Project Description

Autosomal Dominant Leukodystrophy (ADLD) Fast Facts

Autosomal leukodystrophy (ADLD) is a neurological disorder in which a substance essential for nerve cell function, called myelin, breaks down.

ADLD affects the brain and spinal column as well as nerve cells in other parts of the body. It is a progressive disease, meaning its symptoms worsen over time.

The symptoms of ADLD usually first appear in adults between the ages of 40 and 60.

ADLD progresses slowly. It is usually fatal within 10-20 years after the onset of symptoms.

United Brain Association

The symptoms of ADLD usually first appear in adults between the ages of 40 and 60.

What is Autosomal Dominant Leukodystrophy (ADLD)?

Autosomal dominant leukodystrophy (MLD) is a neurological disorder in which myelin, a protective coating vital in nerve cell function, breaks down. The degenerative process, called demyelination, is caused by an accumulation of a particular protein inside nerve cells. Symptoms of ADLD worsen over time, and complications of the disease are usually fatal within 10-20 years of the initial onset.

Symptoms of ADLD

The first symptoms of ADLD are associated with the autonomic nervous system, which controls involuntary body functions such as blood pressure and temperature regulation. These autonomic symptoms may include:

  • Frequent or urgent urination
  • Constipation
  • Sudden drops in blood pressure when standing
  • Erectile dysfunction in men

Later symptoms are often movement-related. Common symptoms include:

  • Stiff or weak muscles
  • Muscles tremors that get worse during movement
  • Problems with coordination
  • Problems walking

What Causes Autosomal Dominant Leukodystrophy (ADLD)?

ADLD is caused by a problem with the LMNB1 gene. Sometimes the disease is caused by an extra copy of the gene, and sometimes it’s caused by other genetic errors near the LMNB1 gene. The problems cause the overproduction of a protein called lamin B1. The protein plays a role in healthy cell function, but too much of it triggers a toxic process that scientists don’t yet fully understand. In nerve cells, which seem to be especially sensitive to excess lamin B1, the toxic effect causes the myelin coating surrounding cells in the brain and elsewhere in the nervous system to break down, impairing the nerve cells’ ability to send and receive signals from one another.

Is Autosomal Dominant Leukodystrophy (ADLD) Hereditary?

ADLD is inherited when parents pass the disease-causing gene mutations to their children. The condition is inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy. In most cases, a person who develops the disorder has at least one parent with ADLD.

How Is Autosomal Dominant Leukodystrophy (ADLD) Detected?

Demyelination of the spinal cord likely begins long before the symptoms of ADLD appear. Degeneration of nerve cells in this part of the central nervous system may be responsible for the disorder’s early autonomic symptoms.

Early symptoms may include:

  • Problems with bowel and bladder function, including frequent urination or constipation
  • A sudden drop in blood pressure upon standing, which may cause dizziness
  • Erectile dysfunction
  • Elevated body temperature caused by an inability to sweat. This symptom is relatively rare.

How Is Autosomal Dominant Leukodystrophy (ADLD) Diagnosed?

A doctor may suspect ADLD if a patient shows neurological symptoms that worsen in a pattern characteristic of the disease. The diagnostic process will usually include evaluating the patient’s medical history and physical, cognitive, and neurological exams. Further diagnostic steps may consist of:

  • Imaging exams such as magnetic resonance imaging (MRI) or computerized tomography (CT) to look for evidence of demyelination in the brain or spinal cord
  • Genetic testing to look for the disease-causing gene mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Autosomal Dominant Leukodystrophy (ADLD) Treated?

ADLD has no cure, and no treatment will reverse symptoms once they appear. Treatment options focus on lessening the severity of symptoms, preventing complications, and improving quality of life. Common treatments include:

  • Medications to treat physical complications
  • Feeding assistance
  • Physical therapy
  • Occupational therapy
  • Speech therapy

How Does Autosomal Dominant Leukodystrophy (ADLD) Progress?

ADLD progresses slowly. Although its complications are ultimately fatal, people with the disease may survive for decades after symptoms first emerge. However, the disorder’s movement-related symptoms and other neurological effects worsen over time, and debilitating impairments are common.

Later symptoms of the disorder may include:

  • Loss of mobility and the ability to walk
  • Slurred speech
  • Loss of ability to swallow
  • Involuntary crying or laughing
  • Cognitive impairment or dementia in the disorder’s late stages

How Is Autosomal Dominant Leukodystrophy (ADLD) Prevented?

People with a family history of ADLD should consult a genetic counselor to assess their risks before becoming pregnant. Parents who have had a child with ADLD should also seek genetic counseling before having more children.

Autosomal Dominant Leukodystrophy (ADLD) Caregiver Tips

  • Learn all you can about ADLD. The disease and its effects on people living with it are complex. You’ll best be able to care for your loved one when you know what to expect from the disorder’s progression.
  • Stay up-to-date on research developments. New therapies and treatments for ADLD are the subjects of active research, and results so far are promising. Keep abreast of the latest studies so you can be an informed part of your loved one’s medical team.
  • Remember that there is a community of people who know what you’re going through, and they can help. The United Leukodystrophy Foundation maintains a directory of resources for families living with ADLD, including links to education, medical referrals, and financial assistance programs.

Autosomal Dominant Leukodystrophy (ADLD) Brain Science

ADLD occurs when problems with the LMNB1 gene cause an overabundance of lamin B1 in the body. Scientists don’t yet fully understand how an excess of lamin B1 causes the disorder’s symptoms. The effect is related to the nuclear lamina, a network of proteins surrounding the nucleus inside the body’s cells. The nuclear lamina is an essential part of many different cell functions. An elevated level of lamin B1 seems to impair the construction of this layer and cause it to harden.

Most of the body’s cells are affected by changes to the nuclear lamina, but brain cells seem to be especially sensitive. In particular, cells called oligodendrocytes, which play a crucial role in the production of myelin, appear to be susceptible to damage from a high level of lamin B1.

As nerve cells in the central nervous system lose their myelin coating, they cease to function correctly. Nerves in the spinal cord seem to be affected first, producing the disorder’s autonomic symptoms. Over time, cells in the cerebellum, the part of the brain that controls voluntary movement, are affected, and ADLD’s movement-related symptoms appear.

Autosomal Dominant Leukodystrophy (ADLD) Research

Title:  LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies

Stage: Recruiting

Principal investigator: Adeline Vanderver, MD

Children’s Hospital of Philadelphia

Philadelphia, PA

Leukodystrophies are a group of approximately 30 genetic diseases that primarily affect the brain’s white matter, a complex structure composed of axons sheathed in myelin, a glial cell-derived lipid-rich membrane. Leukodystrophies are frequently characterized by early onset, spasticity, developmental delay, and are degenerative in nature. As a whole, leukodystrophies are relatively common (approximately 1 in 7000 births or almost twice as prevalent as Prader-Willi Syndrome, which has been far more extensively studied) with high associated healthcare costs. However, more than half of the suspected leukodystrophies do not have a definitive diagnosis and are generally classified as “leukodystrophies of unknown etiology.” Moreover, even when a diagnosis is achieved, the diagnostic process lasts an average of eight years. It results in test expenses in excess of $8,000 on average per patient, including most patients who never achieve a diagnosis at all. 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. The diagnostic workup begins with cranial Magnetic Resonance Imaging (MRI) followed by sequential targeted genetic testing. However, next-generation sequencing technologies (NGS) promise rapid and more cost-effective approaches.

Despite significant advances in diagnostic efficacy, there are still substantial issues concerning the implementation of NGS in clinical settings. First, sample cohorts demonstrating diagnostic efficacy are generally small, retrospective, and susceptible to ascertainment bias, ultimately rendering them poor candidates for utility analyses (to determine how efficient a test is at producing a diagnosis). Second, historic sample cohorts have not been examined prospectively for information about the impact on clinical management (whether the test results in different clinical monitoring, a change in medications, or alternate clinical interventions).

To address these issues, the study team investigated patients with suspected leukodystrophies, or other genetic disorders affecting the white matter of the brain, at the time of initial confirmation of MRI abnormalities. A prospective collection of patients randomly received on a “first come, first served” basis from a network of expert clinical sites was developed. Subjects were randomized to receive early (1 month) or late (6 months) WGS, with SoC clinical analyses conducted alongside WGS testing. An interim analysis performed in May 2018 assessed these study outcomes for a cohort of thirty-four (34) enrolled subjects. Two of these subjects were resolved before complete enrollment and were retained as controls. Nine subjects were stratified to the Immediate Arm, of which 5 (55.6%) were resolved by WGS and 4 (44.4%) were persistently unresolved. Of the 23 subjects randomized to the Delayed Arm, 14 (60.9%) were resolved by WGS and 5 (21.7%) by SoC, while the remaining 4 (17.4%) remained undiagnosed. The diagnostic efficacy of WGS in both arms was significant relative to SoC (p<0.005). The diagnosis time was significantly shorter in the immediate WGS group (p<0.05). The overall diagnostic efficacy of the combination of WGS and SoC approaches was 26/34 (76.5%; 95% CI = 58.8% to 89.3%) over <4 months, greater than historical norms of <50% over more than five years.

The study now seeks to determine whether WGS results in changes to clinical management in subjects affected by undiagnosed genetic disorders of the white matter of the brain relative to standard diagnostic approaches. We anticipate that WGS will produce measurable downstream changes in clinical management, as defined by disease-specific screening for complications or the implementation of disease-specific therapeutic approaches.

 

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

Stage: Recruiting

Principal investigator: Joanne Kurtzberg, MD

Duke University Medical Center

Durham, NC

Inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, primarily involving a single gene mutation resulting in an enzyme defect. In the majority of 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 begin to exhibit disease manifestations during infancy, 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.

 

Title: Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

Stage: Recruiting

Principal investigator: Paul Szabolcs, MD

UPMC Children’s Hospital of Pittsburgh

Pittsburgh, PA

For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies), a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. However, HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage resulting from the underlying disease may remain present after the HSCT.

For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the primary intent of the transplant is to slow down, or stop, the progress of the disease. In a select few cases/diseases, the presence of healthy bone marrow-derived cells may even prevent progression and prevent neurological decline.

In this research study, instead of using the standard myeloablative conditioning, the study uses RIC, in which significantly lower doses of chemotherapy are administered. The lower doses may not eradicate every stem cell in the patient’s bone marrow. However, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to the successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress the patients’ surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe, and late toxic effects should also be reduced.

This study aims to collect data from the patients undergoing reduced-intensity conditioning before HSCT and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with a better survival rate, less organ toxicity, and improved quality of life following the RIC compared to the myeloablative regimen.

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