Leukodystrophy Resource and Research Organisation Inc. | Incorporated No. IA41033

Adrenoleukodystrophy (ALD) Adrenomyeloneuropathy (AMN)

What is ALD?

ALD is an X-Linked genetic, progressive, neurodegenerative disorder that causes the white matter (Myelin) of the Central Nervous System (CNS) to break down or not to develop properly. It damages the brain, the nervous system and creates adrenal insufficiency. The result of this process is a significantly decreased life span.

What causes ALD?

A defective or mutated gene called ABCD1 which is located on the X chromosome (Xq28) that encodes a protein called ALDP (an anagram for ALD protein). This protein is located on the wall of the peroxisome, and its function is to transport the very long chain fatty acids (VLCFA’s) into the cell so that they can be broken down in a process known as beta-oxidisation. This impaired function results in elevated levels of VLCFA’s in the adrenal cortex, testes and the brain which cause the break down of the myelin on the sending arm (axon) of the nerve cell (neuron). The accumulation of these VLCFA’s creates different forms of ALD. It is not understood how this works.

Forms of ALD

Childhood Cerebral Demyelinating ALD (cerALD)

This is the most common form of ALD, representing about 45% of all ALD cases. It is characterized by an inflammatory process that destroys the myelin, causing relentless progressive deterioration to a vegetative state or death, usually within five years. This silent assassin begins and usually presents symptoms between the ages of 2-11 years of age. Up to the point of onset, development is normal.

The most common initial symptoms are difficulty in school, behavioral disturbance, impaired vision, or impaired hearing. After initial neurological symptoms appear, the health of the patients deteriorates rapidly. Further symptoms may include dementia, poor coordination, seizures, hyperactivity, difficulty with speech, and headaches. It is far too often misdiagnosed as ADHD or other behavioural conditions. Sadly this costs the child valuable time where the options of a Bone Marrow Transplant, Stem Cell Transplant or Gene Therapy would have been available. Please refer to the Scientific Paper on the Home Page and print it out for those that need it.

The average time between the initial symptoms and a vegetative state (where the patient is bedridden) or death is approximately 2 years, although it can range anywhere from 6 months to 20 years.

Adolescent cerebral ALD

A small number of patients with X-linked ALD will present between the ages of 11 and 21 years. The symptoms are similar to those of childhood cerebral ALD, though progression of the disease may be somewhat slower.

Adrenomyeloneuropathy (AMN)

AMN has now been described as the “default” phenotype (a collection of symptoms) for the ALD genotype (a specific gene abnormality) because all those with the ALD genotype will acquire it. The first symptoms of AMN usually occur in the twenties. AMN affects the axons in the spinal cord.

Generally symptoms are mild stiffness or “clumsiness” in the legs, tingling in the feet weight loss, attacks of nausea, and generalized weakness. Adrenal impairment occurs, and other manifestations include difficulty with walking, urinary disturbance and impotence and most men will require the assistance of a wheelchair. Cognitive function remains normal (unless they develop cerALD)

Women (AMN)

Women who carry the ALD gene mutation rarely develop any cerebral damage but some display milder symptoms of the disorder. These symptoms usually develop after age 35, and primarily include progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, and urinary problems. The data is showing that the older they become the more prone they are to develop symptoms. The figures are showing an increase of those with AMN symptoms. Because women have a fully functional X chromosome their symptoms are milder than the men.

Asymptomatic ALD

All persons who are Asymptomatic will be free of clinical symptoms despite having elevated levels of VLCFA’s. Women remain this way longer than men.

Addison’s disease (Hypoadrenocorticism)

Most boys and men with ALD/AMN have Addison’s disease, a disorder of the adrenal gland; in about 10% of ALD cases, this is the only clinical sign of the disorder. The adrenal glands produce a variety of hormones that control levels of sugar, sodium, and potassium in the body, and help it respond to stress. In Addison’s disease, the body produces insufficient levels of the adrenal hormone, which can be life-threatening. Fortunately, this aspect of ALD is easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness).

How do we diagnose ALD?

ALD must be diagnosed as early as possible to allow informed choices to be made that can offer the family member an opportunity to have a Bone Marrow Transplant (BMT) , Stem Cell Therapy or Gene Therapy.

The window of opportunity is small and with equally small parameters of functionality to allow a successful procedure. These are therapies not cures.

X-ALD is diagnosed by a simple blood test that analyses the amount of very long chain fatty acids; the levels of these molecules are elevated in X-ALD. While the test is accurate in males, it is only 80% correct in women and gene testing must be done to ensure an accurate finding. 7% of diagnoses of ALD come from a spontaneous mutation therefore they cannot be traced to either parent.

Incidence:

X-ALD is the most common peroxisomal disorder, occurring in 1 in 17,000 births and 1 in 20,000 males.

Inheritance:

Genetics is very much like maths at school; some of us struggled a bit and others did not. It is a numbers game.

The ABCD1 gene is situated on the X – chromosome (Xq28) which is a sex chromosome. Women have 44 autosomes plus two (2) copies of the X chromosome in their bodies whilst men have 44 autosomes plus one (1) copy each of the X and Y chromosome. If a disorder is on the X chromosome of a woman she has two (2) copies, one of which will be normal so she will be a carrier and not likely to be affected by the disorder. If a man has a disorder on his sole X chromosome he will have that faulty gene.

ALD is an X – Linked dominant disorder from a mutation on a single gene (monogenic). If the mother (XX) is a carrier there is a 1 in 2 or 50% chance that her Son (XY) will be affected and a 1 in 2 or 50% chance that her daughter (XX) will be a carrier.

It is most important that all those families involved with ALD contact a genetic counsellor for a full explanation of its inheritance, consequences and of all the available options for having future children.

Treatments for ALD:

Currently we have three (3) options for our ALD children and they are a Bone Marrow Transplantation (BMT) Stem Cell Transplants and Gene Therapy. There are functional parameters that qualify whether your child is in the acceptable area where one of these can be undertaken. The critical point for these procedures is for your child to have a low Loes (pronounced less) score and meet other criteria.
The Loes score was developed to measure the loss of myelin shown on a brain MRI. It operates on a continuous scale of 0-34 points. The higher the points the more myelin loss and it has a direct correlation to functionality.

Loes Score between 1 and 5 would denote normal cognitive functions with no neurological deficits.

Loes Score between <5 and <10 would denote cognitive deficits and closer to 9 or 10 there maybe visual deficits. Loes Score <12 would denote severe cognitive deficits and neurological deficits Loes Score <15-16 could have lost the ability to both walk and talk. There are other determinants that families have to address with these options which are why an early diagnosis is essential and good conferencing with your medical “team” is critical. The transplants are termed Allogeneic because they come from a genetically similar but not identical donor as opposed to Autologous where using Gene Therapy we harvest the patients own stem cells. The following is an excellent explanation by the StopALD Foundation and we gratefully acknowledge the use of their material.

Advantages of Autologous Transplants

Allogeneic Transplants

Autologous transplants

Matching donors often cannot be found. The person is their own donor, so no match is needed. There will always be a perfect match!
Weakening the patient’s immune system via “conditioning” (ablation / chemotherapy / radiation treatment) to prepare the patient to receive donor cells is leaves him with a severely compromised immune system, vulnerable to severe illness and from even a common cold. Conditioning should be much less severe since no foreign cells will be introduced. As a result, the patient will be better equipped to successfully face everyday immune challenges like colds, stomach bugs and viruses.
Cyclosporine, a medication commonly used in BMT and UCBT patients, further damages the myelin, compounding the devastation of the brain. Cyclosporine will not be necessary, so no further destruction of the myelin is expected.
Graft versus host (GVHD) disease is a common and potentially lethal complication following BMT or UCBT. This occurs as the donated cells may attack the recipient’s tissues and organs. Graft versus host (GVHD) disease is eliminated, since each patient will be his own donor.
Adults with cerebral ALD are typically not candidates for BMT or UCBT, because of the particularly lethal risk of GVH disease in these men. If the patient requires therapy as an adult, instead of dying from advanced demyelination lesions, gene therapy will offer an option, since GVH will not be an issue.
Procedure is effective approximately 50% of the time, and has a mortality rate of up to 40%. A significantly higher success rate and considerably lower morbidity rate is anticipated with gene therapy.

Medications:

Daily treatment is based upon symptoms and not all family members endure the same problems. Medication is based upon the symptom and it is essential that steroid (cortisone) replacement is established in a fixed medication regime. Most ALD patients will also require anti-convulsants, muscle relaxants and often treatment for excessive salivation. Other medications could be required for bowel regulation, sleeping problems, pain, dehydration, temperature control, nausea, vomiting, reflux and other health issues.

Those with AMN usually do not require as broad a range of medications with the concentration mainly on the symptoms to treat walking, gait, urinary, impotence problems, motor skills and sometimes visual memory skills. The Adrenal impairment must be treated as in ALD.

Personal hygiene is critical when bed bound and there are various ways that hair washing, dental hygiene, manicure and body washing can be made easier and as effective as the traditional methods. Allied Health Departments can be very helpful here and the most knowledgeable are often those parents who have or are going through this unwelcomed experience.

Lorenzo’s Oil

Lorenzo’s Oil is a combination of a 4:1 mix of erucic acid and oleic acid, extracted from rapeseed oil and olive oil designed to normalize the accumulation of the very long chain fatty acids in the brain thereby halting the progression of adrenoleukodystrophy (ALD).

Lorenzo’s Oil is specific to ALD, does not repair myelin, and does not have any known effect on other demyelinating disorders. In ALD presymptomatic boys, however, Lorenzo’s Oil often (but not always) prevents the onset of the disease by stopping the body from producing the very long chain fatty acids, whose build up leads to demyelination.

The oil, if started early in boys with adrenoleukodystrophy (ALD) showing no symptoms, is now known to have some benefit in preventing the childhood cerebral form of adrenoleukodystrophy. Researchers are still trying to understand the complex relationships among fats in the body, and how Lorenzo’s oil could be further modified to be more effective. The oil is designed to normalize the accumulation of the very long chain fatty acids in the brain that thereby halting the progression of ALD.

It is not a cure.