Adrenoleukodystrophy

Definition

Definition of Adrenoleukodystrophy
Adrenoleukodystrophy (ALD, also called Siemerling-Creutzfeldt Disease or Addison-Schilder's disease is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies, whose chief feature is damage to myelin. In adrenoleukodystrophy, over-accumulation of VLCFAs leads to damage to the brain, adrenal gland, and peripheral nervous system on the age of onset of the disease. The classical, severe type is the childhood cerebral form which, as an X-linked disease, affects primarily males.

Symptoms

Symptoms of Adrenoleukodystrophy
Symptoms normally start between the ages of 4 and 10 and include loss of previously acquired neurologic abilities, seizures, ataxia, Addison's disease, and degeneration of visual and auditory function. It has been seen that infants that have been positively diagnosed by the age of 1 year old have usually become very ill by the age of 1 to 12 years and die soon after. This severe form of the disease was first described by Ernst Siemerling and Hans Gerhard Creutzfeldt. A similar form can also occur in adolescents and very rarely in adults. Addison's disease can be an initial symptom of ALD, and many pediatric endocrinologists will measure very long chain free fatty acids in newly diagnosed males with this condition, as a screening test for ALD.

Causes

Causes of Adrenoleukodystrophy
Adrenoleukodystrophy is passed down from parents to their children as an X-linked genetic trait. It therefore affects mostly males, although some women who are carriers can have milder forms of the disease. It affects approximately 1 in 20,000 people from all races.

Diagnosis

Diagnosis of Adrenoleukodystrophy
The diagnosis is established by clinical findings and the detection of serum very long-chain free fatty acid levels. MRI examination reveals white matter abnormalities, and neuro-imaging findings of this disease are somewhat reminiscent of the findings of multiple sclerosis. Genetic testing for the analysis of the defective gene is available in some centers.

Treatment

Treatment of Adrenoleukodystrophy
While there is currently no cure for the disease, some dietary treatments, for example, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate (Lorenzo's oil) in combination with a diet low in VLCSFA (very long chain saturated fatty acids), have been used with limited success, especially before disease symptoms appear. A 2005 study shows positive long-term results with this approach. A 2007 report also appraises "Lorenzo's oil". See also the Myelin Project. X-linked adrenoleukodystrophy has a very variable clinical course, even within a single family. It is therefore not possible to determine if Lorenzo's oil is preventing progression of the disease in asymptomatic patients, or if these patients would have remained asymptomatic even without treatment. Current double blind placebo-controlled trials may be able to answer the questions regarding the effectiveness of treatment.

Hematopoietic stem cell transplantation (HSCT, including bone marrow transplant) is thought to be able to stop the progression of the X-ALD disease in asymptomatic or mildly symptomatic boys who have a Loes score lower than 9 (an MRI measure of the severity of the disease), though outcomes are markedly poorer in symptomatic boys. HSCT carries a risk of mortality and morbidity and is not recommended for patients whose symptoms are already severe. Umbilical cord blood stem cell transplant may provide an alternative for patients who do not have a matched related stem cell donor. Preliminary studies suggest that the outcome of cord blood stem cell transplant for X-ALD is particularly good in very young, presymptomatic patients.

Lovastatin is an anti-cholesterol drug that appears to have some effect in vitro, but not in mice with the animal model of adrenoleukodystrophy. A clinical study of lovastatin showed encouraging biochemical changes, but no objective clinical improvement. In a randomized, double-blind, placebo-controlled crossover trial, researchers found no effect of lovastatin on tissue levels of very long chain free fatty acids, and they recommended that it not be used in X-ALD.

Prognosis

Prognosis of Adrenoleukodystrophy
Treatment is symptomatic. Progressive neurological degeneration makes the prognosis generally poor. Death occurs within one to ten years of presentation of symptoms. The use of Lorenzo's Oil, bone marrow transplant, and gene therapy is currently under investigation.

Prevention

Prevention of Adrenoleukodystrophy
Although there is no guaranteed method for preventing X-ALD, health care providers can recommend genetic counseling for prospective parents with a family history of X-ALD. Female carriers can be diagnosed 85% of the time based on blood very long chain fatty acid (VLCFA) levels and genetic testing performed by specialized laboratories.