Cerebral adrenoleukodystrophy (ALD) is a debilitating inherited metabolic disorder that progressively destroys the nervous system. It is X-linked recessive (i.e. it affects males almost exclusively and is transmitted by mothers who are asymptomatic carriers of the gene), manifests itself during childhood, and is exceedingly rare (striking approximately 1 in 100,000 male children). Cerebral ALD has a 100% fatality rate. At this date, there is no known cure.

Symptoms

Children with ALD appear healthy and normal until the onset of clinical symptoms, which generally occurs at 4-8 years of age (less than 3% of cerebral ALD sufferers begin showing symptoms in adolescence or adulthood). The initial symptoms of ALD include sudden behavioral changes, decreased performance in school, and slight but noticeable visual or auditory impairment. Hyperpigmentation or "bronzing" due to adrenal insufficiency may also be present. As the disease rapidly progresses, the symptoms become increasingly severe, involving a spastic gait and decreased dexterity that degenerates into paralysis, seizures, blindness, deafness, and eventually, a vegetative state. Soon afterwards, the disease begins to attack the autonomic nervous system, which regulates involuntary functions necessary for life, such as breathing, the beating of the heart, and digestion. The mean period of time between the onset of the initial symptoms and death is 2-5 years.

Causes and Biochemistry

The symptoms of ALD are caused by demyelination. The nervous system operates via electrochemical impulses. Myelin is fatty tissue that sheathes each neuron to prevent it from unintentionally responding to electrical impulses from other neurons. Neurons are roughly analogous to electrical wiring, and myelin can be thought of as electrical insulation.

If the preceding paragraph confused you, you may as well skip to the "Treatments" section, because it's about to get a bit more technical.

In the case of ALD, demyelination is caused by an excessive accumulation of very long chain fatty acids (VLCFA) in the neural tissue. Examples of VLCFAs include hexacosanoic, pentacosanoic, and tetracosanoic acids. The presence of VLCFAs in the body is normal, even necessary, but in ALD patients, the VLCFA levels are grossly elevated. Usually, VLCFAs are metabolized (via beta-oxidization) in the peroxisomes. Traditional theories hold that ALD patients lack the required enzyme or enzymes to catalyze the reaction. Research has isolated a gene that causes ALD, and surprisingly, the ALD gene is not the same as the gene that maps to this enzyme. New theories tentatively suggest that ALD may actually be caused by a protein deficiency in the peroxisomal membrane that prevents the transport of VLCFAs into the peroxisomes.

Adrenoleukodystrophy is so named because one of the hallmarks of the disease is the deterioration of the adrenal cortex (adreno-), and because ALD affects the white matter (leuko-).

Treatments

There is no cure for ALD, as science has yet to discover a way to successfully promote the regrowth of myelin. There are, however, several treatments that can slow or even halt the progress of the disease.

Restricted Diet and Lorenzo's Oil

One possibility for combating ALD is to limit the patient to a diet low in the culprit VLCFAs. By itself, this treatment is not particularly effective as most VLCFAs are not ingested but produced by the patient's own body.

In addition to dietary therapy, a concoction known as Lorenzo's Oil may be administered. Lorenzo's Oil consists of 4 parts oleic acid (found in olive oil, corn oil, and sunflower seed oil) to 1 part erucic acid (found in rapeseed oil). When the oil is used in conjunction with a restricted diet, the plasma levels of several different VLCFAs will normalize within a few weeks. This may hinder the progression of the disease somewhat, although detractors have criticized its efficacy. Because the oil does not cross the blood-brain barrier, it has no effect on VLCFAs that are already present in the brain. Lowering VLCFA levels in the rest of the body may slow the accumulation in the brain, but once the child presents with symptoms, much of the damage has already been done.

Lovastatin

Lovastatin is a medication designed to treat high cholesterol. When administered to ALD patients, it produces similar effects to Lorenzo's Oil (normalizing VLCFA levels) without the need for a restricted diet. The use of lovastatin as a therapy for ALD is recent, and more research in human subjects is necessary.

Bone Marrow Transplant

The closest thing to a cure for ALD is a bone marrow transplant. The transplanted cells have normal peroxisomes and thus contain the protein that is deficient in ALD patients, so the transplanted tissue can metabolize the VLCFAs. However, this therapy is controversial for two reasons. First of all, it is extremely difficult to find a suitable donor - usually, siblings donate bone marrow, but because ALD is inherited, chances are high that the patient's siblings have ALD or are ALD carriers. Secondly, studies have shown that transplants are only effective if the patient has not yet exhibited symptoms or is in the very early stages of ALD. Performing a bone marrow transplant in an ALD patient who has already developed symptoms may actually accelerate the progression of the disease. In one study, 37% of the ALD subjects died within one year of the transplant. Extensive research on bone marrow transplants in ALD sufferers is plagued by ethical problems. As a treatment, it is considered extremely dangerous, but for many ALD patients, it is their only hope.

Related Disorders

Generally, when people talk about adrenoleukodystrophy, they are referring to the cerebral form of the disease as described above. There are, however, two closely related disorders that are caused by the same genetic factors: adrenomyeloneuropathy and Addison's disease.

Adrenomyeloneuropathy

Adrenomyeloneuropathy (AMN) stems from the same cause as cerebral ALD, but presents slightly different symptoms. Most notably, the onset of AMN symptoms does not occur in childhood, but between 30-50 years of age. Sometimes AMN may have some cerebral involvement, but it usually is limited to the spinal cord and peripheral nervous system, leaving cognitive functioning intact. The symptoms may not be quite as severe, and AMN is not necessarily fatal. Not all AMN patients are men: approximately 50% of female ALD carriers develop mild AMN symptoms later in life. The treatment remains the same.

Many cases of adrenomyeloneuropathy are erroneously diagnosed as multiple sclerosis, another demyelating disorder with similar symptoms but a different root cause.

Addison's Disease

As related to ALD, Addison's disease is really more of a symptom than anything else. Addison's, which is characterized by adrenal insufficiency, may be caused by several factors, including (but not limited to) ALD and AMN. 90% of children under the age of 10 who have Addison's disease also have ALD. The percentage of patients who have both diseases drops sharply with age.

There is a form of ALD known as Addison's-only adrenoleukodystrophy in which the patient carries the ALD gene and has adrenocortical insufficiency, but there is no involvement of the nervous system. In these cases, the only necessary treatment is corticosteroids. This form is relatively rare, accounting for 10% of ALD-related diagnoses (AMN accounts for approximately 50%, and cerebral ALD, the most severe, accounts for 40%).

The Odone Family and the Myelin Project

In 1984, Michaela and Augusto Odone noticed that their six year old son Lorenzo began to exhibit symptoms similar to those of attention deficit disorder. When Lorenzo started bumping into walls and having seizures, they knew it was much more serious than that. He was diagnosed with cerebral adrenoleukodystrophy, a disease the Odones had never heard of and one that the medical professionals they consulted knew little about. They thoroughly researched the subject and enlisted the aid of Dr. Hugo Moser, the world's leading expert on ALD.

With Moser's help, the Odones eventually developed Lorenzo's Oil, but not in time to really save their son. Lorenzo was already blind, aphasic, and almost completely paralyzed, with the exception of his eyelids and a few of his fingertips. The Odones, discouraged but not defeated, started the Myelin Project, a research organization dedicated to the study of remyelination. 1992 saw the release of a film based on their lives, aptly titled Lorenzo's Oil. The film has been criticized for exaggerating the beneficial effects of Lorenzo's Oil as well as the Odones' role in developing it, but nevertheless, it served to raise public awareness of adrenoleukodystrophy and aid in fundraising efforts for new research.

Michaela Odone passed away in 2000, but her husband Augusto carried on with their efforts at the Myelin Project. Lorenzo Odone, against all odds, survived until May 30, 2008, the day after his 30th birthday and more than 20 years longer than physicians had predicted when he was diagnosed with cerebral ALD. The cause of death was aspiration pneumonia, which developed after a piece of food lodged in his lungs. He died at his father's home in Fairfax, Virginia while awaiting an ambulance. Lorenzo Odone was the oldest surviving cerebral ALD patient on record.

Sources:
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?300100
http://www.x-ald.nl
http://www.icondata.com/health/pedbase/files/ADRENOLE.HTM
http://www.geneclinics.org/profiles/x-ald
http://www.myelin.org
http://www.aldfoundation.org