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Adrenoleukodystrophy in female heterozygotes: Underrecognized and undertreated

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Abstract

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease resulting from mutations in the gene ABCD1 and alterations in peroxisomal beta-oxidation of long chain fatty acids. As it has been frequently discussed, it manifests a wide range of phenotypes in male, with progressive myelopathy being the most common. Even though the gene is localized to the X-chromosome and a region subject to X-inactivation, female carriers still are affected significantly by this condition. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms and recent evidence has suggested the differences in disease manifestations and relative rates of progression between men and women. However there have been only limited studies specifically addressing this and to date there has been no comprehensive review discussing the different phenotypes in female carriers, as well as the differences in disease onset, progression, disability, nervous system pathology and neuroimaging patterns compared to affected males. This is of key importance as similarities and differences between genders will assist in determining how best to target therapies in all affected individuals as opportunities for treatment present themselves. As will be further addressed in this review, we need to improve our understanding of the associations of emergent neuroimaging techniques to physical disability in this population. We reviewed the clinical presentations in the carrier population, the distinct disability profile and neuroimaging findings in order to put together pieces of this neglected segment in X-ALD and give direction to further studies.

Highlights

► We reviewed all the current literature on females presenting with X-ALD. ► We discuss the importance of detecting and treating carriers. ► We review the distinct clinical presentation and neuroimaging findings in this population. ► We point out the clinical trials in the carriers and outline the emergent therapies.

Introduction

X-linked adrenoleukodystrophy (X-ALD), is a disorder of peroxisomal metabolism of saturated very long chain fatty acids (VLCFAs) [1]. The defective gene ABCD1 is located at Xq28 and codes for a peroxisomal membrane protein [2]. To date, more than 1000 distinct mutations have been identified (www.x-ald.nl) [3].

Impaired beta-oxidation of VLCFAs results in their accumulation, primarily in the nervous system, adrenal cortex, and testis and manifests a wide range of clinical phenotypes in males. This has been previously described in detail [1] and is summarized in Table 1. The various phenotypes co-occur in kindreds. Mutation analysis has failed to establish a consistent correlation between the highly varied genotypes and these phenotypes [1]. While the existence of a modifier gene has been postulated, it has not been identified [1].

The nervous system presentations of X-ALD can be categorized into two distinct phenotypes of adrenomyeloneuropathy (AMN) and cerebral ALD [4]. The cerebral form presents with a rapidly progressive inflammatory demyelination myelinopathy that mostly results in severe disability, vegetative state, and death within one to 2 years of clinical onset. This phenoype is most common during chilhood and adolescence, however 20% of adult-onset cases presenting initially with AMN, may develop the progresseive cerebral form of disease [5]. In contrast, pathology of AMN is fundamentally different from the cerebral form. Predominantly a non-inflammatory distal axonopathy mainly involving the spinal cord tracts and peripheral nerves [6], [7], AMN manifests as a slowly progressive paraparesis in adults and affected individuals can survive to the eighth decade.

The most neglected segment of affected individuals are women who are carriers of X-ALD. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms, but as will be discussed, there have been only limited studies specifically addressing this. The incidence of X-ALD is approximately 1:21,000 in males, and since many of these males die in childhood, it can be shown that the frequency of heterozygote females is near 1 in 14,000 [8]. Understanding of this potentially larger population manifesting the condition is important as opportunities for treatment present themselves.

Section snippets

Neurologic manifestations

Female heterozygotes for X-ALD, can develop a wide range of neurologic abnormalities (Table 2). In an early study, there were 9 affected women out of 21 possible carriers studied [9]. All had an abnormal gait, extensor plantar responses, hypertonia, and urinary symptoms. Only two women had severe symptoms requiring walking assistance. Naidu and her collegues evaluated 165 female carriers who came to their attention because of the latter's affected sons. The investigators presumed that this

Neurophysiologic studies

Evoked potentials have been abnormal in small numbers of heterozygotes [[30], [31], [32]]. When Restuccia et al., [33] studied a slightly larger population of carriers, they could demonstrate abnormalities in motor and sensory evoked responses in 7 out of 14 asymptomatic carriers with no other evidence of neurologic involvement. Most of these patients had normal MRI.

Neuroimaging

Neuroimaging is an important non-invasive method in the evaluation of the pathology of ALD. While the neuroimaging findings of cerebral ALD and AMN have been reported, the findings in women are less clear.

In a study of female heterozygotes using MRI and MR Spectroscopy (MRS), a definite brain abnormality was revealed in 4% of individuals [34]. MRS findings were abnormal in a subset of individuals with normal MRI [34]. Recently new imaging methodologies have been used in affected males and in

Physical impairments and disability

While the use of imaging and other modalities in carriers have been important in understanding the disease state, identifying and quantifying physical disability is essential to the clinical management of symptomatic carriers. Tools such as MRI quantify pathological characteristics and assess disease progression, but they provide only limited information for directing clinical care [39]. Clinical rating scales such as the Expanded Disability Status Scale (EDSS) and Functional Independence

X-linked diseases affecting carrier

While it is often stated that in recessive X-linked disorders heterozygotes are asymptomatic, it is known that for some X-linked disorders the dichotomy between recessive and dominant does not apply and there are conditions where heterozygosity may represent a disease state. Besides X-ALD, these may include Fabry disease, Lowe syndrome, and ornithine transcarbamylase deficiency [42]. A female carrier of an X-linked gene benefits from mosaicism due to “random X-inactivation”and the populations

Is skewed X-inactivation responsible for adrenoleukodystrophy phenotype in female carriers?

In a study conducted by Watkiss et al., on blood leukocytes [45], 12 carriers were investigated; 3 of those showed neurologic findings and 9 were asymptomatic at the time of study. Of 3 manifesting individuals, only one showed a severe skewed pattern whereas 2 of the non-manifesting carriers also showed a high skewing. In an in vitro study in skin fibroblasts of X-ALD carriers obtained from 3 independent families, it was stated that the mutant allele had a selective advantage [46]. By studying

Impact of diagnosis of asymptomatic carriers

There are two issues in identification of carriers. The first is the impact on their reproductive risks and the second is their own health issues as outlined above. There are several differing populations who may come to attention. The first are those females who are identified because of their family. These would include girls whose fathers have AMN and are therefore obligate carriers. Girls whose mothers are known carriers should receive counseling at an appropriate age and the availability

Identification of carriers

Previously carrier diagnosis rested on the results of family screening and the use of very long chain fatty acid analysis in those at risk. From very early on, it was apparent that 15–20% of obligate heterozygotes gave inderterminate values on VLCFA analysis most likely because of the presence of an unaffected gene copy. Initial attempts to improve on this were limited [48], [49]. The definitive determination of carriers is achieved by mutational analysis [50]. which minimizes the risk of false

Current therapies

A definitive treatment for X-ALD is lacking. Currently applied therapies include dietary therapy with Lorenzo's oil (LO), hormone replacement therapy in case of adrenal involvement, and human stem cell therapy (HSCT) in the childhood form of the disease [55]. However their efficacy in the treatment of AMN and female heterozygotes is not clearly determined.

LO is a therapy which can lower the plasma level of VLCFAs, but its role in the treatment of ALD is still unknown. A few studies investigated

Emerging therapies

A relatively new line of research has suggested the role of oxidative damage in initiating the pathology in X-ALD [[62], [63], [64]]. This is more evident in AMN phenotype where axonal degeneration is the key pathology. Rrecently it has been demonstrated that antioxidants can halt and reverse axonal degeneration in a mouse model of AMN [65]. This new concept reinforces conduct of clinical trials to test the efficacy of this potential therapy and clearly understand if there would be a difference

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