Adrenoleukodystrophy

What Causes Adrenoleukodystrophy?

ALD is caused by an abnormal change (mutation) in a gene called the ABCD1 gene. This gene carries instructions for making a protein vital in the normal functioning of cells. In ALD, the gene mutation impairs the normal production of the protein, which results in the accumulation of harmful substances in cells in various parts of the body.

The destructive effect of these accumulated substances is particularly damaging in the myelin-coated nerve cells of the brain and spinal cord (called white matter) and in the cells of the outer part of the adrenal gland. As these cells are damaged, the disorder’s symptoms result, and as the damage continues, symptoms progressively worsen.

Is Adrenoleukodystrophy Hereditary?

ALD is an inherited disorder. The ABCD1 gene is located on the X chromosome, meaning that ALD is an X-linked disorder. Females have two copies of the X chromosome, one inherited from each parent, but males have only one copy of the chromosome. Therefore, females are likely to have only one copy of the mutated gene, so they typically have mild symptoms of the disorder or no symptoms at all. However, males who inherit a mutated ABCD1 gene have no normal copy of the gene to compensate, so they develop more severe symptoms.

X-linked disorders have a unique pattern of inheritance:

• Males with the mutation will always pass the mutation to their daughters.
• Males cannot pass the mutation to their sons.
• Daughters of males with the mutation will be carriers of the mutated gene.
• Females with the mutation will pass the disorder to their sons half the time.
• Daughters of females with the mutation will be carriers half the time.

Most female carriers of the mutation will develop symptoms of adrenomyeloneuropathy by the time they reach the age of 60, but the symptoms are usually milder than those experienced by men.

How Is Adrenoleukodystrophy Detected?

Early diagnosis of ALD is vital because early intervention before symptoms present may prevent or delay the onset of childhood cerebral ALD. Therefore, some states regularly screen newborns for the disorder. A positive screening test result may be followed up with genetic testing to confirm a diagnosis of ALD.

How Is Adrenoleukodystrophy Diagnosed?

A doctor may suspect ALD when a child exhibits symptoms characteristic of the disorder and has a family history of ALD. The diagnostic process usually includes:

• Assessment of the child’s medical and family history
• Physical and neurological exams
• Blood tests to look for elevated levels of very-long-chain fatty acids (VLCFAs), an indicator of ALD
• Imaging scans such as magnetic resonance imaging (MRI) or computerized tomography (CT) to look for loss of white matter in the brain
• ACTH stimulation test to measure the function of the adrenal gland
• Genetic testing to look for disorder-causing ABCD1 mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Adrenoleukodystrophy Treated?

ALD syndrome has no cure, and treatment will not reverse the effects of its symptoms. However, some treatments may prevent or slow the progression of childhood cerebral ALD if they’re administered before symptoms appear or very early in the onset of the disorder. Other treatments and therapies aim to lessen the impact of symptoms and prevent complications. Common treatments and therapies include:

• Bone marrow/stem cell transplants may slow or stop the progression of ALD if the treatment is administered before symptoms are severe
• Oleic acid and erucic acid (Lorenzo’s oil) may prevent the onset of ALD in some cases if given before symptoms appear
• Corticosteroid replacement therapy can effectively treat adrenal gland dysfunction
• Medications for muscle rigidity
• Anti-seizure medications
• Physical therapy
• Special education

How Does Adrenoleukodystrophy Progress?

ALD is a progressive disorder, and symptoms worsen over time. Progression of the childhood-onset form of the disorder is usually rapid, with death occurring within 2-3 years of the initial onset. Progression of adult-onset conditions is generally slower.

The progression of ALD typically involves:

• Behavior problems and learning disabilities
• Loss of motor skills already acquired
• Vision impairment
• Hearing impairment
• Problems walking
• Seizures
• Blindness
• Deafness
• Loss of voluntary movement
• Vegetative state
• Death

How Is Adrenoleukodystrophy Prevented?

There is no known way to prevent ALD when the disorder-causing gene mutations are present. Treatments such as stem cell transplants can significantly impact the disorder’s progression, but they are ineffective after neurological symptoms have begun.

Parents with a family history of the disorder or who have had another child with ALD are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Adrenoleukodystrophy Caregiver Tips

• Stay abreast of the latest research. Scientists are working hard to find effective treatments for ALD; keeping up with the news can help you focus on the positive. The United Leukodystrophy Foundation provides regular updates and opportunities for research advocacy.
• Look for a community of families like yours. Online support groups allow you to share your experiences with others living with ALD.

Some people with ALD also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with ALD:

• ALD is sometimes associated with bipolar disorder.
• ALD may increase the risk of cognitive decline and dementia.
• ALD is sometimes associated with neurological symptoms, including vision problems and seizures.

Adrenoleukodystrophy Brain Science

The ABCD1 gene carries instructions for making X-linked adrenoleukodystrophy protein (ALDP). ALDP is involved in the process of transporting substances called very long-chain fatty acids (VLCFAs) into cell structures called peroxisomes, where the VLCFAs are broken down. When ABCD1 mutations impair the production of ALDP, leading to an abnormal accumulation of VLCFAs inside cells.

White matter nerve cells seem to be particularly sensitive to VLCFA accumulation. Recent research has suggested that damage to these cells comes not from a direct effect of VLCFAs but possibly from an immune response to the presence of the fatty acids. The immune system reaction causes inflammation that may be responsible for white matter deterioration.

Scientists don’t yet know why VLCFA accumulation damages the adrenal gland, but a similar autoimmune response may be to blame there, too.

Adrenoleukodystrophy Research

Title: A Study to Assess the Pharmacodynamics of VK0214 in Male Subjects With AMN

Stage: Not Yet Recruiting

Principal investigator: Marianne Mancini

Viking Therapeutics

Palo Alto, CA

Subjects will be administered multiple doses of VK0214 in a cohort dose escalation process. A total of up to 36 subjects will be enrolled in the study into one of three dose cohorts. For each cohort, up to 12 subjects will be randomized to receive VK0214 or placebo in a 3:1 ratio so that there will be a total of up to 9 subjects for each of the active doses and up to 3 subjects dosed with placebo in each cohort.

The first part of VK0214-102 will include the first two dose cohorts and placebo, which will be dosed in parallel (up to N=24). The first two doses used in these cohorts will be 20 mg QD and 40 mg QD for 28 days. A Dose Level Review Team (DLRT) meeting will be held at the end of the first two parallel doses.

The DLRT will review safety, tolerability, and preliminary efficacy data from cohorts 1 and 2. If the data analyzed show that the first two doses are safe and well-tolerated, the DLRT may recommend proceeding to commence dosing in the third dose cohort.

Based upon outcomes in Cohorts 1 and 2, the sponsor may decide to include a third dose cohort. Before screening may be initiated in Cohort 3, data to support dosing in this cohort will be submitted to the FDA, together with the amended protocol and the dosing recommendation of the DLRT.

Title: A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

Stage: Recruiting

Contact: Ami Shah, MD

Lucile Packard Children’s Hospital

Palo Alto, CA

Study ALD-104 is an international, non-randomized, open-label, multi-site study in male participants (<or=17 years of age at enrollment) with cerebral adrenoleukodystrophy (CALD). Approximately 35 participants will be infused with Lenti-D Drug Product after myeloablative conditioning with busulfan and fludarabine.

This trial will evaluate the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector, to treat CALD. A subject’s blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the subject following myeloablative conditioning.

Title: UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (DUOC-01)

Stage: Recruiting

Contact: Carsten G. Bonnemann, MD

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, MD

The primary objective of the study is to determine the safety and feasibility of intrathecal administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of metabolism who have evidence of early demyelinating disease in the central nervous system (CNS) who are undergoing standard treatment with unrelated umbilical cord blood transplantation (UCBT). The study’s secondary objective is to describe the efficacy of UCBT with intrathecal administration of DUOC-01 in these patients.

The inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, most of which involve a single gene mutation resulting in an enzyme defect. In most cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or interfere with normal cellular function. Often, patients may appear normal at birth but during infancy begin to exhibit disease manifestations, frequently including progressive neurological deterioration due to absent or abnormal brain myelination. The ultimate result is death in later infancy or childhood.

Currently, the only effective therapy to halt the neurologic progression of the disease is allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed engraftment of donor cells in the CNS when administered through the intravenous route, which is associated with ongoing disease progression over 2-4 months before stabilization. The engraftment of donor cells in a patient with an IMD provides a constant source of enzyme replacement, thereby slowing or halting the progression of the disease.

This study will evaluate the safety of a potential new treatment for patients with certain IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention, intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01), will serve as an adjunctive therapy to a standard UCB transplant. This therapy aims to accelerate the delivery of donor cells to the CNS, thereby bridging the gap between systemic transplant and engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and cells used for HSCT will be derived from the same UCB donor unit.