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  • Updated 12.29.2019
  • Released 02.03.1994
  • Expires For CME 12.29.2022

Adrenoleukodystrophy

Introduction

This article includes discussion of adrenoleukodystrophy, ALD, Addison disease with cerebral sclerosis, Addison-Schilder disease, bronzed Schilder disease, encephalitis periaxialis diffusa, Flatau-Schilder disease, melanodermic leukodystrophy, myelinoclastic diffuse sclerosis, Schilder disease, Schilder encephalitis, Schilder encephalopathy, Siewerling-Creutzfeldt disease, sudanophilic leukodystrophy, Addison-only adrenoleukodystrophy, adolescent adrenoleukodystrophy, adrenomyeloneuropathy, adult adrenoleukodystrophy, adult cerebral adrenoleukodystrophy, adult-onset adrenoleukodystrophy, autosomal recessive adrenoleukodystrophy, childhood adrenoleukodystrophy, childhood cerebral adrenoleukodystrophy, neonatal adrenoleukodystrophy, X-ALD, and X-linked adrenoleukodystrophy. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy, with an estimated incidence of 1:17,000. Both men and women may be affected. Plasma very long chain fatty acid (VLCFA) concentrations are already elevated at birth. VLCFA screening of at-risk relatives and of patients with idiopathic Addison disease permits diagnosis prior to neurologic involvement. Three therapies are in current use: adrenal steroid replacement, preventive therapy with Lorenzo Oil for asymptomatic patients with normal MRI, and hematopoietic stem cell transplantation for patients with early cerebral involvement. The latter, however, does not correct the adrenal insufficiency. or prevent the myelopathy. Ex-vivo lentiviral gene transfer to hematopoietic stem cells shows great promise. Newborn screening for this disorder has been developed and is beginning to be applied.

Key points

• X-linked adrenoleukodystrophy is the most common leukodystrophy.

• It combines a genetic defect with an inflammatory brain reaction and adrenal insufficiency.

• The frequency of symptomatic heterozygote women increases sharply with age.

• If initiated very early in the disease process, X-linked cerebral adrenoleukodystrophy can be effectively treated using hematopoietic stem cell transplantation.

• Initial success in gene therapy using ex-vivo gene transfer has been described, and it seems to have clear advantages over allogeneic hematopoietic stem cell transplantation.

• Newborn screening for X-linked adrenoleukodystrophy is available but presents practical, economic, and ethical challenges.

Historical note and terminology

Adrenoleukodystrophy was first described in 1923 by Siemerling and Creutzfeldt (126). In 1963 Fanconi and colleagues proposed an X-linked mode of inheritance on the basis of pedigree analysis (27). In 1981 the gene was mapped to Xq28, the terminal segment of the long arm of the X-chromosome (76), and the putative gene was isolated in 1993 (95). The identity of the gene and the defective protein, which is referred to as ALDP, is now established firmly because all patients who have been studied in sufficient detail have a mutation in this gene (19; 51), and transfection of mutant cells with the normal gene corrects the biochemical defect (15). The principal biochemical abnormality, namely the abnormal accumulation of saturated very long-chain fatty acids in the brain white matter and adrenal cortex, particularly hexacosanoic acid (C26:0), was identified by Igarashi and colleagues (45). Singh and colleagues showed that this accumulation is due to the impaired capacity to degrade very long-chain fatty acids (127), a reaction that normally takes place in the peroxisome (128). Lazo and colleagues pinpointed the defect more precisely by showing that patients with adrenoleukodystrophy have an impaired capacity to form the coenzyme A derivative of very long-chain fatty acids (60). The enzyme that catalyzes this reaction, very long-chain Acyl-Coenzyme A synthetase, has been cloned (138). It came as a surprise that the gene that has been proven to be deficient in adrenoleukodystrophy does not code for this enzyme, but rather for a peroxisomal membrane protein, ALDP, which is a member of the ATP binding cassette protein family, a group of proteins that is involved in a variety of transport functions (38). The relationship between ALDP and very long-chain fatty acid metabolism is not yet understood.

The nomenclature of adrenoleukodystrophy has evolved over time. The patient with "encephalitis periaxialis diffusa" described by Paul Schilder in 1913 almost certainly had what we now refer to as adrenoleukodystrophy (123), and sometimes the designation of Schilder disease is still applied to adrenoleukodystrophy patients. This may lead to confusion because Schilder disease is heterogeneous (111). In the German literature adrenoleukodystrophy was sometimes termed "bronzed Schilder disease," referring to the pigmentation associated with the frequently associated adrenal insufficiency. Up to the mid-1970s the disorder was often referred to as "Addison-Schilder disease," or "melanodermic type of leukodystrophy." The term "adrenoleukodystrophy" was coined by Blaw in 1970 and is now generally accepted (09). In 1976, Budka and colleagues and Griffin and colleagues showed independently that an adult form of the disease, now referred to as "adrenomyeloneuropathy," is a variant of adrenoleukodystrophy (13; 36), and the whole group of disorders is at times referred to under the umbrella term of "adreno-testiculo-leukomyeloneuropathy-complex" (113). The condition referred to as "neonatal adrenoleukodystrophy" represents a possible source of confusion and must be differentiated sharply (50). Neonatal adrenoleukodystrophy is a disorder with an autosomal recessive mode of inheritance, and its basic defect involves the import of a variety of proteins into the peroxisome (59). Its clinical manifestations are totally different from the X-linked form of adrenoleukodystrophy described in this chapter. In spite of this plethora of historically-based designations, the classification and nomenclature can now be applied precisely. We recommend that the designation adrenoleukodystrophy be applied to all males who have a defect in the x-linked gene that codes for ALDP. All of these persons have demonstrable defects in very long-chain fatty acid metabolism. Their clinical manifestations may vary from asymptomatic, to isolated primary adrenal insufficiency, to various degrees of neurologic involvement. When there is clinical and radiological evidence of involvement of the cerebral hemispheres we refer to them as childhood, adolescent, or adult cerebral forms of adrenoleukodystrophy. When nervous system involvement affects mainly the spinal cord and peripheral nerves, the condition is referred to as adrenomyeloneuropathy. The term neonatal adrenoleukodystrophy refers to a totally unrelated disorder that has an autosomal recessive mode of inheritance, and that nearly always manifests in the neonatal period, with multiple and distinct biochemical abnormalities due to a defect in peroxisome biogenesis (59).

Studies have defined the molecular basis of neonatal adrenoleukodystrophy, and these are summarized in a review (85). Neonatal adrenoleukodystrophy is now considered to be member of a clinical continuum, with Zellweger syndrome the most severe, neonatal adrenoleukodystrophy of intermediate severity, and infantile Refsum disease the least severe. Each of these disorders can be associated with 10 separate genetic defects, all of which impair the import of proteins into the peroxisome. The severity of disease expression relates to some extent with the nature of the mutation. Mutations that abolish import completely are most likely to be associated with the Zellweger syndrome phenotype, whereas in patients with milder phenotypes the import function is partially retained. Mosaicism has been demonstrated in some other patients with milder phenotypes.

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