MinireviewAdrenoleukodystrophy in female heterozygotes: Underrecognized and undertreated
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
References (67)
- et al.
Adrenoleukodystrophy
Endocrinol. Metab. Clin. North. Am.
(1991) - et al.
Delay in diagnosis of X-linked adrenoleukodystrophy
Clin. Neurol. Neurosurg.
(1993) - et al.
Serum autoantibody responses to myelin oligodendrocyte glycoprotein and myelin basic protein in X-linked adrenoleukodystrophy and multiple sclerosis
J. Neuroimmunol.
(2001) - et al.
Detection of adrenoleucodystrophy carriers by means of evoked potentials
Lancet
(1982) - et al.
Identification of female carriers of adrenoleukodystrophy
J. Pediatr.
(1983) - et al.
Accurate DNA-based diagnostic and carrier testing for X-linked adrenoleukodystrophy
Mol. Genet. Metab.
(1999) - et al.
Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999
Blood
(2004) - et al.
X-linked adrenoleukodystrophy
Nat. Clin. Pract. Neurol.
(2007) - et al.
Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters
Nature
(1993) - et al.
ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations
Hum. Mutat.
(2001)
Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy
Brain
Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy
Ann. Neurol.
The dorsal root ganglia in adrenomyeloneuropathy: neuronal atrophy and abnormal mitochondria
J. Neuropathol. Exp. Neurol.
Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy
J. Neuropathol. Exp. Neurol.
Adrenoleukodystrophy: incidence, new mutation rate, and results of extended family screening
Ann. Neurol.
Adrenoleukodystrophy: clinical and biochemical manifestations in carriers
Neurology
The adrenoleukodystrophies
Crit. Rev. Neurobiol.
Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy
Dev. Neurosci.
X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy
J. Neurol. Neurosurg. Psychiatry
Adrenoleukodystrophy mimicking multiple sclerosis
Can. J. Neurol. Sci.
Heterozygous X-linked adrenoleukodystrophy-associated myelopathy mimicking primary progressive multiple sclerosis
J. Neurol.
Multiple sclerosis-like syndrome in a woman heterozygous for adrenoleukodystrophy
Eur. Neurol.
Adrenoleukodystrophy mimicking multiple sclerosis
Nervenarzt
Addison disease and cerebral sclerosis in an apparently heterozygous girl: evidence for inactivation of the adrenoleukodystrophy locus
Clin. Genet.
Pathologic findings in adrenoleukodystrophy heterozygotes
Arch. Pathol. Lab. Med.
Adrenoleukodystrophy in an adult female. A clinical, morphological, and neurochemical study
J. Neurol.
Symptomatic adrenoleukodystrophy heterozygote with fluctuated neurological symptoms—a case report
Rinsho Shinkeigaku
Cerebral X-linked adrenoleukodystrophy in a girl with Xq27-Ter deletion
Ann. Neurol.
Phenotypes of female adrenoleukodystrophy
Neurology
Addison's disease in association with spastic paraplegia
Br. Med. J.
Combination of Addison's and Schilder's disease in a woman aged 43 years (author's transl)
Acta. Neuropathol.
Sparse hair and multiple endocrine disorders in two women heterozygous for adrenoleukodystrophy
Am. J. Med. Genet.
Assessment of adrenal function in women heterozygous for adrenoleukodystrophy
J. Clin. Endocrinol. Metab.
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2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1Hematopoietic Stem Cell Transplantation to Treat Leukodystrophies: Clinical Practice Guidelines from the Hunter's Hope Leukodystrophy Care Network
2019, Biology of Blood and Marrow TransplantationCitation Excerpt :A portion of men with AMN (approximately 20%) will also develop cALD with similarly poor outcomes [68]. Female carriers are at risk for developing AMN, but adrenal insufficiency and cerebral disease is rare [29]. HSCT is indicated only for patients with early cALD [1,3,69,70].
Long-term outcome of patients with X-linked adrenoleukodystrophy: A retrospective cohort study
2017, European Journal of Paediatric NeurologyCitation Excerpt :Our study adds new patients and their long-term outcome to increase our knowledge regarding natural history of X-ALD in males and females. Diagnosis of symptomatic females is difficult, as many of symptomatic females are initially diagnosed with multiple sclerosis (MS) until identification of index male in the family.21,22 In a prospective study of 33 female X-ALD carriers, prevalence of symptomatic females was 87% who had clinical and neurophysiological impairments.23