Adrenoleukodystrophy: Title and subTitle BreakNew Approaches to a Neurodegenerative Disease

X-linked adrenoleukodystrophy (X-ALD)¹ was first described in Germany by Siemerling and Creutzfeld in 1923.² They named it “Bronzekrankheit und Sklerosierende Encephalitis” because of the unique combination of primary adrenal insufficiency with an inflammatory demyelinating process that affects the cerebral hemispheres. In Vienna, Paul Schilder provided a detailed description of the neuropathology,³ which led to its designation as “Schilder’s disease.” X-linkage was proposed in 1963 on the basis of pedigree analysis.⁴ The name “adrenoleukodystrophy” was introduced 1970 by Michael Blaw and is now generally used.⁵

Until 1976, X-ALD was thought of as a poorly understood and very rare disorder that affected boys with inexorably progressive neurological and behavioral deficits that led to death within a few years. Since then, the biochemical and genetic basis of X-ALD have been defined; it occurs more frequently, the range of phenotypic expression is wider than had been recognized, and methods of prevention and therapy are emerging.

In 1976 Igarashi and colleagues⁶ made the seminal observation that saturated very long chain fatty acids (VLCFAs), such as hexacosanoic acid (C26:0), accumulate in the postmortem brain and adrenal tissue of patients with X-ALD.⁶ It was shown later that this excess is also present in plasma.⁷ The capacity to degrade VLCFA, a reaction that takes place in the peroxisome, is impaired in patients with X-ALD.¹ The defective gene in X-ALD that maps to Xq28 and codes for a peroxisomal membrane protein (ALDP) is a member of a large family of proteins referred to as the “ATP binding cassette (ABC) transporters,” specifically ABCD1.⁸ More than 500 different mutations of ABCD1 have been identified in patients with X-ALD (updated periodically on the X-linked Adrenoleukodystrophy Database Web site [available at: www.x-ald.nl]).

The overall frequency of X-ALD is estimated to be 1:17 000,⁹ close to that of phenylketonuria (1:14 000). All ethnic groups are affected, with no apparent difference in frequency. Our laboratory has identified 1441 kindreds with 3831 affected males and 3356 women who are heterozygous for X-ALD. Markedly different phenotypes often co-occur within a family. No correlation has been demonstrated between phenotype and the ABCD1 mutation.

Until 1976, the inflammatory demyelinative process that involved the cerebral hemispheres in young and adolescent boys was the only X-ALD phenotype generally recognized. In 1976, Budka and associates¹⁰ and Griffin et al¹¹ independently and simultaneously reported a form of X-ALD that presents as a slowly progressive paraparesis in adults and is now referred to as “adrenomyeloneuropathy” (AMN). The pathological basis of AMN is a noninflammatory distal axonopathy that involves the long tracts of the spinal cord and, to a lesser extent, the peripheral nerves.¹² Adrenomyeloneuropathy confined to the spinal cord tracts and peripheral nerves and without radiological evidence of diffuse cerebral involvement¹³ is referred to as “pure AMN.” Approximately 20% of patients with pure AMN also develop inflammatory cerebral involvement. This group is referred to as “AMN-cerebral.” X-ALD can also manifest as Addison disease without evidence of neurological involvement. Such patients are referred to as the “Addison-only” phenotype.

The Table shows the great variability of phenotypic expression as well as the wide range of disorders for which X-ALD has been mistaken. In children and adolescents, it is often misdiagnosed as an attention-deficit/hyperactivity disorder (ADHD), and in adults as multiple sclerosis. Screening for VLCFA in at-risk relatives is identifying an increasing number of asymptomatic males with X-ALD.⁹ Women who are carriers may develop an AMN-like syndrome, but cerebral involvement and adrenal insufficiency are rare.¹⁵

In the past, the diagnosis of X-ALD had often been delayed, at times until a decade or more after symptoms began or even not until after death. This is unfortunate, because therapies could have been offered, and the opportunity for timely genetic counseling was lost. Lack of awareness of X-ALD and of the wide range of the phenotypic expression of X-ALD has been the most frequent cause of delay.

The plasma VLCFA assay⁷ is the recommended diagnostic procedure in males. Plasma VLCFA levels are increased on the day of birth. The assay provides a rapid distinction between X-ALD and all other conditions it can mimic. It is particularly important that the assay be performed in all males with idiopathic Addison disease and in men with progressive paraparesis. The early symptoms of childhood cerebral ALD are difficult to distinguish from the much more frequent ADHD. While it is not practical to screen all boys with ADHD for X-ALD, the assay should be performed when there are unusual or progressive features. It is crucially important to screen at-risk family members of known patients with X-ALD. This screen should include the extended family—hundreds of asymptomatic boys have been identified in this way.⁹

Plasma VLCFA levels are increased in women who are heterozygous for X-ALD,⁷ but false-negative test results can occur. DNA-based diagnosis in carriers is reliable¹⁶ and is recommended as the diagnostic assay in women. After the DNA mutation in an X-ALD kindred has been defined, heterozygotes can be identified accurately and rapidly by determining whether the mutation is present in at-risk women. Levels of VLCFA are increased in cultured amniocytes and chorion villus cells, which has permitted prenatal identification of hundreds of affected male fetuses,¹⁷ but confirmation by DNA analysis is recommended.

Brain magnetic resonance imaging (MRI)¹⁸ often shows characteristic, but not totally specific, changes in the cerebral forms of X-ALD. Brain MRI is often normal in patients with pure AMN and in heterozygotes.¹⁵ Spinal cord MRI in patients with AMN shows nonspecific cord atrophy, but magnetization transfer permits quantification.¹⁹

Three modes of therapy are available at this time. They improve the prognosis of X-ALD significantly when offered in the early stages of the illness, but a definitive cure does not yet exist.

Adrenal hormone replacement therapy must be provided for the more than 70% of male X-ALD patients who have adrenal insufficiency. Patients with impaired adrenal reserve can be identified and treated at 6 to 12 months of age.²⁰ This can prevent a potentially life-threatening adrenal crisis, which in the past contributed to significant morbidity and mortality, and improves general strength and well-being. However, there is currently no definitive evidence that steroid replacement therapy slows neurological progression.

Lorenzo’s oil is a 4:1 mixture of glyceryl-trioleate and glyceryl-trierucate, which normalizes plasma VLCFA levels in X-ALD patients within 4 weeks.²¹ While Lorenzo’s oil therapy does not alter the progression after the onset of cerebral disease, recent data suggest that it may significantly reduce the risk of developing cerebral disease.²² Carefully supervised Lorenzo’s oil therapy is recommended for asymptomatic boys with X-ALD who have a normal MRI result, particularly those who are younger than 8 years, and can now be provided as part of a research protocol. This must be combined with adrenal hormone replacement therapy as indicated and monitoring of brain MRI. Patients who show early evidence of cerebral involvement should be considered for hematopoietic stem cell transplantation (HSCT).²³ A placebo-controlled trial evaluating therapeutic efficacy of Lorenzo’s oil in patients with pure AMN is now in progress.

Hematopoietic stem cell transplantation has been shown to be of long-term benefit in the inflammatory cerebral forms of X-ALD.²⁴ Peters et al²³ have analyzed the outcome in 126 patients and found that this varied greatly with the severity of the process at the time of HSCT. An excellent outcome (92% 5-year survival) was achieved in boys in whom the involvement was still mild (performance IQ >80 and limited MRI abnormality).²³ For patients with more advanced disease, the mortality and quality of life outcomes were unfavorable and the procedure is not recommended. It is also not recommended for asymptomatic patients with normal MRI findings, because half of them may never develop the cerebral forms of X-ALD (it is not known whether HSCT benefits patients with pure AMN). The “window of opportunity” for HSCT is narrow. Half or more of the patients with cerebral forms who are diagnosed when they became symptomatic no longer meet the criteria for HSCT at diagnosis. Neurologically asymptomatic boys who are identified by screening at-risk relatives of known patients or those with idiopathic Addison disease have the best chance of benefiting from HSCT.

In the absence of a definitive treatment strategy, timely identification of carriers and genetic counseling are imperative. Women heterozygous for X-ALD can be identified accurately by mutation analysis or pedigree analysis (daughters of X-ALD men are obligate heterozygotes). Studies of chorion villus sampling or amniocentesis permit accurate prenatal identification of affected male fetuses. Preimplantation diagnosis of X-ALD is now available and offers an important new alternative for women who are carriers.

Unlike many other inherited metabolic disorders, X-ALD does not compromise cognitive development²⁵ ; hence, appropriate management improves the chances of a meaningful and productive life. This, combined with the severity of the untreated illness, the encouraging effects of therapy applied in the early stages, and its relatively high incidence,⁹ provides compelling rationale for neonatal screening. Methods to accomplish this are now under investigation and are likely to become available. New methods of therapy, such as gene therapy and new pharmacological approaches, are being developed and some are being tested in animal models. Neonatal screening will make it possible to provide therapies to all patients before their nervous system has been damaged. Advances in therapy and prevention are taking place concurrently and will lessen the burden of this devastating disorder.