Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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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.
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.
• 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.
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.
Until 1976 it was thought that adrenoleukodystrophy affected children only, and that it always presented as what is now referred to as the childhood cerebral form. Milder adult phenotypes are now recognized, as is the fact that more than 20% of female carriers have some degree of neurologic disability. In a series of 1475 adrenoleukodystrophy patients studied at the Kennedy Krieger Institute, 48% had the childhood cerebral form of the disease (91). In another series in which ascertained bias, which may cause mildly involved cases to be underrepresented, was minimized, it was estimated that 33% to 39% of adrenoleukodystrophy patients had the childhood cerebral form (84), and in a survey in the Netherlands this proportion was found to be 31% (141). The mean age of onset is 7 years, with the earliest onset noted at 2.75 years. Early neurologic development is entirely normal. First symptoms are in the behavioral sphere, and often are diagnosed as hyperactivity or attention deficit disorders. These are followed by signs of dementia, or impaired auditory discrimination, impaired vision, ataxia, and later, signs of corticospinal tract involvement (131). A seizure may be the initial symptom. Once neurologic involvement becomes evident, the illness advances rapidly and may lead to an apparently vegetative state within 2 years, and death at variable intervals thereafter. The disease onset may be associated with a stress, such as head trauma (11).
Adrenomyeloneuropathy is the most common adult form. It was found in 26% to 32% of adrenoleukodystrophy patients in the Kennedy Krieger Institute series (84) and in 46% of patients in the Netherlands (141). As its name implies it affects mainly the spinal cord and peripheral nerves (36). The mean age of onset is 27 years. The main clinical findings are a slowly progressive spastic paraparesis with sensory disturbances most severe in the distal aspects of the lower extremities and sphincter disturbances. Impotence develops in the later stages although many of the patients have fathered children. In accordance with the X-linked recessive mode of inheritance, none of their male offspring are affected, but all of their daughters are carriers. The illness tends to progress slowly over decades, and some patients are now in their seventies. Approximately 40% of the adrenomyeloneuropathy patients also develop some degree of cerebral involvement, and this may be associated with more rapid progression of the illness. Van Geel and colleagues have studied the evolution of phenotypes over a 10-year period in 129 male patients with adrenoleukodystrophy who were 20 years or older (143). Among 32 patients who were neurologically asymptomatic at time of diagnosis, 50% developed neurologic deficits. Among 68 patients with the adrenomyeloneuropathy phenotype (with demonstrable deficits confined to spinal cord and peripheral nerves), cerebral involvement became evident during the 10-year follow-up period. These findings underscore that the distinction between the cerebral and spinal cord is not absolute. Progressive cerebral involvement in adulthood occurs in a significant proportion of patients who initially presented with “pure” adrenomyeloneuropathy. Evidence of small nerve fiber dysfunction was found in a cohort of males and females with X-linked adrenoleukodystrophy, with findings indicating loss of peripheral small nerve fibers and possibly also fibers of the spinothalamic tracts (41).
Twenty percent of the adrenoleukodystrophy patients were free of overt neurologic disability. Half of these patients had adrenal insufficiency and are referred to as the "Addison only" phenotype. It is now recognized that a significant proportion of male patients with Addison disease have the biochemical defect of adrenoleukodystrophy (43). Reports have re-emphasized that X-ALD is a common cause of Addison disease (04), and the need to test for X-ALD in patients with idiopathic Addison disease (120). The other half of the neurologically intact patients did not have overt adrenal insufficiency. Both these patients and the "Addison only" group are at risk of developing childhood cerebral adrenoleukodystrophy or adrenomyeloneuropathy, but some of these persons have escaped neurologic disability until the fourth decade or later. Rarer male phenotypes are the adolescent or adult cerebral forms that resemble the childhood cerebral form except for the later age of onset. Japanese authors have described adult phenotypes that resemble olivopontocerebellar degeneration or multisystem atrophy (101).
Screening of at-risk relatives of known X-ALD patients with the plasma VLCFA assay (08) has identified hundreds of boys who have the biochemical and genetic abnormality but are free of symptoms; many also have a normal brain MRI. Such patients would not have been identifiable. In the clinic at the Kennedy Krieger Institute, they now represent 1 of the most frequent phenotypes, and present an important therapeutic challenge and opportunity. In respect to therapeutic interventions, it is encouraging to note that cognitive function in most of these boys is entirely normal (18).
Neurologic disability may occur in female carriers (102). The syndrome resembles adrenomyeloneuropathy, but is of later onset (mean 35 years) and somewhat milder. More than 90% of boys with childhood cerebral adrenoleukodystrophy and 70% of adrenomyeloneuropathy patients have Addison disease or impaired adrenal reserve. In contrast, in the adrenoleukodystrophy heterozygotes adrenal insufficiency is rare. It is found in less than 1% of the heterozygotes.
The prognosis of adrenoleukodystrophy varies a great deal with the phenotype. It is most severe for the patients with the childhood, adolescent, or adult cerebral forms. Here the rate of progression usually is rapid and often leads to an apparently vegetative state within 2 years. Duration of life depends on the capacity to avoid the complications of confinement to bed and the need for total support services. Patients may survive in this helpless state for a decade or more. Loes and colleagues have developed a set of formulas that appear to be predictive of the increases in the Loes MRI severity score (62; 63). The predictive formulas are based on the patient’s age, the Loes severity score, the location of the brain MRI abnormalities and the presence or absence of contrast enhancement. It is expected that these formulas will facilitate the evaluation of therapeutic interventions.
The prognosis for the patients with adrenomyeloneuropathy, and the asymptomatic or "Addison only" patients is more favorable. However, approximately 40% of the adrenomyeloneuropathy patients do develop some degree of cerebral involvement and depression is common (143). Some adrenomyeloneuropathy patients whose neurologic involvement originally was confined to the spinal cord may later develop cerebral involvement and then progress rapidly. Other complications are decubitus ulcers, bowel perforation secondary to constipation, or urinary infections.
Some patients with adrenomyeloneuropathy have had a comparatively benign course and have lived to the eighth decade, albeit with moderate to severe paraparesis, sphincter disturbances, and impotence. It should be emphasized that a considerable number of adrenomyeloneuropathy patients have been gainfully employed. Some have held highly responsible positions.
Adrenal insufficiency is a frequent and important complication of adrenoleukodystrophy and 1 that often is not recognized. The cumulative proportion of patients who developed adrenal insufficiency was age dependent and highest in early childhood, and the lifetime prevalence of adrenal insufficiency in male patients with X-linked adrenoleukodystrophy is about 80% (43). Symptoms include weakness, periodic vomiting and even coma, and greater than usual exhaustion and incapacity secondary to minor infections or gastrointestinal upsets. Generalized skin hyperpigmentation is a typical sign of chronic adrenal insufficiency in these patients (97). All these symptoms respond readily to hormone replacement therapy. Various diagnostic and therapeutic aspects of endocrine abnormalities in X-linked adrenoleukodystrophy have been reviewed (14).
It is not yet possible to predict whether an asymptomatic boy with the biochemical defect of adrenoleukodystrophy is "destined" for the severe or the milder forms of the illness.
Patient with childhood cerebral form of adrenoleukodystrophy. A 7.3-year-old boy was noted to have developed a short immature behavior and short attention span, tearfulness, difficulty in following verbal instructions, and difficulty in sports, exemplified by his running from first to third base during a baseball game. His behavior, motor, and cognitive development had been normal until that time. However, he had intermittent vomiting and dehydration since 2.5 years of age, and his skin had been excessively tan since 4.8 years of age. Laboratory studies revealed primary adrenocortical insufficiency, symmetrical periventricular demyelination in the occipital region, and elevated levels of very long-chain fatty acids in plasma. He was started on "Lorenzo Oil" therapy that led to partial normalization of the levels of very long-chain fatty acids in plasma and on hydrocortisone. Progression of neurologic symptoms continued. At 8.1 years his speech was dysarthric, he was unable to follow verbal commands, but could read out of a second grade reader. He continued in school with teacher's aides. At 8.3 years he had developed intermittent urinary and bowel incontinence and had seizures controllable with phenytoin sodium. At 9.0 years he had become totally disabled and was admitted to a hospice.
Family studies revealed that the patient's mother, who was asymptomatic, had elevated levels of very long-chain fatty acids in plasma. Two brothers had normal very long-chain fatty acid levels and are without symptoms. The maternal grandfather had been diagnosed to have multiple sclerosis at age 50 years and died at 67 years with increasing neurologic disability. In retrospect, it is likely that he too had adrenomyeloneuropathy.
Patient with adrenomyeloneuropathy. A 24-year-old man with progressive spastic paraparesis was diagnosed to have adrenomyeloneuropathy on the basis of clinical history and demonstration of elevated very long-chain fatty acids in plasma. Review of history revealed normal psychomotor development. He had frequent episodes of dehydration since the age of 2 years. Addison disease was diagnosed at 18 years and he has been on adrenal steroid replacement therapy since then. Episodes of depression appeared in adolescence. He was an excellent student and graduated from college. At 22 years he noted clumsiness and difficulty walking upstairs. At 24 years he noted difficulty in running, difficulty with bladder control, erection, and ejaculation, and dysesthesias in his legs. Examination at 30 years of age revealed severe spastic paraparesis with distal sensory impairment in his legs and a distal axonopathy. Cognitive testing revealed superior performance, and brain magnetic resonance studies were normal. He was employed as a computer programmer. At age 35 years he was started on "Lorenzo Oil" therapy that led to normalization of the levels of very long-chain fatty acids in plasma. Now at age 42 years his spastic paraparesis has increased further and he requires a wheelchair, but continues to function successfully as a computer programmer.
Family history revealed that his mother and maternal aunt had a progressive spastic paraparesis and that a maternal grandfather, who died at age 52 years of unrelated causes, also had spastic paraparesis. The patient's mother and maternal aunt had elevated levels of very long-chain fatty acids in plasma and were presumed to be manifesting heterozygotes. The family had previously been diagnosed to have an autosomal dominant form of familial spastic paraparesis.
Adrenoleukodystrophy is a genetically determined disorder with an X-linked recessive mode of inheritance. The gene has been mapped to Xq28 (76) and the putative gene has been isolated (95). The mouse model of X-ALD did not show a deficiency of very long chain fatty acid synthetase activity (66), and a very long chain fatty acid synthetase deficient mouse model did not show any of the features of X-ALD (37). Work by Pei and colleagues, however, raises the possibility for a possible role of another, novel very long chain fatty acid synthetase referred to as “bubblegum” or lipidosin (106). Unlike the other very long chain fatty acid synthetase enzymes, which are expressed mainly in liver and only weakly in brain, bubblegum is expressed most strongly in those tissues that are most involved in X-ALD, brain, zona fasciculata of the adrenal cortex and testis. The disease has been modeled in oligodendrocytes derived from induced pluripotent cells that were derived from patients’ skin fibroblasts (49; 148). Very long chain fatty acids increased only in differentiated oligodendrocytes and were higher in those derived from the cerebral form than from oligodendrocytes derived from a patient who had adrenomyeloneuropathy (49).
The gene that is defective in X-ALD is now referred to as ABCD1 and has been mapped to Xq28. Its gene product is referred to as ALDP, and is a peroxisomal membrane protein (96). A gene that is closely related to ABCD1 has been mapped to chromosome 12 (12q11). This gene is referred to as ALDR or ABC2. Its gene product, referred to as ALDRP has 66% homology to ALDP (64), has a similar exon organization (12), is also localized to the peroxisomal membrane, and, similar to ALDP, can correct the defect in very long-chain fatty acid metabolism in cultured fibroblasts of X-ALD patients (98).
The mechanism by which the defect in the peroxisomal protein leads to the accumulation of very long chain fatty acids is still unclear. It had been proposed that the membrane protein is required for the transport of the very long chain fatty acids into the peroxisome, but studies by Steinberg do not support this. They suggest that there is an as yet undefined synergistic interaction between the membrane protein and the very long-chain fatty acid synthase (130). The mutations in the adrenoleukodystrophy gene have been defined in more than 400 families. Dodd provided a listing of all mutations that were known in 1997 (19). Kemp and colleagues provide a detailed analysis of 406 ALD mutations and present 47 novel mutations identified up to 2001 (51). O’Neill and colleagues have described a large family that is unique because all of the 12 affected males and 10 heterozygous women have had the pure adrenomyeloneuropathy phenotype without a single instance of cerebral involvement (103). The defect was found to be a 26 base pair deletion in exon 1 that affected translation initiation. Interestingly, the authors demonstrated the expression of an N-terminal truncated ALDP, which missed the first 65 amino acids and was found in 100% of the heterozygotes. The authors speculate that this gene product exerts a dominant negative effect and that this accounts for the consistent clinical symptomatology in the affected females.
A mutational database web site is now available at Mutation Database for X-linked Adrenoleukodystrophy.
Most families have "private" mutations, ie, mutations that are unique to that particular family. Approximately 15% of families have an adenine-guanine nucleotide (AG) deletion in nucleotides 1801-1802 in exon 5. This deletion has been observed in families of widely varying ethnic backgrounds and appears to represent a mutation hotspot. With the possible exception of the family described by O’Neill and colleagues, there is no correlation between the nature of the mutation and the phenotype (103; 152).
Animal models of X-linked adrenoleukodystrophy in the mouse have been developed by targeted disruption of the gene. Pujol and colleagues demonstrated that these animals develop an adrenoleukodystrophy-like syndrome at the advanced age of 18 months to 24 months (115). The inflammatory demyelination in the cerebral forms of human X-ALD has never been observed in the animal model of X-ALD.
The pathophysiology has been reviewed (06). The initiation of cerebral demyelination could well be directly related to the amount of VLCFA in complex lipids, such as phosphatidylcholines, sulfatides, or gangliosides (06). These changes cause demyelination and an inflammatory cascade that leads to a dying-back axonopathy, resulting in clinical disease. Very long-chain acyl-CoA esters are transported into peroxisomes by ABCD1 independently of additional synthetase activity (153). However, ABCD1 remains a susceptibility gene, necessary but not sufficient for inflammatory demyelination to occur (06). Oezen and colleagues conducted a comprehensive study of mitochondrial function in muscle tissue of the X-ALD mouse model (100). They demonstrated increased VLCFA in that tissue, but found mitochondrial function to be normal in all respects. They concluded that mitochondrial dysfunction is not a cause of VLCFA excess in this tissue. Studies suggest that oxidative stress contributes to the pathogenesis to the X-ALD (32). In addition to pioglitazone, the authors identify SIRT1 ligand resveratrol and the autophagy activator temsirolimus as potentially useful therapies (32). Studies in the animal model suggest that loss of ABCD1 gene function hampers oxidative stress homeostasis and may be reversible by alpha-tocopherol analogs (33).Oral administration of pioglitazone, an agonist of PPAR-gamma, to a mouse model of X-ALD restored mitochondrial content and expression of master regulators of biogenesis, neutralized oxidative damage to proteins and DNA, and reversed bioenergetic failure in terms of ATP levels, NAD+/NADH ratios, and pyruvate kinase and glutathione reductase activities (79). The treatment halted locomotor disability and axonal damage in X-linked adrenoleukodystrophy mice (79). This work also supports the hypothesis that mitochondrial biogenesis is affected in X-ALD.
Schmidt and colleagues have reported that 25% of adult X-ALD patients have antibodies to myelin oligodendrocyte glycoproteins compared to 10% in controls (124). The inflammatory process is reflected in elevation of various cytokines and matrix metalloproteinases in CSF of X-ALD patients. The abnormalities and total CSF protein significantly correlate with disease severity determined by MRI (67; 136).
Paintlia and colleagues have made a detailed correlation of the anatomical localization of inflammatory lesions in the postmortem tissues of X-ALD patients with the levels of very long-chain fatty acids in various lipid fractions and the expression of inflammatory cytokines and postulate that the very long-chain fatty acids excess in membrane domains associated with signal transduction pathways activates resident microglia and astrocytes and that this results in loss of oligodendroglia and myelin (105). The microglia damage precedes active demyelinating lesions and can be seen before white matter is disrupted (07). Microglial dysfunction leading to excessive neuronal and synaptic phagocytosis has been recognized in the spinal cord of patients and a mouse model of the disease (35).
It was noted earlier that the phenotype of adrenoleukodystrophy varies widely. The sharpest contrast exists between the rapidly progressive childhood adrenoleukodystrophy and the milder more slowly progressive adrenomyeloneuropathy. A summary of the effort to identify genetic modifiers in X-ALD has been published (152).
Adrenoleukodystrophy is a genetically determined disorder transmitted as an X-linked recessive trait. This pattern of inheritance implies that the disease is transmitted mainly through carrier females, half of her male children will have adrenoleukodystrophy, and half of the daughters will be carriers. It must be emphasized that many men with adrenomyeloneuropathy do father children. Although none of their sons will be affected, all of their daughters will be carriers. Studies indicate that X-ALD is more common than had been recognized in the past (08). The minimum incidence of affected males in the United States is estimated to be 1 per 21,000 males, and the combined incidence of affected males and heterozygous women in the total USA population 1:16,800. Somewhat higher figures have been obtained in France, with the most recent estimate of affected males set at 1:15,000 males. Kondrashov estimated that the mutation rate of ABCD1 is 2.64 times 10-8. X-ALD has been observed in all ethnic groups, without evidence of differential rates (54). Only 1.7% of affected males have been found to have new mutations. An extended family screening led to the identification of 594 additional affected males, 250 of them asymptomatic, at a time when therapy has the greatest chance of being beneficial, and 1,270 heterozygotes. It is recommended that screening be offered to all at-risk relatives of X-ALD patients, and that this screening include the extended family (08).
The most important preventive technique is the identification of carriers and affected males who are asymptomatic or only mildly symptomatic, followed by intensive counseling. Affected male fetuses can be identified prenatally (90; 147). When a new male patient with adrenoleukodystrophy is diagnosed, it is important that at-risk family members be identified and counseled. At risk members include brothers, sisters, and maternal relatives. In some instances, the at-risk family members number more than a hundred, and not infrequently they may not know that they are related and often are not familiar with the illness. Bezman and colleagues applied this technique to screen 4,169 at risk family members and identified 594 affected males and 1,270 female carriers (08). The search, therefore, requires sensitivity and cooperation of family members, and, not infrequently involves complex issues of privacy and informed consent. The most widely used screening instrument is the measurement of very long-chain fatty acids levels in plasma (89; 88). For males this technique has a high degree of sensitivity and specificity. However, for females there is a 15% to 20% incidence of false negative results (92). In approximately 70% of families the accuracy of heterozygote identification can be improved by an indirect immunofluorescence assay (149; 30). In this procedure cells are stained with an antibody to ALDP. In the 70% of families in which the male proband lacks immunoreactive material, cultured fibroblasts or leukocytes of at-risk female relatives are tested for the presence or absence of immunoreactive material. Nearly all women heterozygous for adrenoleukodystrophy display a proportion of cells that lack immunoreactive material. In those families in which the nature of the mutation has been identified, heterozygote status can be determined by searching for this mutation in the at-risk female relative. The capacity to identify heterozygotes has been increased greatly by the development of an accurate DNA-based assay (10). This assay can now be provided as a service. Once the mutation in the kindred has been identified, it is possible to determine whether this mutation is present in women who are at risk of being heterozygotes. If the mutation is absent, heterozygote status can be excluded for practical purposes. A method for screening has been developed and will likely be used for routine newborn screening (40; 80). Newborn screening in the state of Minnesota found that the birth prevalence of X-linked adrenoleukodystrophy in screened infants was 1 in 4845 and 1 in 3878 males, more than 5 times previous reported incidences (151). These findings suggest that the spectrum of X-linked adrenoleukodystrophy may be broader than previously described and that milder cases may previously have been underrepresented (151). Although screening is very effective in identifying subjects at risk and providing effective therapy, it presents significant challenges, such as that not all cases of X-linked adrenoleukodystrophy will require treatment, but all cases of X-linked adrenoleukodystrophy require monitoring for a period of years to determine if treatment is indicated (52). Harms of screening include false positive results, over-diagnosis, and the risks associated with hematopoietic stem cell transplantation performed earlier than needed (52). As already noted, extended family screening, which permits the identification of women heterozygous for X-ALD, and asymptomatic affected males, provides the opportunity for disease prevention by genetic counseling. Preimplantation genetic diagnosis can, indeed, be successful (46). Confirmation of this procedure in a larger number of patients would enhance greatly the reproductive alternatives available to women who are carriers for X-ALD.
The differential diagnosis of adrenoleukodystrophy must be considered separately for each of the major phenotypes.
Childhood cerebral adrenoleukodystrophy. In the early stages of the illness the main differential is from the hyperactivity or attention deficit disorders. In the earliest phases this may not be possible on the basis of clinical findings alone. Early clues to the diagnosis of childhood cerebral adrenoleukodystrophy are evidence of dementia, difficulty in auditory discrimination, and deterioration of handwriting. In the later stages, the disease must be differentiated from encephalitis, seizure disorders, brain tumors, and other neurodegenerative disorders. The typical findings on MRI should help differentiate it from other leukodystrophies (122; 145). Brain magnetic resonance imaging studies and the plasma very long-chain fatty acids assay (see below) will lead to definitive diagnosis.
Adrenomyeloneuropathy. This must be distinguished from chronic progressive multiple sclerosis, familial spastic paraparesis, cervical spondylosis, and spinal cord tumors. When Addison disease is combined with a progressive myelopathy, adrenomyeloneuropathy is by far the most likely diagnosis. The characteristic increase in plasma very long-chain fatty acids is the most reliable diagnostic tool (89; 88). The abnormal oligoclonal bands that are present in multiple sclerosis patients are usually not present in adrenoleukodystrophy patients. Adrenomyeloneuropathy patients do not exhibit the exacerbations and remissions that are common in multiple sclerosis.
Addison disease. The "Addison-only" adrenoleukodystrophy phenotype cannot be distinguished from other causes of Addison disease by history and physical examination. The plasma very long-chain fatty acids assay (89; 88) provides the only reliable method of identification. The plasma very long-chain fatty acids levels are increased in adrenoleukodystrophy and not in Addison disease due to other causes. Serum adrenal antibody levels are not increased in adrenoleukodystrophy-caused Addison disease. Adrenocorticotropic hormone levels are always increased. Reports from Thailand (133) and Taiwan (44) emphasize further the importance of very long-chain fatty acid screening of patients with idiopathic Addison disease in order to identify those in whom the adrenal insufficiency is caused by X-ALD.
Addison disease combined with neurologic deficits. Other disorders cause adrenal insufficiency combined with neurologic disturbances: (1) brain damage due to hypoglycemic episodes in Addisonian crises; (2) central pontine myelinolysis--this disorder may occur when serum sodium levels are replenished rapidly in a patient in Addisonian crisis (99); (3) mental retardation and Addison disease often co-occur in the X-linked genetic disorder glycerol kinase deficiency (155). Adrenal insufficiency, mental retardation, achalasia, and deficient tear production co-occur in a syndrome described by Allgrove and colleagues (02). Apart from the clinical findings, definitive distinction depends on the demonstration of increased levels of very long-chain fatty acids in plasma in adrenoleukodystrophy. These levels are normal in all of the other conditions.
Distinction between neonatal and X-linked adrenoleukodystrophy. Neonatal adrenoleukodystrophy (50) manifests already in the neonatal period, whereas in X-linked adrenoleukodystrophy psychomotor development is normal at least until 3 years of age or later. Neonatal adrenoleukodystrophy patients usually are dysmorphic and severely or profoundly retarded in mental development. Distinction between X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy is of crucial importance for genetic counseling because neonatal adrenoleukodystrophy has an autosomal recessive mode of inheritance. As is evident from the differences that have been cited, the clinical distinction between neonatal adrenoleukodystrophy usually does not present a problem. However, a few neonatal adrenoleukodystrophy patients are more mildly involved and have survived to the third decade. Differential diagnosis may then depend on laboratory tests. Plasma very long-chain fatty acids determination does not help here because these substances are increased in both conditions. Distinction depends on the demonstration in neonatal adrenoleukodystrophy of defective peroxisome structure and of defects in other peroxisomal functions, such as the accumulation of pipecolic and phytanic acids and the impaired synthesis of plasmalogens (82). Steinberg and colleagues have developed a screening method that permits the definition of the molecular defect in a high proportion of patients with peroxisome biogenesis disorders (129). These other abnormalities never occur in X-linked adrenoleukodystrophy. The differential diagnosis of X-ALD with neonatal onset has been complicated further by the identification of CADDS (Contiguous deletion of the X-linked adrenoleukodystrophy gene, (ABCD1) and DXS1357E) (17). This disorder presents in the neonatal period with profound psychomotor retardation combined with cholestasis, with death during the first year. Due to the severe neurologic deficit that is present neonatally, these patients might be mistaken for neonatal adrenoleukodystrophy. Distinction is crucial for genetic counseling, because the mode of transmission of neonatal adrenoleukodystrophy is autosomal recessive, and X-linked for CADDS.
Neurologic dysfunction in women who are heterozygous for adrenoleukodystrophy. Slowly progressive paraparesis, sensory and sphincter disturbances are the most common neurologic manifestations in women heterozygous for adrenoleukodystrophy. This syndrome is difficult to distinguish from multiple sclerosis or other progressive spinal cord disorders (31). Most commonly the diagnosis is made in a woman who is a relative of a male adrenoleukodystrophy patient. Plasma very long-chain fatty acids levels are increased in more than 80% of the carriers (92). As noted previously, the DNA-based assay permits the accurate identification of heterozygotes (10). Adrenal function is almost always normal. Maier and colleagues demonstrated skewed inactivation of the X-chromosome in 32% of 22 symptomatic X-ALD carriers but not in 7 related and 35 unrelated controls (69). These findings suggest that the X-inactivation patterns in women heterozygous for X-ALD are 1 of the factors that influence phenotypic expression. However, a cross-sectional study (26) found that X-linked female heterozygotes with adrenoleukodystrophy develop signs and symptoms of myelopathy (63%) and/or peripheral neuropathy (57%), as well as fecal incontinence (28%). The frequency of symptomatic women increased sharply with age (from 18% in women < 40 years of age to 88% in women > 60 years of age) (26).
The main diagnostic procedure is the demonstration of increased levels of very long-chain fatty acids in plasma (89; 88). The levels are increased in all male adrenoleukodystrophy patients and in approximately 80% of carriers (92). False positives are rare. Methodological advances have further improved the specificity of the very-long-chain fatty acid assay and reduced the time and sample size required to carry out the assay (134; 139). Plasma very long-chain fatty acids levels are increased also in other peroxisomal disorders, such as the Zellweger syndrome or neonatal adrenoleukodystrophy (82), and in children with seizure disorders who are on a ketogenic diet (135), but all of these are readily distinguished on the basis of history and clinical presentation. Seventeen years’ experience with the plasma very long chain fatty acids in more than 1,000 patients with X-linked adrenoleukodystrophy and 29,000 controls has been analyzed (81). Utilization of a computer-derived discriminant function permits reliable distinction between male X-linked adrenoleukodystrophy patients and controls. The abnormality is already present on the day of birth and appears to remain constant throughout life.
Brain MRI studies are of great diagnostic value for the childhood, adolescent, and adult cerebral forms of adrenoleukodystrophy. The most frequent pattern is symmetrical demyelination commencing in the parieto-occipital region and with the accumulation of contrast material at the advancing edge of the lesion (57). These features are sufficiently characteristic so that they often represent the first clue to the diagnosis of adrenoleukodystrophy. Adults with X-linked adrenoleukodystrophy may experience slower progression of atypical findings than those reported in childhood; in adults the corticospinal tract is often involved (25). Atypical brain MRI may occasionally appear with subtle abnormalities in the internal capsule and even brainstem pyramidal lesions (97). Specialized techniques such as magnetization transfer (73) and magnetic resonance spectroscopy have been applied to adrenoleukodystrophy (116; 112; 72). Studies have shown that the degree of MRI abnormality as assessed by the Loes scoring system (63), when coupled with age, aids the prediction of future course and the selection of patients who are candidates for bone marrow transplantation (86). For instance, patients who have maintained a normal MRI at age 7 years, are at only small risk of developing the childhood cerebral form of X-ALD. Melhem and colleagues have shown that the presence or absence of contrast enhancement adds to the predictive accuracy (75). In 20 of 22 patients without contrast enhancement the MRI abnormality remained stable during the next year, whereas it increased in 19 of 21 patients in whom there was contrast enhancement at the first examination. A large cohort of asymptomatic patients with X-linked adrenoleukodystrophy showed lesion progression during the asymptomatic period (61). It has also been shown that diffusion tensor brain imaging (48) and Dual-Echo Fast Fluid-Attenuated Inversion Recovery MRI (74) can help to distinguish between zones in which early and active demyelination is on-going, from those in which the process is no longer active. This information is significant for the selection of patients who are candidates for bone marrow transplantation and for the evaluation of therapeutic interventions. Loes and colleagues have developed a formula based on the patient’s age, the severity of the Loes MRI score (63), the pattern of MRI brain lesions, and the presence or absence of enhancement that permits with considerable accuracy the rate of progression during the next 12 months (62). Diffusion tensor imaging can detect subtle abnormalities that are not evident on conventional MR imaging (71). However, Loes scores predict outcome after bone marrow transplantation better than diffusion tensor imaging (71). Wilken and colleagues examined the prognostic significance of MR spectroscopy for patients who received bone marrow transplants (154). They found an association between outcome and the N-acetylaspartate levels in affected brain white matter. A high level was associated with a positive outcome, whereas low levels had a negative predictive value, as did increased levels of choline-containing compounds. The degree of gadolinium enhancement correlates with the severity of inflammation and predicts neurologic outcome after bone marrow transplantation (78). Lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease (58). This vascular dysfunction needs to be confirmed as an early indicator of impending cerebral ALD, thus allowing timely critical therapy.
Eichler and colleagues demonstrated that proton MR spectroscopy imaging predicts lesion progression (24). They focused on the regions that were adjacent to the MRI lesions in X-ALD patients. When the MR spectroscopy pattern in these regions was normal (11 patients) the MRI abnormality did not progress, whereas it did progress in all the 6 patients in whom the MR spectroscopy pattern was abnormal in this region. The NAA/choline ratio was the most sensitive measure with a value of 5.0 as the cutoff point. The specificity was 83%, the positive predictive value was 66% and the negative predictive value was 100%. Oz and colleagues reported on the results of high field (4 tesla) MRS studies in 17 ALD patients and 26 normal volunteers (104). They were able to assess the absolute levels of 12 metabolites. N-acetyl-aspartate, glutamine. The “lipids-lactate” peaks were the most valuable markers for the demonstration of the presence and progression of lesions. An important encouraging feature was that it was possible to carry out these studies without the use of sedation. The use of these techniques may permit detection of cerebral abnormalities at a time when MRI is still normal, and are they are also of value for the identification of patients who have the greatest chance of benefit from bone marrow transplantation. Biomarkers that can predict deterioration are being looked for. For example, superoxide dismutase activity shows a decrease prior to and at the time of cerebral diagnosis over a period of 13 to 42 months (137). It should be noted, however, that in approximately 15% of patients the MRI abnormality presents first in the frontal region (47). Asymmetric mass lesions have also been reported and have led to the incorrect diagnosis of brain tumor (01; 132; 68). Sakakibara and colleagues reported an X-ALD patient who presented with a unilateral high signal T-2 region in the right caudate nucleus that simulated a brain tumor (121). Ito and colleagues have shown that the quantitative apparent isotropic diffusion coefficient and fractional anisotropy in X-ALD brain were significantly different from those in normal-appearing white matter and correlated with postulated histopathological zonal changes (48). Schneider and colleagues reported that diffusion tensor imaging studies can be used to detect early phases of demyelination in X-ALD (125).
Fatemi and colleagues studied brain MRI in 76 women heterozygous for X-ALD (28). Brain MR abnormalities attributable to X-ALD were found in only 2. Brain MRI was normal in 65 who had an adrenomyeloneuropathy-like syndrome. MR spectroscopy studies were performed in 8 and revealed a statistically significant reduction in N-acetyl aspartate levels in the corticospinal tract and parieto-occipital regions. These studies indicate that brain involvement demonstrable by MRI is rare, even in those women who have adrenomyeloneuropathy, but the preliminary MR spectroscopy studies suggest that there are subtle axonal abnormalities even in those women with normal MRI. These axonal changes may be indicative of the distal axonopathy that represents the principal neuropathological change in adrenomyeloneuropathy (114). Dubey and colleagues have provided evidence that axonopathy represents the initial abnormality in pure adrenomyeloneuropathy (20; 21). They demonstrated spectroscopic evidence of cerebral axonopathy in adrenomyeloneuropathy patients whose conventional brain MRI studies were normal. In a study in which diffusion-tensor MRI imaging was combined with 3-dimensional fiber tracking, they presented evidence of occult tract-specific microstructural abnormalities. Fatemi and colleagues demonstrated that magnetization transfer MRI permits quantitation of spinal cord abnormalities in men with adrenomyeloneuropathy and also in women heterozygous for X-ALD (29). This technique may become of value for the evaluation of therapeutic interventions.
The therapy of the adrenal insufficiency associated with adrenoleukodystrophy is the 1 form of therapy that is known to be effective. Dubey and colleagues tested adrenal function in 49 asymptomatic boys with X-ALD who had been identified by plasma VLCFA screening of relatives of known X-ALD patients (22). They found that in 69% of these boys plasma ACTH levels were increased and in 43% ACTH stimulation test was reduced at baseline (0 to 2 years of age) even though there was no clinical evidence of adrenal insufficiency and baseline cortisol levels were normal. They concluded that these patients had impaired adrenal reserve, and that careful follow-up of these patients and early initiation of adrenal hormone therapy should make it possible to prevent overt Addison disease and the morbidity and mortality associated with it. Although it can overcome virtually all of the handicaps related to the adrenal insufficiency, it does not appear to alter the course of the neurologic disease. The glucocorticoid dose requirement is usually the same as for other forms of primary adrenal insufficiency. To mimic the diurnal rhythm of physiological cortisol secretion, 25 mg of cortisone acetate or 20 mg of hydrocortisone is administered in the early morning with a smaller second dose, 12.5 mg or 10 mg, respectively, given in the late afternoon. Patients are instructed to augment glucocorticoid coverage during stress, provided with a parenteral methylprednisolone dose for potential use if vomiting prevents oral dosing, and are strongly encouraged to wear Medic-Alert identification declaring their dependency on adrenal steroid therapy. Other management details for the adrenal insufficiency are by Burtman and Regelmann (14).
Therapeutic approaches to alter the progression of the neurologic disease have received a great deal of attention both in the medical literature and in the lay media, but their effectiveness remains unproven. Dietary therapy involves the administration of a diet that restricts the intake of very long-chain fatty acids (140) combined with the oral intake of a 4:1 mixture of glyceryl trioleate and glyceryl trierucate oils (119), also referred to as Lorenzo's Oil (83). Both of these oils contain monounsaturated fatty acids that have been shown to reduce the rate of synthesis of saturated very long-chain fatty acids. The dietary regimen has the promising biochemical effect of normalizing the plasma levels of very long-chain fatty acids levels in adrenoleukodystrophy patients within 4 weeks. Unfortunately, the clinical results have been disappointing in patients who are already symptomatic. The diet does not alter the progression of neurologic involvement in patients who are already symptomatic (142). However, the results of a multicenter international trial suggest that administration of Lorenzo Oil to boys who are less than 6 years old and who are neurologically asymptomatic and have a normal MRI reduces the risk for the subsequent neurologic involvement (93). Another study provides more definitive evidence of a preventive effect (94). This study involved 89 boys, mean age 4.7+4.1 years, who were neurologically asymptomatic and whose brain MRI was normal. They were placed on Lorenzo oil therapy combined with moderate fat restriction. Plasma fatty acids, clinical status and brain MRI were followed for 6.9+2.7 years. Changes in plasma hexacosanoic acid levels were assessed by measuring the length adjusted area under the curve, and a proportional hazards model was used to evaluate association with the development of MRI results and neurologic abnormalities. Of the 89 boys, 24% developed MRI abnormalities and 11% developed both neurologic and MRI abnormalities. Abnormalities developed only in the 64 boys who were aged 7 years or younger at the initiation at the time that therapy was started. There was a significant association between the Lorenzo oil induced reduction of plasma hexacosanoic acid levels and the development of MRI abnormalities. Reduction of hexacosanoic acid by 0.1 µg/ml reduced the risk of developing an MRI abnormality by 36% (p value < 0.01). Because hexacosanoic acid levels can be reduced by 0.5 µg, it appears that a 2-fold or greater reduction of the risk for developing the childhood cerebral disease can be achieved. The authors recommended that Lorenzo oil therapy be offered to asymptomatic patients with normal MRI who are less than 8 years old. Careful monitoring of nutrition, plasma very long chain fatty acids and essential fatty acid levels, and platelet counts, is required. With this supervision and good communications with the family, most boys were able to adapt well to this dietary regimen. Consistent with reduction of VLCFA levels, normal gains in weight and body length and normal cognitive and social development were achieved without serious adverse events. It is essential to monitor brain MRI at 6 to 12 months intervals. Should MRI abnormalities develop, hematopoietic transplant may be considered, in accordance with the recommendations formulated by Peters and colleagues (107).
Bone marrow transplantation has shown favorable effects when the transplant is performed early in the course of cerebral involvement and a human lymphocyte antigens matched donor is available (03; 56; 91). Later studies provide additional encouragement that bone marrow transplantation can be effective for patients in the early stages of cerebral involvement (55; 70).
Peters and colleagues report the follow-up data on 126 patients with X-ALD who had received bone marrow transplants between 1982 and 1999 (107). Complete data were available and analyzed for 94. The estimated 5-year and 8-year survival was 56% at a median follow-up of 3.1 years. The leading causes of death were disease progression (n = 19) and graft versus host disease (n = 4). Sixty-six percent of patients showed no or limited neurologic deficit before transplant compared to 42% after. The mean decreases in verbal and performance IQ were 11.9 (p < 0.1) and 11.2 (p < 0.1). The overall survival of 92% in patients with zero or 1 neurologic deficit and an MRI severity score less than 9 before transplant was superior to survival for all other patients (ie, 45% p < 0.1). Most surviving boys with advanced disease stabilized at a low level with severe neurologic deficits after transplant. It was concluded that boys with early stage cerebral X-ALD benefit from transplant, but that the procedure should not be performed in boys with advanced involvement. It should be stressed that bone marrow transplantation does not reverse the adrenal insufficiency, and it may develop after this procedure (108). Monocytes are particularly susceptible to ABCD1 dysfunction; therefore, allogeneic hematopoietic stem cell transplantation in X-linked adrenoleukodystrophy halts the inflammation, particularly by the replacement of the monocyte lineage, but not the lymphocytes, which surprisingly had normal very long-chain fatty acid metabolism in X-linked adrenoleukodystrophy patients (150). It should be stressed that patients who undergo hematopoietic stem cell transplantation for cerebral X-linked adrenoleukodystrophy may still develop the myelopathy in adulthood (144). The quantitative natural history of myelopathy in adults with adrenoleukodystrophy has been described and it shows clear progression over 2 years of follow up (42). Hematopoietic stem cell transplantation is also effective in adults with cerebral X-ALD (146). Early transplantation is critical because boys with cerebral ALD who have greater than minimal cerebral disease detected on MRI scans at the time of hematopoietic stem cell transplantation are at risk for severe, persistent neurocognitive deficits (109). The effect of bone marrow transplantation on X-ALD was confirmed by showing better overall and freedom from major functional disabilities survival in those transplanted compared to those who were not (118).
Patients with significant MRI involvement (Loes score > 10) had a lower quality of life than those with a minimal MRI involvement prior to bone marrow transplantation (05). Poorer performance on baseline neurocognitive tests requiring fine motor skills and visual perception were associated with inferior adaptive functioning after bone marrow transplantation (110).
Gene therapy using autologous ex-vivo gene transfer has been described in a study; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms (23). This study confirms that early treatment in the disease course and a sufficient number of engraftable transduced stem cells as well as the level of expression of the transgene may be critical to the prevention of neurologic disease progression (23).
As has been mentioned above, there has been increasing realization that VLCFA generates radical oxygen species and oxidative damage to proteins in X-linked adrenoleukodystrophy (65; 32). A cocktail of 3 molecules thought to be antioxidants (N-acetyl-cysteine, alpha-lipoic acid, and alpha-tocopherol) improved pathological and neurologic parameters in a mouse model of this disease (65). The increased reactive oxygen species cause blunting of the activity of the nuclear factor erythroid 2‐like 2 (NRF2), the master regulator of endogenous antioxidant responses. This NRF2 dysfunction causes mitochondrial dysfunction, axonal degeneration, and locomotor deficit in the mouse model for X-ALD (117). An activator of NRF2 reversed these abnormalities in the mouse model (117).
Because the capacity to alter the course of disease progression once significant neurologic abnormalities develop is still limited, a major part of management then involves general support, counseling, and advice in respect to schooling, employment, access to rehabilitative and supportive services, and the management of food intake, sphincter disturbances, impotence, spasticity, and seizures. Baclofen in gradually increasing dosages (5 mg twice a day to 25 mg every 6 hours) has been the most effective therapy for spasticity. Intrathecal administration of baclofen has been of benefit and well tolerated by several patients with adrenomyeloneuropathy (39) and has also been reported to benefit 1 boy with the childhood cerebral form of X-ALD (16). The United Leukodystrophy Foundation, Inc. (224 North Second Street, Suite 2, DeKalb, IL 60115 | (800) 728-5483 | (815) 748-3211 | F: (815) 748-0844; http://ulf.org) has been a major source of information and support for many families.
In 1 of the largest studies of allogeneic hematopoietic stem cell transplantation, the 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas the cumulative incidence of transplantation-related mortality at day 100 was 8% (77). Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status (77). The cumulative incidence of grade II-IV graft versus host disease was 18%.
Adrenoleukodystrophy does not affect the course of pregnancy. Affected boys are normal at birth. Prenatal identification of affected male fetuses is achieved by measurement of very long-chain fatty acids levels in cultured amniocytes (90) or chorion villus cells, and has been reliable in our laboratory (87; 147). Mutation analysis is the most reliable method of prenatal diagnosis in families in which the nature of the mutation has been defined. Single cell co-amplification of polymorphic markers for the indirect preimplantation genetic diagnosis of X-ALD has been reported (34).
Care must be taken to evaluate adrenal function and to provide appropriate steroid replacement therapy (53). Dobson and Lyons describe successful induction of anesthesia in a severely disabled 5-year-old boy with X-ALD. Because of concern about side effects, they did not use muscle relaxants. They used a modified rapid sequence induction with cricoid pressure and performed laryngoscopy and tracheal intubation successfully using sevoflurane and oxygen only.
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
AHM M Huq MD PhD
Dr. Huq of Wayne State University has no relevant financial relationships to disclose.See Profile
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