Adrenoleukodystrophy (ALD)

What is ALD?

ALD or Adrenoleukodystrophy is an X-linked genetic, progressive, neurodegenerative disorder that causes the white matter (Myelin) of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) to break down or not to develop properly. It is named for the parts of the body that it affects;  Adreno = adrenal glands, leuko = for the white matter of the brain and spinal cord (myelin) and dystrophy = meaning abnormal growth or impaired development. It damages the brain, the nervous system and over 80% of boys have Primary Adrenal Insufficiency (PAI). The result of this process is a significantly decreased life span. Please note that neonatal adrenoleukodystrophy (NALD) is not related to X-linked ALD and is part of the Zellweger spectrum which is a Peroxisomal Biogenesis Disorder (PBD)

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.

How ALD happen
ALDP CELL

Forms of ALD

Cerebral ALD (cALD)

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 conditions such as Multiple Sclerosis (MS). Sadly this costs the child valuable time where the options of a Bone Marrow Transplant or Gene Therapy would have been available.

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.

Myelopathy

Virtually all men with ALD who reach adulthood will develop myelopathy which is a serious condition referring to neurological damage to the spinal cord. Onset can be between 20-40 years of age. Symptoms are limited to the spinal cord and the peripheral nerves. Progression is normally slow generally with symptoms such as mild stiffness or “clumsiness” in the legs, tingling in the feet weight loss, attacks of nausea, and generalized weakness.  Other manifestations include difficulty with walking, urinary disturbance and impotence and most men will require the assistance of a wheelchair by the 5th -6th decade of life. Cognitive function remains normal (unless they develop cerebral ALD)

Adrenomyeloneuropathy (AMN)

Refers to men who have both Myelopathy as well as Addison Disease also known as Primary Adrenal Insufficiency (PAI).

Most men with 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 the levels of sugar, sodium, and potassium in the body, and help it to 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 AMN is more easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness).

Adult cerebral AMN affects only about 3-5 percent of men and can have an onset between the ages of 20 to the 50’s.

Women with ALD

Contrary to what was believed women who carry the ALD gene are not asymptomatic and in fact more than 80% of women will develop some symptoms of neurological dysfunction (myelopathy) by the age of 60 years. Symptoms primarily include progressive stiffness, weakness, or paralysis of the lower limbs, numbness, pain in the joints, fecal and urinary problems. Progression is slower than the men however fecal incontinence appears to be more prevalent than with the men. It is rare for women to develop adrenal issues or the cerebral form. It should be noted that women with myelopathy are frequently misdiagnosed with multiple sclerosis (MS).

Primary Adrenal Insufficiency (PAI) also known as Addison Disease

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 more easily treated, simply by taking a steroid pill daily (and adjusting the dose in times of stress or illness).

How do we diagnose ALD?

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.

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) also referred to as a Haematopoietic Stem Cell Therapy (HSCT) or Gene Therapy.

If detected at birth through Newborn Bloodspot Screening (NBS) or before symptoms have commended the son has a very chance of living a healthy and natural life into adulthood; with the successful intervention of a BMT.

The window of opportunity is small after birth as a successful procedure depends upon being correctly diagnosed before noticeable symptoms are present. BMT’s are not permanent cures but allow a healthy journey into adulthood.

Common Parental Concerns Before Correct Diagnosis

Most parents experience some or all or of these initial changes with their son which are very often misdiagnosed or misunderstood by their doctor. These are not in order as it will be different for most families. Generally, the more severe the neurological symptoms the further the progression.

  1. Change in usual behaviour  
  2. Schooling drops off
  3. Bronzing of skin – a red flag for Primary Adrenal Insufficiency (PAI)
  4. Hyperactivity
  5. Behavioural changes
  6. Aggressive behaviour
  7. Handwriting deteriorates  
  8. Loss of hearing
  9. Memory difficulties
  10. Eyesight problems such as transposing information from one source of information to another
  11. Reading difficulties
  12. Difficulty thinking
  13. Difficulty swallowing
  14. Seizures
  15. Muscle spasms
  16. Language comprehension
  17. Poor coordination
  18. Difficulty with speech
  19.  Dementia
  20. Bladder control
  21. Vomiting
  22. Fainting

Common Misdiagnoses

Attention Deficit Hyperactivity Disorder (ADHD)

Multiple Sclerosis (MS)

Incidence:

X-ALD is the most common peroxisomal disorder, occurring in 1 in 15,000 births.

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 may not 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 recessive 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.

X-linked Inheritance

Treatments for ALD:

Currently we have two (2) options for our ALD children and they are a Bone Marrow Transplantation (BMT) 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 very low number in the 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 Table

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.
Comparison between types of Bone Marrow Transplants

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 Myelopathy and 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 with cortisol replacement.

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 (VLCFA’s) in the brain thereby halting the progression of adrenoleukodystrophy (ALD). It was originally thought to hold great hope but many subsequent trials showed that it did not improve neurological and endocrine function or that it could halt the progression of ALD. It does not cross the blood-brain barrier. It is not a cure and it is not recommended by the medical profession and is not easily available in most countries of the world.

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