Adrenoleukodystrophy (ALD) is a rare, genetic disorder characterized by the breakdown or loss of the myelin sheath surrounding nerve cells in the brain and progressive dysfunction of the adrenal gland. ALD is one of a group of genetic disorders called the leukodystrophies that cause damage to the myelin sheath – the fatty covering – on nerve fibers in the brain.
A demyelinating disease is any of the nervous system in which the sheath of neurons is damaged. This impairs the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions depending on which nerves are involved.The term describes the effect of the disease, rather than its cause; some demyelinating diseases are caused by genetics, some by infectious agents, some by autoimmune reactions, and some by unknown factors. Multiple Sclerosis is perhaps the most common demyelinating illness.
The most common symptoms are usually behavioral changes such as abnormal withdrawal or aggression, poor memory, and poor school performance. Other symptoms include visual loss, learning disabilities, seizures, poorly articulated speech, difficulty swallowing, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, increased skin pigmentation, and progressive dementia.
The milder adult-onset form is also known as adrenomyeloneuropathy (AMN), which typically begins between ages 21 and 35. Symptoms may include progressive stiffness, weakness or paralysis of the lower limbs, and ataxia. Although adult-onset ALD progresses more slowly than the classic childhood form, it can also result in deterioration of brain function. Almost half the women who are carriers of X-ALS will develop a milder form of AMN but almost never will develop symptoms seen in boys the X-ALD. X-ALD should not be confused with neonatal adrenoleukodsystrophy, which is a disease of newborns and young infants and belongs to the group of peroxisomal biogenesis disorders.
X-linked adrenoleukodystrophy – Mutations in the ABCD1 gene cause X-linked adrenoleukodystrophy. The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP), which is involved in transporting certain fat molecules called very long-chain fatty acids (VLCFAs) into peroxisomes. Peroxisomes are small sacs within cells that process many types of molecules, including VLCFAs.
ABCD1 gene mutations result in a shortage (deficiency) of ALDP. When this protein is lacking, the transport and subsequent breakdown of VLCFAs is disrupted, causing abnormally high levels of these fats in the body. The accumulation of VLCFAs may be toxic to the adrenal cortex and myelin. Research suggests that the accumulation of VLCFAs triggers an inflammatory response in the brain, which could lead to the breakdown of myelin. The destruction of these tissues leads to the signs and symptoms of X-linked adrenoleukodystrophy.
The prevalence of X-linked adrenoleukodystrophy is 1 in 20,000 to 50,000 individuals worldwide. This condition occurs with a similar frequency in all populations.
Causes
The genetic defect in ALD causes a decrease in the ability to degrade very long chain fatty acids. These build up in the adrenal glands, brain, plasma, and fibroblasts. The build-up of very long chain fatty acids interferes with the ability of the adrenal gland to convert cholesterol into steroids and causes demyelination of nerves in the white matter of the brain. Demyelinated nerve cells are unable to function properly.
The condition results in the buildup of very-long-chain fatty acids in the nervous system, adrenal gland, and testes, which disrupts normal activity. There are three major categories of disease:
- Childhood cerebral form — appears in mid-childhood (at ages 4 – 8)
- Adrenomyelopathy — occurs in men in their 20s or later in life
- Impaired adrenal gland function (called Addison disease or Addison-like phenotype) — adrenal gland does not produce enough steroid hormones
Symptoms
Signs of childhood cerebral ALD include –
- Muscle spasms
- Seizures
- Trouble swallowing
- Loss of hearing
- Trouble with language comprehension
- Impaired vision
- Hyperactivity
- Paralysis
- Coma
- Deterioration of fine motor control
- Crossed eyes
Signs of adrenomyelopathy include –
- Poor control of urination
- Weak muscles
- Stiffness in the legs
- Difficulty thinking and remembering visual perceptions
Signs of adrenal gland failure or Addison’s disease include –
- Poor appetite
- Weight loss
- Decreased muscle mass
- Vomiting
- Weak muscles
- Coma
- Darker areas of skin color or pigmentation
Treatment
Adrenal Replacement – the replacement of the faulty adrenal function often present in X-ALD. The adrenal glands are next to the kidney, and produce certain important hormones. If the adrenal functions are not properly functioning, these hormones need to be replaced. If adrenal function is reduced, provide replacement therapy.
Bone Marrow Transplantation – bone marrow transplantation has not been successful in patients with advanced neurological involvement, but only in patients in earlier stages of the disease.
Lorenzo’s oil – This is a mixture of two oils (glyceryl trieucate, or GTE, and glyceryl trioleate, or GTO). It is thought to aid in the normalization of the fatty acid levels. However, this oil does not seem to alter the progression of the disease once the brain is involved. It is not yet clear if Lorenzo’s oil could prevent progression prior to symptoms.
Alternative Treatment