Adrenal Insufficiency Due to X-Linked Adrenoleukodystrophy...Once adrenal insufficiency is present,...

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Adrenal Insufficiency Due to X-Linked AdrenoleukodystrophyGeorge Kanakis, MD, PhDEndocrinologist & Clinical Andrologist (EAA Cert.),Athens Naval & VA Hospital, Athens [email protected] author.

Gregory Kaltsas, Md, PhDProfessor of Endocrinology, Dept of Pathophysiology, Laikon University Hospital, Athens 11527, [email protected] author.

Created: October 12, 2018.

ABSTRACTX-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder, involving mainly the white matter and axons of thecentral nervous system, the adrenal cortex, and the testis and a frequent but under-recognized cause of primary adrenocorticalinsufficiency. X-ALD is caused by a defect in the gene ABCD1 that maps to Xq 28 locus. The primary biochemical disorder is theaccumulation of saturated very long chain fatty acids (VLCFA) secondary to peroxisomal dysfunction. The incidence in males isestimated to be 1:21,000 and in females 1:14,000, without any difference in the prevalence among different ethnicities. At least sixdistinct phenotypes have been described that differ in the age and severity of clinical presentation; however, there is no correlationbetween X-ALD phenotype and mutations in the ABCD1 gene. When suspected, the diagnosis is established biochemically and prenataltesting is possible in affected families. Currently, there is no satisfying treatment to prevent the onset or modify the progression of thechronic myelopathy of X-ALD. The administration of a mixture of glyceryl-trioleate and glyceryl- trierucate, also referred as Lorenzo'sOil, has been shown to prevent disease progression in asymptomatic patients with cerebral involvement of X-ALD. Allogeneichematopoietic stem cell (HSC) transplantation is the treatment of choice for individuals with early stages of the cerebral form of thedisease. An alternative option for patients without HLA-matched donors is autologous HSC-gene therapy with lentivirally correctedcells. Once adrenal insufficiency is present, hormonal replacement therapy is identical to that of autoimmune Addison’s disease. Forcomplete coverage of this area and all of Endocrinology, visit www.endotext.org.

INTRODUCTIONLeukodystrophies are inherited neurodegenerative disorders, primary affecting the brain myelin. X-linked adrenoleukodystrophy (X-ALD; OMIM:300100)) is the most common leukodystrophy usually presenting as chronic myelopathy and peripheral neuropathy, aclinical entity called adrenomyeloneuropathy (AMN), frequently accompanied by adrenocortical insufficiency (1). The pattern ofinheritance is X-linked and the disease is clinically evident in almost all male patients and in more than 80% of female carriers olderthan 60 years, though with milder manifestations. Occasionally, male patients and very rarely female carriers may develop a rapidlyprogressive, devastating cerebral form of the disease known as Cerebral Adrenoleukodystrophy (CALD). The pathophysiological basisof the disease is peroxisome dysfunction and accumulation of very long chain fatty acids (VLCFA, >C22:0) due to impaired VLCFAdegradation (2).

In the early 20th century, patients with signs and symptoms belonging in the Leukodystrophies spectrum were grouped under the name“Addison–Schilder disease”. It was not until the 1960s that Blaw introduced the term “adrenoleukodystrophy” as a distinct diseaseentity with X-linked inheritance (3). In 1976 it was shown that the principal biochemical disorder in X-ALD was the accumulation ofVLCFA (4). In 1993, the gene responsible for the disease was identified at Xq28 locus and it was subsequently shown to be the ABCD1gene, which encodes the Adrenoleukodystrophy Protein (ALDP) (5).

This chapter summarizes the latest data in the literature regarding the progress made in elucidating the pathogenesis of the disease, thestrategies for early diagnosis, and the results of established as well as of newer experimental therapies.

GENETICS & PATHOPHYSIOLOGYX-ALD is associated with the accumulation of saturated VLCFA, particularly hexacosanoic (C26:0) and lignoceric (C24:0) acids, due toimpaired degradation by the peroxisomes (6,7).

The gene that is defective is referred to as ABCD1 (GenBank accession number: NM_000033). It is located on Xq28, covers 19.9 kband contains 10 exons (5). It encodes a peroxisomal trans-membrane protein of 745 amino acids, ALDP, a member of the ATP bindingcassette (ABC) transport protein family, which helps to form the channel through which VLCFAs move into the peroxisome as VLCFA-

Adrenal Insufficiency Due to X-Linked Adrenoleukodystrophy... https://www.ncbi.nlm.nih.gov/books/NBK278944/?report=...

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CoA (8).

The mode of inheritance of X-ALD is X-linked recessive, thus the possibility of a son of a female carrier developing X-ALD is 50%,whilst 50% of female off-springs will also be heterozygous carriers. All female off-springs of an affected male will be carriers but noneof his male off-springs will be affected. Significant intra-familiar phenotype variability has been observed as different clinicalphenotypes can occur even among monozygotic twins (9). Fifty percent of ABCD1 mutations lead to a truncated ALDP, whereas manymissense mutations result in the formation of an unstable protein (10). The complete absence of a functional ALDP does not necessarilylead to the severe form of X-ALD, implicating the existence of additional factors that could modify disease’s clinical expression.Environmental factors, such as moderate head trauma, have been shown to trigger the progression of the disease to the severe centralnervous system (CNS) form (11). In contrast, mutations with residual transporter activity or over-expression of ALDP-related protein(ALDRP, ABCD2), the closest homolog of ALDP, might prevent this progression (12). Variations in methionine metabolism have alsobeen associated with the wide phenotypic spectrum of X-ALD (13).

The incidence of the disease is estimated to be 1:17,000 (1:21,000 in males and 1:14,000 in females), a disproportion that may reflectthe morbidity related to adrenal insufficiency in males preceding the diagnosis of X-ALD. No difference has been observed in theprevalence among different ethnicities (2,14). More than 1000 different mutations have been identified in X-ALD patients and areupdated in the website http://www.x-ald.nl. Of these mutations, 51% are missense mutations, 28% frame-shift mutations, 12% nonsensemutations, 6% point mutations and 3% larger deletions of one or more exons (10). Nine hotspot mutations have been identified, whichtogether account for 20% of all cases; the most common among them being a micro-deletion in exon 5 (p.Gln472Argfs*83) (15). Near4% of patients are affected by a de novo mutation; however in a recent study from Norway, this figure is reported to be as high as 19%(16).

Accumulation of abnormal VLCFA in affected organs is regarded to represent the underlying pathologic process in X-ALD, leading tocell death due to a combination of disruption of cell membranes as well as an induction of oxidative stress and apoptosis (17). Singh andco-workers have demonstrated that the β-oxidation of C24:0 and C26:0 is reduced in fibroblasts from X-ALD patients to approximately25% of control levels (6), leading to the accumulation of VLCFA-CoA esters in the cytosol. These esters are prone to further elongationcarried out by an elongase specific for VLCFA (ELOVL1), further increasing the intracellular levels of VLCFA (18). Transfection ofX-ALD cell lines with normal ABCD1 gene restores their capacity to degrade VLCFA (19). Interestingly, injection of C24:0 complexedto phospholipids (C24:0–lysophosphatidylcholine) into the cortex of wild type mice caused widespread microglial activation andapoptosis (20). Such effects were not produced by injections of long-chain lipids (C16:0–lysophosphatidylcholine), implying a fatty-acyl chain length dependent cytotoxicity. In fact, VLCFA are extremely hydrophobic compounds and experimental data suggest thatinclusion of C26:0 in a model membrane can disrupt its structure (21). This effect has been shown to be toxic mainly to the myelin-producing oligodendrocytes and Schwann cells, causing the breakdown or loss of the myelin sheath surrounding the nerve cells in thebrain and the peripheral nerves respectively. The pathogenesis of X-ALD is summarized in Figure 1.


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Figure 1.

The pathogenesis of X- ALD: The mutated ABCD1 gene encodes a defective Adrenoleukodystrophy Protein (ALDP) that impedesVery Long Chain Fatty Acids (VLCFAs) from entering the peroxisome to undergo degradation. This leads to accumulation ofVLCFAs in the cytosol, which is further aggravated by the elongation of LCFAs carried out by a specific VLCFA elongase(ELOVL1). VLCFA accumulation of has been shown to be toxic by causing the breakdown of cell membranes and by evokingmitochondrial dysfunction as a result of oxidative stress

Moreover, it is suggested that VLCFA can induce cell death by disturbing calcium homeostasis and/or evoking oxidative stress-relatedmitochondrial dysfunction (22,23). The theory of elevated oxidative stress has been supported by experiments showing thatlymphocytes of X-ALD patients contain low amounts of total and reduced glutathione, whereas the proportion of oxidized glutathioneforms is elevated (24). Oxidative stress may impair mitochondrial function by inducing the formation of the Mitochondrial PermeabilityTransition Pore (MPTP), which represents an increased permeability of the mitochondrial membranes to molecules of less than 1500Daltons. Induction of the MPTP is associated with mitochondrial swelling and cell death. Cyclophilin D, the most studied component ofMPTP has been found particularly expressed in the affected zones of the brain in patients with X-ALD and in the spinal cord of a mousemodel of X-ALD. Notably, these changes can be experimentally reversed by treatment with anti-oxidants (25). In addition, the oxidationof cholesterol and linoleic acid, leads to the formation of cholesterol oxide derivatives oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), which further aggravate peroxisomal dysfunction (26).

The pathogenic mechanism that triggers the progression to CALD has not been elucidated as yet. Inflammatory demyelination seems toplay a key role and plasmatic VLCFA concentration has been positively correlated to the levels of pro-inflammatory cytokines (27).Moreover, a higher VLCFA content has been reported in the non-affected white matter of patients with CALD compared to patients withnon-cerebral ALD, possibly representing a precursor lesion (28). Breakdown of the blood-brain-barrier is also implicated by recentstudies that have demonstrated an elevation of the matrix metalloproteinases in the cerebrospinal fluid of CALD compared to AMNpatients (29). Progression of the cerebral lesions has also been associated with elevated oxidative stress and impaired plasma antioxidantcapacity as expressed by superoxide dismutase (SOD) levels. Plasma SOD levels from patients with CALD demonstrated an inversecorrelation to brain magnetic resonance imaging (MRI) severity score, while longitudinal samples from the same patients showed adecrease in plasma SOD activity prior to and at the time of diagnosis (30).

Regarding the adrenal gland, abnormal VLCFA accumulation is believed to cause apoptosis and ultimately atrophy of the adrenalcortex. Increased esterification of cholesterol with VLCFAs may further impair cortisol secretion due to a relative shortage of substratefor steroidogenesis (31). Impaired cortisol response to ACTH stimulation usually precedes frank hypocortisolism indicating that loss ofadrenal function is a gradual, progressive phenomenon (Figure 2). A possible explanation for this early adrenal dysfunction may be theincorporation of VLCFAs into the adrenocortical cell membrane, which may impair the stimulatory effects of adrenocorticotropin(ACTH) on the adrenocortical cells (32).

Similarly, male patients may present with testicular insufficiency due to the toxicity of VLCFAs on Sertoli and Leydig cells.Testosterone levels are usually in the lower-normal range with elevated luteinizing hormone, while the response to human chorionicgonadotropin is blunted, indicating primary hypogonadism (33). However, in a recent case report, hypogonadism was attributed to tissuespecific androgen resistance rather than to primary testicular failure, probably mediated through VLCFA accumulation at the androgenreceptor and/or post-receptor levels (34).


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Figure 2.

Impaired Cortisol response to ACTH stimulation from adrenocortical cells cultivated in VLCFA (- - -) and (-----), compared toethanol (…….) and linoleic acid _._._.

PATHOLOGYIn the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells, but not in most neurons (35).Lipid inclusions containing cholesterol, phospholipids and gangliosides esterified with saturated VLCFA have been found in all affectedtissues, even in morphologically normal regions, indicating that the biochemical abnormality precedes histopathological changes (17).Lesions of the spinal cord and peripheral neural system observed in AMN have been traditionally characterized as a non-inflammatorydistal axonopathy with minimal myelin changes (36). Nevertheless, recent studies have shown that affected spinal cord microglia is alsovulnerable to phagocytosis, allowing the injury of neurons that reside within an altered metabolic milieu (37). The regions that aremostly affected in AMN are the dorsal columns in the cervical cord segments and the cortico-spinal tracts in the lower thoracic andlumbar segments of the spinal cord (38). AMN can also insult peripheral nerves and this is evident in the epidermis where low nervefiber densities can be found, indicating a loss of the thin unmyelinated nerve fibers (39). Such alterations may also appear in the opticnerve and can be detected by optical coherence tomography as thinning of the retinal nerve fiber layer (stratum opticum) and of themacula (40).

On the other hand, brain lesions in CALD are evident as large areas of demyelination of the white matter, while the cortex is typicallyspared. The parieto-occipital regions are affected in 85% of cases, with asymmetric progression of the lesions towards the frontal ortemporal lobes, whereas the frontal lobes are involved in only 5% of cases (41). In general, arcuate fibers are spared, except in chroniccases, where axonal loss may be considerable, but myelin loss is usually greater. Lesions may sometimes involve the brainstem,especially the pons, whereas the spinal cord is usually spared, except in cases of bilateral cortico-spinal tract degeneration (42).Occasionally, demyelinated areas may be seen in the cerebral white matter of asymptomatic patients, however, these are scattered in apatchy manner and without signs of inflammation.

The severe and rapidly progressive cerebral form of X-ALD is associated with the evolution of an inflammatory process besidesdemyelination. Upon microscopic examination, these inflammatory lesions of CALD consist of three distinct concentric zones. Themost outward zone contains many lipid-laden macrophages and destruction of myelin albeit with axonal sparing. The second zone alsocontains many macrophages and a mixture of myelinated and demyelinated axons. A hallmark finding in this zone is perivascularinfiltration with lymphocytes (43,44). The pathological process involving this zone is responsible for the gadolinium enhancementobserved on MRI scans. The third zone is the innermost and largest one, consisting of a dense grid of glial fibrils and scatteredastrocytes. This distinct zonal pattern of CALD lesions can be also detected on MRI scans (45).

VLCFA accumulation is also evident in the adrenal cortex of patients with X-ALD, particularly in the zona reticularis and the zonafasciculate, with a relative sparing of the zona glomerulosa. Microscopically adrenocortical cells become ballooned and striated due tothe accumulation of lamellae and lamellar-lipid profiles, which consist of cholesterol molecules esterified with saturated VLCFA (31).These distinct pathological features can also be demonstrable in the fetal adrenal gland, indicating that accumulation of VLCFA ispresent already in utero. Similar lesions can be found in the testes of X-Ald men, primary affecting Leydig cells that are responsible forsteroidogenesis (46).

CLINICAL MANIFESTATIONS OF X-ALDThe range of clinical expression of X-ALD varies widely. Tables 1a and 1b summarize the principal clinical phenotypes. A hallmark thatdistinguishes X-ALD from other inherited neurodegenerative diseases is that patients are asymptomatic at birth (1); however, in malepatients adrenocortical insufficiency may develop even during the first year of life (47). In contrast, AMN the most frequent form of thedisease is rarely present before adulthood and reaches 100% penetration over the age of 55 years. The presence of asymptomatic malesbeyond this age is exceptional. In fact, ALD is more accurately considered as a progressive disorder and this phenotypic classification isdue to systematic reasons: approximately 60% of male patients, including 20% of those initially diagnosed as AMN, will eventuallypresent CALD during their lifespan with the childhood form being the most severe (48). The clinical course of the disease andparticularly the presence of CALD is thought to be the result of an interplay between genetic and environmental factors (Figure 3).

( ).


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Figure 3.

The clinical course of X-ALD in men: patients are born asymptomatic, whereas Addison’s disease is usually the first manifestationof the disease, affecting up to 80% of men. Adrenomyeloneuropathy appears later in life (3 decade) with an incidence increasingwith increasing age and affecting almost 100% of men. Cerebral form of ALD may be apparent in early childhood, however it canemerge at any age and is thought to be the result of an interplay between genetic and environmental factors (modified from Kemp etal. 2016)

Adrenomyeloneuropathy

AMN is a disorder that affects mainly the long tracts of the spinal cord characterized by an absent or mild inflammatory response(36,38) and such patients may survive to the eighth decade of life. The disease onset is usually between the third and fourth decade andin two-thirds of patients, the neurologic disability progresses slowly over a span of 10-15 years. In the remaining, a more rapidprogression is observed within 3–5 years. The primary manifestation is gait disorder due to spastic paraparesis and sensory ataxia withimpaired vibration sense, which mainly affects the lower limbs; loss of dexterity or strength in the arms is exceptional (49). Sphincterdysfunction initially presenting as urge complaints, progressing to full incontinence as well as impotence are accompanying features;whereas in some cases a characteristic diffuse hair loss is observed (50). Signs of peripheral neuropathy may also be present, howeverthey are usually masked by the most prominent clinical features of myelopathy (51). The course of AMN is gradually progressive, withmost patients losing ambulation by the 6 decade of life (52).

Up to 63% of AMN patients are reported to have additional cerebral demyelination (53) and subtle cerebral manifestations are oftenpresent. The rate of depressive illness appears to be elevated at least two-fold (54) and mood change fluctuations according to thehormonal replacement of adrenal insufficiency frequently occur. Approximately 20-30% of the AMN patients may develop at a laterstage progressive cerebral involvement in which the inflammatory response is present (55). In such cases, the survival is reported to beas poor as in childhood cerebral adrenoleukodystrophy. However, this risk decreases markedly after the age of 45 years.

Cerebral ALD

The risk of a newborn male carrier of the ABCD1 mutation developing CALD is 35 – 40% between the ages of 5 and 12 years. Diseaseonset prior to 3 years of age is rare and this risk is substantially lower among boys whose brain MRI remains normal until 7 years of age(56). The earlier the onset of disease, the more rapid the progression is, whereas patients may remain asymptomatic as long asdemyelinating lesions are not visible on brain MRI. Generally, the onset of CALD is insidious, and can be confused with the AttentionDeficit Hyperactivity Disorder which is characterized by hyperactivity, impulsiveness and an abrupt decline in school performance.Cognitive deficits can be accompanied by neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired centralauditory discrimination, visual field defects, cortical blindness, and often seizures (1).

The presentation in adults is similar and initially may appear as a psychiatric disturbance resembling the manifestations of obsessive-compulsive personality disorder (57). These psychiatric symptoms may precede frank motor or cognitive changes by some years.Infections or head trauma may trigger the onset of CALD, but usually no extrinsic factor is identified (58). Nevertheless, once thedisease becomes inflammatory, as evidenced by the post-contrast enhancement of the borders of the brain lesions as shown in MRI, itusually progresses rapidly to a devastating form, leading to a vegetative state within two to five years (59). Interestingly, 10% of maleswith imaging evidence of CALD may never enter into the active inflammatory stage, a phenotype referred to as “chronic or arrestedcerebral X-ALD ” (60); however it is possible that these lesions may be reactivated many years later.

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Female Heterozygotes

Contrary to previous beliefs, that considered female heterozygotes as being asymptomatic, it is now accepted that approximately 65% ofsuch individuals will develop an AMN-like syndrome by the age of 60. In general, the onset of neurologic symptoms occurs at a laterage than in males, and there is a strong association between the onset of symptoms and age. Typically symptoms appear in the fourth tofifth decade of life and disease manifestations are less severe with a notable occurrence of early fecal incontinence (61). Scanty scalphair can also be found in females (62). Only a few females have been reported to develop CALD and this has been attributed to skewedinactivation of the X-chromosome carrying the mutated ABCD1 gene (63).

Incidence of Primary Adrenal Deficiency in X-ALD

The incidence of primary adrenal insufficiency (PAI) in males with X-ALD has been reported to be 50-86% and the correspondingfigures in the various phenotypes are shown in Tables 1 and 2. The incidence of PAI in the patients with the childhood cerebral forms ofALD appears to be higher than in the AMN patients. While many patients have both neurologic involvement and adrenal insufficiency, aconsiderable number has only one or the other. The patients with the "Addison only" phenotype by definition are free of demonstrableneurologic involvement; however, due to the progressive nature of the disease, many individuals in this category will later developneurological involvement. ALD is the cause for up to 20 percent of male cases of idiopathic Addison’s disease. Biochemical evidence ofadrenal insufficiency can be present for up to two years before the development of relevant clinical signs and the youngest boy detectedwith subclinical PAI was 5 months of age (47). Elevated ACTH levels and impaired cortisol response to ACTH administration are themost frequent findings. Frank hypoaldosteronism with salt wasting is not frequent, but impaired aldosterone response to ACTH may beobserved in approximately one third of men with X-ALD (64).

Addison’s disease is rare in women heterozygous for X-ALD (1% or less), and considerably less frequent than the AMN-like syndrome,which develops in approximately 50% of women in middle age or later. Even though it is rare for heterozygous women to showclinically evident adrenal insufficiency, post-mortem studies have revealed adrenal abnormalities resembling those in affected males(65). When more subtle tests of adrenal function, such as the response to ovine corticotropin-releasing-hormone, were performed,subnormal responses were demonstrated in five of eight women with previously normal ACTH stimulation tests (66).

Table 1.

X-ALD Phenotypes in Males

Phenotype Description Estimated RelativeFrequency

Adreno- corticalInsufficiency

Childhood cerebral Onset 3-10 years. 31-35% 79%

Progressive behavioral, cognitive, neurologic deficits.

Total disability often within 3 years.

Adolescent cerebral Like childhood cerebral; somewhat slower progression 4-7% 62%

Adult cerebral Dementia, behavioral disturbances focal neurologicdeficits without preceding adrenomyeloneuropathy

2-3% >50%

Adrenomyeloneuropathy Onset 28 ± 9 years. 40-46% 50-70%

Slowly progressive paraparesis, sphincter disturbances

Addison only Primary adrenal insufficiency without neurologicinvolvement.

Varies with age. Up to50% in childhood

100%

Most common onset 5-7 years. Most eventually developAMN or cerebral forms

Asymptomatic No demonstrable neurologic or adrenal involvement Common before 4 years.Diminishes with age.

50% plus withtesting

Table 2.

Phenotypes in Female X-ALD Carriers

Phenotype Description Estimated relative


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1.

2.

3.

4.

5.

frequency

Asymptomatic No neurologic or adrenal involvement Diminishes with age

Mild myeloneuropathy Increased deep tendon reflexes and sensory changes in lowerextremities

Increases with age.~ 50% at age >40 years.

Moderate to severemyeloneuropathy

Resembles AMN, but milder and later onset Increases with age>15% at age >40.

Clinically evident Addison’sdisease

Rare at any age <1%

X-ALD appears to be a more frequent cause of Addison's disease in males than is generally recognized. Lauretti et al. found that 5 of 14male patients between 12 and 45 years of age, previously diagnosed as having PAI, had abnormally high plasma VLCFA levels in thesetting of X-ALD (67). Jorge et al. diagnosed X-ALD in ten of 37 patients with idiopathic Addison’s Disease (27%), and found that theincidence was 100% in patients in whom adrenal insufficiency became evident before 7.5 years of age (68). These findings are of greatclinical importance, as prompt diagnosis of X-ALD has profound implications for prognosis, therapy and genetic counseling. It istherefore important that screening for X- ALD is carried out in all male patients with idiopathic Addison’s Disease. The need to do so isparticularly relevant in patients in whom PAI was manifested before 7.5 years of age.

Other X-ALD Phenotypes

More than 200 X-ALD males have been reported to remain completely asymptomatic, even without signs of PAI, up to the age of 40–50 years. This is referred to as the “asymptomatic-normal MRI” phenotype (14). Men with X-ALD may also present with gonadaldysfunction, however, neurological involvement in such patients is usually already evident at the time they develop testicularinsufficiency. Therefore, the presence of erectile dysfunction might be related to myelopathy, while decreased libido may be associatedwith depression and/or the presence of a chronic disease rather than hypogonadism (33). Interestingly, a negative impact of X-ALD onmale fertility has not been demonstrated so far (69).

DIAGNOSIS OF X-ALDThe plasma assay for VLCFA is the hallmark diagnostic procedure as it is very reliable for the identification of affected males (70).VLCFA levels are already increased on the day of birth and in untreated patients remain approximately the same throughout life.Testing, typically includes three VLCFA parameters: the level of hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0), and theratio of these two compounds to docosanoic acid (normal values of C24:0/C22:0 ratio <1.0 and C26:0/C22:0 ratio <0.02). Hexacosanoicacid is the one most consistently elevated, and is therefore considered to be diagnostic of the disease. It should be noted though, thatVLCFA levels are also elevated in some other peroxisomal disorders, whereas they can be falsely elevated in patients on ketogenic diets(71). On the other hand, grape-seed and mustard-seed oils may cause false negative results. So far, no correlation has been establishedbetween the degree of VLCFA elevation and the severity of the disease or the onset of certain manifestations (72). The assay can also beused to identify asymptomatic patients by screening members of the extended family (49). Notably, false negative results may occur inapproximately 15 to 20% of obligate female heterozygotes. In such patients, mutation analysis by molecular genetic testing of theABCD1 gene locus is the most accurate method for a definitive diagnosis (73). Nevertheless, in some cases mutation analysis mayreveal a sequence variant of the ABCD1 gene with unknown clinical significance, presenting a diagnostic conundrum for the clinician.

The diagnosis of X-ALD should be sought in:

Boys with progressive behavioral, cognitive or neurologic disturbances beginning at 3 years of age or later.

Males with Addison's disease in whom the etiology has not been defined (e.g. absent auto-antibodies against adrenal antigens).Since the plasma VLCFA assay is non-invasive, and the practical and genetic implications of the diagnosis of X-ALD aresignificant, the VLCFA assay could be part of the routine initial evaluation of male patients with Addison’s disease.

Men and women with progressive myelopathy. AMN is often misdiagnosed as multiple sclerosis. Nevertheless, a relapsing andremitting evolution is never seen in AMN. The diagnosis of X-ALD should be considered even when there is no clinical orbiochemical evidence of PAI. In a large series from Germany adrenal function was normal in 20 of 41 men with AMN, and PAIoccurred in less than one percent of women with and AMN-like syndrome (74).

Patients in whom PAI occurs in combination with neurologic disability (Table 3).

Patients who are at genetic risk of having X-ALD on the basis of pedigree. Because X-ALD is X-linked recessive, a large number ofrelatives in the nuclear and extended family are at genetic risk. Detection of asymptomatic patients is particularly important, since


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therapeutic interventions have the greatest chance of success when clinical manifestations are still mild.

Table 3.

Conditions in Which Adrenocortical Insufficiency is Associated with Neurologic Dysfunction.

Disorder Nature of Neurologic Disturbance

X-linked adrenoleukodystrophy See text

Neonatal adrenoleukodystrophy Autosomal recessive; early onset; dysmorphic features, multiple organ involvement

Triple A syndrome (OMIM 231550) Achalasia, alacrima, adrenal insufficiency

Peripheral neuropathy, cerebellar ataxia.

Mild dementia, autosomal recessive, gene defined

Glycerol kinase deficiency Autosomal recessive. Psychomotor retardation

Newborn Screening

Newborn screening (NBS) is justified for a disorder, provided that a therapy is available and that early diagnosis allows timelyimplementation. This is particularly relevant for X-ALD after the promising results of hematopoietic stem cell transplantation (HSCT):early diagnosis at birth would allow the early detection of PAI in order to initiate timely adrenal steroid replacement therapy, whereasearly detection of CALD would permit HSCT before severe neurologic impairment is established. Important improvements towards thistarget was the development of mass spectrometry methods to assess the presence of VLCFA in dried-blood spots as well as a combinedliquid chromatography/tandem mass spectrometry (LC-MS/MS) high-throughput assay that could measure VLCFA enrichedlysophosphatidylcholine (lysoPC , thus providing the technical background for NBS (75). Eventually, New York State (NYS) in 2013was the first authority to include screening for X-ALD in the NBS program, while more states are expected to add screening for X-ALDto their own NBS program since it has been added to the Recommended Universal Screening Panel (RUSP) (76).

NYS NBS for X-ALD is based on a 3-tier algorithm. The first tier, refers to all newborns and includes C26:0 VLCFA assessment indried blood spots. In case of a pathological result, the second more specific tier, measuring C26:0- lyso-PC is employed. If the C26:0lyso-PC is also elevated, then sequencing of the 10 exons of the ABCD1 gene is performed as part of the third tier of screening. Ifsequencing reveals a relevant mutation, a confirmatory VLCFA analysis should be ordered in an independent laboratory. If ABCD1mutation analysis is negative, then a rare peroxismal disorder should be sought (76). The whole procedure is reported to be both highlysensitive and specific and might be used as a template to diagnose X-ALD in symptomatic patients. It is however; still premature todraw conclusions about the health and social impact that NBS has on the diagnosed individuals and their families.

Genetic Counseling

As soon as an index case is detected either as a consequence of symptoms or as a result of NBS, genetic counseling should be offered tothe family. If the index case is male, testing should be offered to his mother and female offspring. If the mother is confirmed to be acarrier for an ABCD1 mutation, testing should also include all the male siblings of the index case. If the index case is female, initialtesting should include both parents. Regarding mutation testing of minor females of an affected family, there is no consensus whether itshould be performed on a routine base. (76).

Prenatal diagnosis is an option for women who are heterozygous carriers of the ABCD1 gene (77). Recently, a non-invasive prenataldetermination of fetal sex being able to detect Y chromosome sequences in maternal blood by molecular techniques (78). However,since a significant number of heterozygous women will develop AMN in adulthood, prenatal diagnosis may also be considered for afemale fetus. Sex determination along with ABCD1 mutational analysis can be performed on a fresh chorionic villus sample (CVS) at11–13 weeks of pregnancy. Amnioparacentesis can still be performed at 15–18 weeks of gestation; however, this option might delay thedecision-making process since amniotic cell culture requires an additional 2 – 3 weeks. If the ABCD1 gene mutation has not beenrecognized but the maternal phenotype is highly suspicious, prenatal diagnosis of a male fetus can be done by the measurement ofVLCFA levels in cultured CVS cells or amniotic cells (79). Preimplantation genetic diagnosis is an additional option, particularly usefulfor heterozygous female carriers who have already had pregnancy interruption due to prenatal diagnoses of an X-ALD male fetus.

Imaging

All individuals with confirmed ALD/AMN complex should undergo neuroimaging to determine if cerebral involvement is present.Brain MRI is the procedure of choice and should be performed every 6 months in pre-symptomatic male patients between 3 and 12


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years of age and yearly after that up to 45 years (80). Brain MRI abnormalities precede symptoms in patients with the cerebral forms ofX-ALD (56). Findings are always abnormal in symptomatic patients, demonstrating cerebral white matter demyelination (Figure 4). Thelesions typically begin in the splenium of the corpus callosum before gradually expanding to the occipito-parietal region and they areusually bilateral, but occasionally can be limited to only one side, particularly if a previous head trauma has triggered CALD (11). Thepresence of contrast enhancement just behind the outermost edge of the lesions as seen in T1-weighted images (WI), heralds theprogression to inflammatory devastating form of CALD (59). Loes et al. has introduced a grading system to assess the degree of MRIabnormalities in X-ALD (81). This is a 32-point scale score (0: normal, 32: most severe) that assesses the degree and extent ofhyperintense lesions on FLAIR or T2W images as well as the degree of regional atrophy, and has proven to have predictive value for theresponse to HSCT (82). Regarding AMN, MRI of the spinal cord is unremarkable on standard sequences, it can however show atrophyin advanced cases (83). Contrast enhancement is not observed in AMN, since inflammation is not a feature of extra-cerebral lesions.

Functional imaging such as Proton MR Spectroscopy may detect white matter abnormalities that are not apparent on conventional MRimaging and may predict disease progression (84). A decrease of N-acetyl-aspartate (NAA)/creatinine ratio is observed, reflectingaxonal loss and an increase of choline / creatinine and myo-inositol/creatine ratios associated lipid turnover changes (85). Brain F18fludeoxy-glucose positron emission tomography (PET) may reveal hypometabolic regions particularly in cerebellum and temporal lobeareas, before lesions emerge in MRI (86). In contrast, hypermetabolism may be evident in the frontal lobes, related to the clinicalseverity of the disease (57).

Figure 4.

MRI of a patient with CALD, showing reduced volume and increased signal intensity of the white matter localised mainly at theparieto-occipital regions. The anterior white matter is spared.

(http://en.wikipedia.org/w/index.php?title=Adrenoleukodystrophy&oldid=506277486)


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Testing of Adrenal Function

Adrenal function should be evaluated as soon as the diagnosis of X-ALD is set by measurement of basal (8:00 AM) plasma ACTH andcortisol concentrations. A combined ACTH value more than twice the upper limit of normal (>100 pg/mL) with a cortisol value of lessthan 10 mcg/dL (270 nmol/L) make the diagnosis of PAI high likely and should prompt the initiation of proper cortisol replacementtherapy (87). If results are equivocal (e.g. normal cortisol levels but elevated ACTH), a formal stimulation test following ACTH /cosyntropin administration should be offered. A response of cortisol less than 18 mg/dL, 60 minutes after the administration ofcosyntropin is also indicative of PAI, which requires replacement therapy at least in situations of physical stress (surgery, acute febrileillness, vomiting etc.). In case the diagnosis of X-ALD is made in infancy, cosyntropin stimulation test is also indicated to diagnose PAI,since ACTH and cortisol production is not predictable until 6 to 12 months of age (88). Regarding asymptomatic patients with X-ALD,according to the NYS NBS guidelines, screening for PAI should be repeated every 6 months (76). Evaluation for mineralcorticoiddeficiency is not currently recommended, due to the relative sparing of the zona glomerulosa, however it should be considered in thepresence of symptoms, such as salt-craving and polyuria (89).

THERAPY

Allogeneic Hematopoietic Stem Cell Transplantation

Therapy of the neurologic aspects of X-ALD is a major challenge. Currently, there is no satisfying treatment to prevent the onset ormodify the progression of the chronic myelopathy of X-ALD. Allogeneic HSCT is the treatment of choice for individuals with earlystages of cerebral involvement of X-ALD, which may increase disease specific survival and can lead to long-term stabilization andoccasionally improvement (90–92). Stem cells can be harvested from peripheral blood, bone marrow, and umbilical cord blood ofimmune-compatible donors. Although the mechanism of this effect is still unclear, bone marrow cells do express the ABCD1 gene andplasma VLCFA levels are reduced after bone marrow transplantation, offering a useful biomarker for the assessment of engraftment,graft failure, or rejection (93). It has been shown that bone marrow-derived cells do enter the brain-blood barrier and that a portion ofperivascular microglia is gradually replaced by donor derived cells (94). HSCT may also diminish the brain inflammatory response aswell as lipid peroxidation and protein damage. Stabilization of the disease is usually evident about 6 months after the transplantation.The outcomes of allogeneic HSCT for CALD have been mainly studied among adolescents: the 5-year survival among boys of Loesscore < 10 is as high as 89%, whereas in those with a score ≥10 is only 40%. On the other hand, the cumulative incidence oftransplantation-related mortality is 8% (92). A recent study has also evaluated the potential long-term neurological benefits and thecomplications of allogeneic HSCT in adult CALD, with less compelling results (95).

Current strategy is to monitor asymptomatic patients by MRI at 6-month to yearly intervals depending on their age and consider HSCTwhen the MRI abnormality is advancing and clinical disability is still mild (96). Because HSCT carries a substantial mortality risk (5%),it is not recommended for patients who already have advanced cerebral involvement (e.g. IQ<80 and a Loes score ≥10), because there isevidence that such an approach may not reverse severe deficits and in some instances may accelerate disease progression (97). HSCThas not been tested systematically in AMN because of concern that the risk-benefit ratio may not be favorable: up to 50% of AMNpatients will never develop cerebral involvement, whereas it is high unlikely that HSCT will affect the non-inflammatory distalaxonopathy which is the main pathological feature in AMN (36). Moreover, in retrospective series of patients who successfullyunderwent HSCT for CALD in childhood, it was shown that it could not prevent the onset of AMN in adulthood (98). It is still aquestion whether the progression of myelopathy in X-ALD might be slowed down by HSCT.

In case of patients without HLA-matched donors or adult patients with CALD (given the higher mortality risk of allogeneic HSCTcompared to children), an alternative option is autologous HSC-gene therapy with lentivirally corrected cells (19). In this procedure,CD34+ cells from X-ALD patients are transfected ex vivo using a lentiviral vector encoding the wild-type ABCD1 cDNA. As a result ofthis therapy, 7-14% of granulocytes, monocytes, T and B lymphocytes express the lentivirally encoded ALDP. In a recent phase 2-3study including 17 boys, short-term clinical outcomes were reported to be comparable to that of allogeneic HSCT (99). Nevertheless,concerns regarding long-term efficacy, biosafety of lentiviral vectors, as well as the high cost of this therapy need to be taken intoaccount (100,101). An alternative approach is performing allogeneic HSCT from healthy siblings conceived after preimplantation HLAmatching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child (102). Regardingadrenal function, there is no evidence for the reversal of adrenal failure after either HSCT or autologous HSC gene therapy (103).

Dietary Treatment

Other therapeutic options include dietary therapies with restriction of fat intake and particularly of VLCFAs and saturated fats to avoidtheir accumulation. In order to achieve this, total fat intake is restricted to 15% of the total calorie supply and a maximum of 5-10 mg ofC26:0 are allowed on a daily basis (Table 4). However, since the majority of VLCFA are of endogenous origin (104), this approach isnot sufficient. A mixture of glyceryl trioleate and glyceryl trierucate, also referred as Lorenzo's Oil (LO), which is shown to halt theelongation of VLCFA by inhibiting ELOVL1, has also been applied (105).


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This therapy normalizes plasma VLCFA levels within four weeks and in a recent study involving 89 asymptomatic X-ALD patients withnormal brain MRI, dietary treatment with LO resulted in a twofold or greater reduction in the risk of developing the childhood cerebralform of X-ALD (106). However, its therapeutic effects in patients who are already symptomatic has been disappointing. Besides, it iswidely admitted that LO therapy does not improve adrenal function (52).The daily dosage of LO is 2-3 mL/kg/day and is usually welltolerated. Its most severe side effects are thrombocytopenia and lymphopenia, which usually revert to normal after treatmentdiscontinuation. Treatment with LO may be continued for an indefinite time until disease progression and/or severe side effects occur. Itis not recommended in children under one year of age, as it causes a decrease in the levels of other fatty acids, particularly ofdocosahexaenoic acid, which is essential for neurocognitive development.

Table 4.

Dietary restrictions in X-ALD. Adopted form ref. 2.

Foods rich in VLCFAs Foods rich in saturated fat

Vegetable oilsFatty fish and meatPlant cover and cuticleFruit peel and seedsGrains and nuts

Vegetable oilsFatty fish and meatMilk and milk productsEgg yolkIndustrial pastry

Experimental Therapies

Current research on novel treatment options for X-ALD is focused on a) agents that bypass the defective ALDP by inducing alternativepathways for VLCFA degradation, b) combinations of antioxidants that diminish oxidative stress, c) agents that halt VLCFA elongationand d) the use of neurotrophic factors

Apart from ALDP, three additional closely related ABC half-transporters exist: ALDRP, PMP70 and PMP69, which are located on themembrane of peroxysomes. ALDP must dimerize with one of these half-transporters to form a functional full-transporter (107). Over-expression of ABCD2, the gene producing ALDRP has been shown to compensate for ABCD1 deficiency and ameliorate VLCFAproduction from X-ALD cell series (12). Valproic acid (VPA), a widely used anti-epileptic drug, 4-phenylbutyrate, and other histonedeacetylase inhibitors, are known inducers of the expression of ALDRP. In a 6-month pilot trial of VPA in X-ALD patients markedcorrection of the protein oxidative damage was observed (108). Other agents known to evoke induction of the ABCD2 gene are ligandsto several nuclear receptors: fibrates for PPAR alpha, thyroid hormones and thyromimetics, retinoids, and lately LXR antagonists andare being tested in vitro and in vivo for the treatment of X-ALD (109–111). Lately, it has been shown that AMP-activated protein kinase(AMPKα1) is reduced in X-ALD, raising the question if metformin, a well-known AMPKα1 inducer, may have a therapeutic role forX-ALD (112).

Regarding the use of antioxidative treatments, experimental data show that treatment of ABCD1 null mice with a combination ofantioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage, axonal degeneration, andlocomotor impairment (22). Similar results have been observed with the oral administration of pioglitazone, an agonist of the PPARgamma receptor, which restored oxidative damage to mitochondrial proteins and DNA, and reversed bioenergetic failure . Lately,bezafibrate, a PPAR pan agonist has been demonstrated to reduce VLCFA levels in X-ALD fibroblasts (113). The mechanism for thisaction is by decreasing the synthesis of C26:0 through a direct inhibition of ELOVL-1 and subsequent fatty acid elongation activity.Unfortunately, these actions could not be confirmed in vivo as in a recent clinical trial, bezafibrate was unable to lower VLCFA levels inplasma or lymphocytes of X-ALD patients (114).

The options for treatment of the advanced progressive form of CALD remain limited. Even though the presence of inflammatory lesionsis well recognized, trials of immunosuppressive therapies have yielded poor results. Cyclophosphamide, interferon, IVIG, and otherimmunomodulators have been used without success (80,115). Promising results have been extracted by the use of the antioxidantN-acetyl-L-cysteine as adjunctive therapy to HSCT in patients with advanced CALD (116).

Treatment of Adrenal Insufficiency and Hypogonadism

For those patients with X-ALD who have impaired adrenal function glucocorticoid replacement therapy is mandatory. Glucocorticoidreplacement requirements are generally the same as in other forms of PAI whereas most patients may not require mineralocorticoidreplacement. While there is one report of substantial improvement of neurologic function when replacement therapy was administeredto a patient with AMN (117), the general impression is that adrenal replacement therapy does not alter neurologic progression.

Male patients who present clinical manifestations of hypogonadism and confirmed low serum testosterone levels, should be treated with


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testosterone. Nevertheless, careful evaluation should be warranted, since impotence, in most instances may imply spinal cordinvolvement or neuropathy, rather than testosterone deficiency.

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Adrenal Insufficiency Due to X-Linked Adrenoleukodystrophy...Once adrenal insufficiency is present,...

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