Canavan disease is a deficiency of myelin that results from a chromosomal mutation. Affected individuals show neurological deficits and usually die in their teens. To date, the disease is incurable despite gene therapy approaches.
What is Canavan disease?
Canavan disease is a genetic leukodystrophy known as Canavan disease. In 1931, Myrtelle Canavan first described the condition. The autosomal recessive disorder is more common in Arab and Ashkenazi Jewish people than in the rest of the world. Like all lucodystrophies, Canavan’s disease presents with a deficiency of white matter in the brain. Accordingly, leukodystrophies are metabolic diseases that affect myelin, which is relevant to the nervous system. Affected individuals suffer from progressive demyelination. Due to the degradation of myelin, nerve tracts are impaired. Neurological deficits develop. Canavan’s disease is often referred to as spongy degeneration of the nervous system, as the brain swells and the myelin becomes spongy. Leukodystrophies such as Canavan disease must be distinguished from genetic storage diseases such as Krabbe disease. Krabbe disease also demyelinates the nervous system and the cause of both phenomena is a chromosomal mutation. However, the chromosomes affected differ.
Causes
Biological transcription involves the creation of an image of DNA strands, also known as mRNA. During biological translation, this mRNA is translated into protein sequences. In Canavan disease, mutations occur during these processes. These are mutations of the ASPA gene. This gene is located on the short arm of chromosome 17 and codes for the enzyme aspartoacylase. Aspartoacylase is found exclusively in the brain, where it degrades N-acetylaspartate. A mutation of the coding gene results in a deficiency of the enzyme. As a consequence, less N-acetylaspartate is broken down in the brain. The substance is therefore stored. This storage manifests itself in spongy changes and causes the brain to swell. The myelin in the brain is damaged and partially lost as a result. Myelin nourishes, protects and insulates nerve tissue. Damaged myelin leiets nerve impulses only delayed or not at all. In Canavan’s disease, the transmission of information between brain regions no longer works because of the processes described. Myelin loss is accompanied by secondary neuronal impairment.
Symptoms, complaints, and signs
In most cases, children with Canavan disease are rather inconspicuous immediately after birth. Beginning at three months of age, the first symptoms appear in infantile forms of the hereditary disease. As a rule, the first symptoms concern psychomotor development. Control of the head is disturbed and an oversized skull often develops. Affected individuals usually exhibit a lack of tension in the muscles. The further course of the disease is characterized by motor disorders such as the impossibility of walking, sitting and standing freely. Swallowing disorders or seizures are also included in the clinical picture. Spastic paralysis often occurs. Perceptual centers of the brain can also be affected by demyelination. As a rule, restrictions in the ability to perceive mainly affect the ability to see. Complete blindness does not necessarily occur. The infantile form of Canavan disease is the most common. It can be distinguished from the congenital and juvenile forms. In the juvenile form, the first symptoms appear after the first few years of life.
Diagnosis and course of the disease
Physicians diagnose Caravan’s disease primarily by magnetic resonance imaging of the brain. In this imaging, the disease presents a relatively typical picture. The subcortical matter of the cerebrum and cerebellum shows lesions. This damage spreads centripetally as the disease progresses. The symmetrically appearing lesions particularly affect the globus pallidus and the thalamus, but not the putamen or the nucleus caudatus. Detection of elevated urinary N-acetylaspartate confirms the diagnosis. Molecular genetic testing to detect the gene mutation may also be considered. However, these complex procedures are not mandatory, since elevated urinary N-acetylaspartate is specific for Canavan disease. For the congenital form, the prognosis is unfavorable. Life expectancy is a few days or weeks.Patients of the infantile form usually reach teenage age. In the juvenile form, disease progression is slowed and patients often live past 20.
Complications
Canavan disease results in a greatly reduced life expectancy in most affected individuals, causing patients to die at a young age as teeangers. In the process, the disease also has a strong effect on the relatives and parents, so that they suffer from severe psychological complaints or depression. Especially after death, treatment by a psychologist is necessary in many cases. The patients suffer mainly from paralysis and severe limitations in sensitivity. Those affected may also be dependent on the help of their parents in order to cope with their daily lives. There are restrictions in movement and the quality of life of the patients decreases considerably. Spasticity and seizures also occur with this disease. It is not uncommon for those affected to also suffer from vision or hearing problems. They also require special support and are significantly restricted in their development. Canavan’s disease can be limited by various therapies, but a complete and above all causal treatment is not possible. No further complications occur during the treatment itself. However, the life expectancy of the patient is significantly reduced by the diseases.
When should you go to the doctor?
In Canavan disease, the first signs of irregularity usually appear within the first six months of life, but they are more rarely noticed immediately after birth. If disturbances in movement patterns as well as general motor skills become apparent during the child’s growth and development process, a visit to the doctor is advisable. If the child shows weak muscles when grasping, this is a cause for concern and should be examined by a doctor. If there are significant delays in development compared to children of the same age, a doctor should be consulted. Targeted testing can provide an objective assessment of the child’s health and treatment can be initiated. If the child does not learn to walk, sit or stand independently, this is considered unusual. A doctor is needed so that an investigation of the cause can take place. Seizures, a seizure disorder, and spasticity should be evaluated and treated by a physician. If paralysis occurs on the body, a doctor’s visit should be made immediately. The child needs medical care to ensure relief from the symptoms. Delayed perception as well as processing of sensory stimuli should be clarified by a doctor. Decreased vision or hearing are characteristic of the disease and must be treated. In severe cases, blindness of the patient occurs. Therefore, a physician should be consulted as soon as possible at the first irregularities or suspicion of a disorder.
Treatment and therapy
Canavan disease is incurable. To date, instead of causative therapies, there are only supportive therapy options. Delaying the disease and assured prolongation of life are also not feasible to date. The supportive therapeutic approach is based on the symptoms. Agitation, pain and seizures, for example, can be alleviated with drug therapies. In the case of dysfunctions of the respiratory system, respiratory assistance is considered. The relatives of those affected often receive additional therapeutic care as well. As a rule, they are assisted by a psychotherapist. Gene therapy approaches to cure the disease have been in the works for several years. The ASPA gene is to be introduced into the patient’s brain via a viral gene shuttle from adenoviruses as part of the gene therapy treatment. In the animal model, the concentration of N-acetylaspartate in the urine decreased via this measure. However, myelin remained spongy despite these partial successes. Nevertheless, medical research currently continues to strive to develop a causative therapy. Improvement of gene ferries has already taken place, but still has not been able to deliver breakthrough success.
Outlook and prognosis
The prognosis of Canavan disease is based on the form of the disease. The infantile form takes a fatal course. Most children die in the second year of life. Other forms of progression offer a life expectancy of five to ten years. The exact determination of the mutation is decisive for the prognosis.Canavan’s disease takes a progressive course. This is associated with a decline in physical and mental abilities and a continuous reduction in the child’s quality of life. The relatives are also heavily burdened by the condition. In most cases, they require therapeutic counseling and comprehensive care. There is no prospect of a cure for Canavan’s disease. However, the symptoms can be alleviated by symptomatic therapy. For some years now, gene therapy has also been available, by which the gene is to be introduced into the brain. So far, this treatment has not been approved for humans. If diagnosed at an early stage, children with the disease can live a short but relatively symptom-free life. In the mild form of the disease, life expectancy is normal. Various therapeutic approaches have been developed in recent years and improve the prognosis considerably. As a result, the prognosis is favorable in mild Canavan disease but much worse in the severe form.
Prevention
Genetic diseases such as Canavan disease cannot be prevented. However, couples in family planning can have your risk assessed via molecular genetic testing.
Follow-up care
In most cases, the person affected by Canavan disease has very few or limited aftercare options available to him or her. For this reason, the affected person must ideally see a doctor very early in the course of this disease to prevent the further occurrence of complications and symptoms. Since this is a genetic disease, it cannot usually be completely cured. Therefore, if a person wishes to have children, he or she should have genetic testing and counseling to prevent the recurrence of the disease in descendants. Most patients depend on taking various medications to alleviate the symptoms. Care should always be taken to ensure that the medication is taken regularly and also in the correct dosage. If there is any uncertainty or if there are any questions, a doctor should be consulted first. Furthermore, most of those affected are dependent on the help and support of their own family in their everyday lives. In this context, loving conversations also have a positive effect on the further course of the disease and can prevent depression and other psychological upsets.
What you can do yourself
Canavan disease almost always takes a fatal course. For many parents, the most important self-help measure is to make contact with other relatives. Suitable places to start are self-help groups as well as forums on the Internet. To educate the child about his or her disease, a specialist center for nerve disorders should be visited. In the course of this, parents can find out about novel treatment options, for example gene therapy, which is expected to make Canavan’s disease curable in the future. If the course of the disease is positive, the necessary caregivers as well as modifications in the child’s own home should be organized at an early stage so that the child can be treated without complications. A further improvement of the quality of life is possible through an adapted diet and moderate sport. Nevertheless, Canavan’s disease always takes a severe course. Relatives should discuss the options for palliative treatment with the physician in charge. In families where cases of Canavan disease have been observed, the necessary genetic testing should be performed. An ultrasound examination can determine whether the child has Canavan disease. Once the diagnosis is made, the necessary measures can be taken to allow those with the disease to live a relatively symptom-free life.
