologist or developmental pediatrician.
Providing personalized care and support is essential in managing Canavan disease and enhancing the quality of life for affected individuals and their families.
Preventing Canavan Disease and Managing Complications
– Genetic counseling is strongly recommended for couples planning to have children, especially if there is a family history of Canavan disease.
– This counseling is particularly crucial for couples of Ashkenazi Jewish descent, as DNA testing can reliably determine carrier status.
– Prenatal diagnosis allows for the detection of Canavan disease before birth by testing the amniotic fluid that surrounds the developing fetus.
Preventing Secondary Complications in Neonatal/Infantile Canavan Disease
– Prevent contractures and pressure ulcers by incorporating exercise and regular changes in position.
Feeding Difficulties and Seizures Management:
– Feeding difficulties and seizures increase the risk of aspiration, which can be minimized by utilizing a G-tube for feeding.
Taking proactive steps through genetic counseling and prenatal diagnosis can help families at risk of Canavan disease make informed decisions. Additionally, managing complications in neonatal/infantile Canavan disease is crucial for enhancing the quality of life for affected individuals.
Prognosis and Outlook in Canavan Disease
Canavan disease brings about the deterioration of the central nervous system, leading to potential disabilities. The prognosis varies depending on the disease’s form:
- Neonatal Form: Individuals with the neonatal form typically do not survive beyond childhood. However, in some cases, children may live into their teenage years.
- Juvenile Form: Those with the juvenile form of Canavan disease often enjoy a normal lifespan.
Understanding the prognosis for each form of Canavan disease is essential for patients and their families to plan for the future and provide the necessary care and support.