Canavan Disease

What Causes Canavan Disease?

Canavan disease is caused by abnormal changes (mutations) in a gene called the ASPA gene. This gene is responsible for the production of an enzyme called aspartoacylase. Aspartoacylase is responsible for breaking down a naturally occurring chemical called N-acetylaspartic acid (NAA). Certain mutations in the ASPA gene lead to abnormally low levels of aspartoacylase in cells which, in turn, allows NAA to accumulate to unusually high levels.

Scientists don’t understand the function of NAA, but an elevated level of the chemical in nerve cells seems to interfere with myelin production. The resulting dysfunction of the cells produces the symptoms of CD.

Is Canavan Disease Hereditary?

Canavan disease is an inherited disorder. Most cases are inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the mutated ASPA gene, one from each parent, for the disorder to develop.

The parents in these cases carry just one copy of the mutation each, so they typically do not show any symptoms of CD themselves. When two parents both carry the mutated gene, they have a 25 percent chance of having a child with the disorder with each pregnancy. Fifty percent of the time, the pregnancy will produce a child who is a carrier like the parents. Twenty-five percent of the time, the child will not carry the mutation at all.

CD is more common in people of Ashkenazi Jewish descent. More than two percent of people in this population may be carriers of the CD-causing gene mutations, likely far higher than the rate in the general population. Research suggests that the disease affects as many as 1 in 6,400 people with Ashkenazi ancestry.

How Is Canavan Disease Detected?

Canavan disease can be detected before birth by conducting tests that measure the fetus’ NAA level or look for a disease-causing gene mutation. These tests may be recommended if the parents are known to be carriers of the associated gene mutations or if they have a family history of the disease.

Prenatal testing for CD can include these tests:

• Amniocentesis. This test extracts a small amount of the amniotic fluid that surrounds the fetus in the womb and measures the NAA level in the fluid. This test can be conducted between 16 and 18 weeks of pregnancy.
• Chorionic villus sampling (CVS). This test removes a small sample of cells from the placenta and checks the cells for the presence of a CD-producing gene mutation. This test can be conducted between10 and 12 weeks of pregnancy.

How Is Canavan Disease Diagnosed?

A doctor may suspect Canavan disease if a child exhibits symptoms characteristic of the disorder, including lack of head control or an enlarged head. A doctor will typically conduct tests to look for more definitive signs of the disease to confirm a diagnosis.

Commonly used tests include:

• Chromatography-mass spectrometry, a test that can detect NAA in urine
• Blood tests that can reveal a deficiency of aspartoacylase in white blood cells
• Examination of skin cells that can detect abnormally low levels of aspartoacylase

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Canavan Disease Treated?

CD has no cure. Treatment options focus on lessening the impact of symptoms, preventing complications, and improving the child’s quality of life.

Common treatments include:

• Physical therapy
• Feeding tubes
• Anti-seizure medications

How Does Canavan Disease Progress?

The degeneration of brain tissue in Canavan disease continues as the child gets older, and the symptoms progressively worsen. Motor and intellectual decline is often rapid and can become severe very early in childhood.

The disorder is often fatal before two years of age, and most children will not survive until the age of 10. Survival into the teens or early twenties is rare but can occur.

How Is Canavan Disease Prevented?

There is no known way to prevent Canavan disease. Parents with a family history of the disorder or who have had another child with CD are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Canavan Disease Caregiver Tips

• Allow time to grieve. A Canavan disease diagnosis comes with a flood of conflicting, overwhelming emotions. Take the time you need to process them, and don’t expect the process to be quick.
• Get help, and pay attention to your health. Caring for your child will be highly demanding, and you’ll need a break sometimes. Don’t hesitate to accept help from family and friends, and make time to tend to your mental and physical health needs.
• Remember that you are not alone. Online and local support groups can put you in touch with other families who are living with Canavan disease.

Canavan Disease Brain Science

Researchers are studying the cellular chemical processes involving aspartoacylase and NAA to understand how Canavan disease develops. Aspartoacylase breaks NAA down into the chemicals acetate and aspartate. Cells with an ASPA gene mutation have abnormally low levels of aspartoacylase and, consequently, high levels of NAA and low levels of acetate.

Theories for how this imbalance damages cells include:

• High levels of NAA may cause fluid to build up inside cells and damage them.
• Low levels of acetate may hinder the production of fatty compounds necessary for building myelin.

Other research is focused on potential therapies that could treat CD directly. Scientists are developing gene therapy techniques that can deliver normal copies of the ASPA genes directly into the cells of children with CD. Such a therapy could potentially lessen symptoms or even cure the disease.

Canavan Disease Research

Title:  rAAV-Olig001-ASPA Gene Therapy for Treatment of Children With Typical Canavan Disease (CAN-GT)

Stage: Recruiting

Principal Investigator: Christopher G. Janson, MD

Dayton Children’s Hospital

Dayton, OH

Canavan Disease is a congenital white matter disorder caused by mutations to the gene encoding for aspartoacylase (ASPA). Expression of ASPA is restricted to oligodendrocytes, the sole white matter producing lineage in the brain. ASPA supports developmental myelination in the capacity of its sole known function, namely, the catabolism of N-acetylaspartate (NAA). Inherited mutations that result in loss of ASPA catabolic activity result in a typically severe phenotype characterized by chronically elevated brain NAA, gross motor abnormalities, hypomyelination, progressive spongiform degeneration of the brain, epilepsy, blindness, and a short life expectancy. Disease severity is correlated with residual levels of enzyme activity. Reconstitution of ASPA function in oligodendrocytes of the brains of Canavan patients is expected to rescue NAA metabolism in its natural cellular compartment and support myelination/remyelination by resident white matter producing cells. This protocol directly targets oligodendrocytes in the brain, which are intimately involved with disease initiation and progression. Targeting oligodendrocytes offers the safest and most direct therapy for affected individuals.

The latest generation AAV viral vector (rAAV-Olig001-ASPA) will be administered to patients using a minimally invasive neurosurgical procedure that involves direct administration of gene therapy to affected regions of the brain. Outcome measures for the open-label clinical trial include longitudinal clinical assessments and brain imaging.

Currently, there is no effective treatment for Canavan Disease. The purpose of this study is to validate a new technology targeted to the cells most affected by Canavan Disease in the safest way possible.

Title: Natural History Study of Patients With Canavan Disease, CAN Inform

Stage: Recruiting

Principal investigator:  Florian Eichler, MD

Massachusetts General Hospital

Boston, MA

CANInform, the Canavan disease natural history study, will be the first multinational effort to rigorously gather both retrospective and prospective data from this patient population. Data collection will include the extraction of retrospective data from medical records of living patients and deceased patients and collecting prospective, longitudinal data from living patients and their parent(s)/caregiver(s). Motor function assessments will be performed in the home by qualified study team members. In addition, families will be invited to attend clinic visits or will be followed by the clinical site remotely for up to 3 years).

Title: The Myelin Disorders Biorepository Project (MDBP)

Stage: Recruiting

Principal investigator:  Adeline Vanderver, MD

Children’s Hospital of Philadelphia

Philadelphia, PA

Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years, and this “odyssey” results in testing charges to patients and insurers above $8,000 on average per patient, including the patients who never achieve a diagnosis at all. With next-generation approaches such as whole-exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. This remaining group of patients (unclassified leukodystrophy) offers the opportunity to describe novel disorders and provide improved diagnostic tools. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients.

Moreover, the mechanisms of disease in many leukodystrophies of known cause are very poorly understood: many are systemic abnormalities that manifest only testing white matter. Finally, little is known about the best symptomatic management of the many leukodystrophies without an etiologic cure. Thus limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; and (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders.

It is hoped that the present study will help clarify the nosology of the leukodystrophies and significantly advance our understanding of the pathogenesis of these diseases, the best diagnostic testing tools, and the best symptomatic management of these conditions. Due to the breadth of this approach, and the rarity of these conditions, these approaches will be carried out at multiple clinical centers with specialized expertise in the leukodystrophies.