Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in ... Adrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes. ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins. Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by Moser (1997). Moser et al. (2005) provided a clinical review of ALD.
Moser et al. (1981) developed a plasma method for the detection of very long chain fatty acids providing for the diagnosis of affected individuals and assisting in carrier identification. Moser et al. (1999) reported the results of testing ... Moser et al. (1981) developed a plasma method for the detection of very long chain fatty acids providing for the diagnosis of affected individuals and assisting in carrier identification. Moser et al. (1999) reported the results of testing with this assay, the most widely used procedure for the diagnosis of X-linked ALD and other peroxisomal disorders, in 3,000 patients and 29,000 controls. VLCFA levels are elevated at birth, and the assay is highly accurate in hemizygotes. Eighty-five percent of obligate heterozygotes will have an elevated level, but a normal result did not exclude carrier status. A variety of other peroxisomal disorders, including Zellweger syndrome and other single enzyme defects in peroxisomal beta oxidation, also share an elevation of VLCFA levels, but can readily be discerned from ALD by the clinical situation. Moser and Moser (1999) provided an authoritative discussion of the prenatal diagnosis of X-linked ALD. They concluded that measurement of VLCFA levels in cultured amniocytes and chorionic villus cells (the most frequently used procedure) is reliable provided that care is taken to minimize the risk of false-negative results by performance of subcultures in appropriate media. The procedure can be complemented by assays of VLCFA oxidation, and under certain circumstances, immunocytochemical assays for the expression of ALDP. Mutation analysis is the most reliable diagnostic procedure when the nature of the mutation in the at-risk family is known. Inoue et al. (1996) found abnormal lignoceric acid oxidation in 19 of 19 ALD patients and in 3 of 3 obligate heterozygous carrier women. Among 10 women at risk of being a carrier, 3 with normal levels of VLCFA had abnormal lignoceric acid oxidation. Inoue et al. (1996) suggested that this combined biochemical procedure could improve the accuracy of carrier detection in ALD. Various techniques have been developed to identify ALD carriers more accurately. Boehm et al. (1999) developed and validated a robust DNA diagnostic test involving nonnested genomic amplification of the ALD gene, followed by fluorescent dye-primer sequencing and analysis. Lachtermacher et al. (2000) noted that a very small percentage (0.1%) of affected males had plasma C26:0 levels that are borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguous determination of genetic status. Of particular concern are female members of kindreds segregating X-ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. Lachtermacher et al. (2000) described a fast method for detection of X-ALD mutations. The method was based on SSCP analysis of nested PCR fragments followed by sequence-determination reactions. Using this method, they found X-ALD mutations in 30 kindreds, including 15 not previously reported. Using records from the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998, Bezman et al. (2001) estimated that the minimum frequency of X-linked ALD hemizygotes in the US is 1:42,000, and that of hemizygotes plus heterozygotes is 1:16,800. Five percent of male probands were estimated to have new mutations. Extended family testing identified asymptomatic hemizygotes, who could benefit from therapy, and heterozygotes, who could benefit from genetic counseling.
Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. Moser et al. (2000) stated that there are 7 phenotypes which include the childhood cerebral form, adrenomyeloneuropathy ... Adrenoleukodystrophy can present at a variety of ages and with different manifestations depending on the presence and type of neurologic findings. Moser et al. (2000) stated that there are 7 phenotypes which include the childhood cerebral form, adrenomyeloneuropathy (AMN), adult cerebral, adolescent, adrenal insufficiency without neurologic disease, asymptomatic, and heterozygotes. The clinical presentation can vary within the same family. One male may have the childhood form of the disorder and his brother may have the adult form. It is apparent that neither the genetic mutation nor the level of biochemical abnormality predicts the phenotypic presentation. Davis et al. (1979) observed a family with 4 cases of adrenoleukodystrophy and 1 of adrenomyeloneuropathy, suggesting the fundamental identity of the 2 disorders. The patient with adrenomyeloneuropathy was well until age 21 years when he developed spastic paraparesis. He subsequently fathered 2 daughters and a stillborn child. He was 41 years old at the time of study and showed no clinical manifestations of adrenal insufficiency. A brother of his developed paraparesis at age 13 and progressed to death at age 19. A nephew became ill at age 4 and died at age 7. Autopsy showed atrophic adrenals although no clinical signs of adrenal insufficiency were observed. O'Neill et al. (1982) studied a kindred in which 14 members were affected with a variable combination of neurologic and adrenal manifestations. Abnormality was identified by increased content of C(26:0) fatty acid (hexacosanoic acid) in cultured skin fibroblasts and abnormal C26/C22 fatty acid ratios. The latter ratios were not proportional to severity of disease, duration, or character of the neurologic syndrome. In the family reported by O'Neill et al. (1980, 1982), clinically apparent Addison disease without neurologic involvement was the expression of adrenoleukodystrophy in males, and spastic paraplegia and sphincter disturbances occurred in female carriers. Berg et al. (1989) described phenotypic features of a 362-member kindred spanning 6 generations. They observed clustering of phenotypes within individual sibships of the pedigree. Willems et al. (1990) showed that patients with ALD and AMN in the same pedigree had identical haplotypes, demonstrating that they are not caused by different allelic mutations. Holmberg et al. (1991) described a remarkable family in Sweden in which there was Addison disease in a 13-year-old boy, adrenomyeloneuropathy in a 58-year-old man, and spastic paraparesis and peripheral neuropathy in at least 3 heterozygous females, including the 85-year-old mother of the man with AMN. Sobue et al. (1994) described considerable phenotypic heterogeneity between 2 proven monozygotic twins, both of whom had myeloneuropathy. Extensive demyelination in the brain was only prominent in the older twin, while adrenal insufficiency was prominent in the younger twin. They suggested that nongenetic factors were important determinants of the phenotypic variation of the adrenoleukodystrophy gene. Korenke et al. (1996) and Di Rocco et al. (2001) also reported pairs of identical male twins with different clinical expressions of ALD. Wilichowski et al. (1998) found no difference in mitochondrial DNA in the twins reported by Korenke et al. (1996). Di Rocco et al. (2001) stated that the discordant adrenoleukodystrophy phenotypes in 3 pairs of monozygotic twins indicated that modifier genes were not involved in determining the occurrence of CNS degeneration. They suggested that identifying environmental factors could be important for effectively preventing CNS degeneration in this disorder. By neuropsychologic testing, Cox et al. (2006) found normal cognitive function in 48 of 52 neurologically asymptomatic boys with ALD (mean age, 6.7 years). All of the patients had normal brain MRI studies. However, there was a negative correlation between age and visual perception as well as age and visuomotor skills. Cox et al. (2006) concluded that a subset of patients with the childhood form of ALD have normal neurodevelopment despite an inherent defect in the ABCD1 gene. - Childhood Cerebral Adrenoleukodystrophy The classic presentation of childhood cerebral ALD has been analyzed in several large series (Schaumburg et al., 1975; Aubourg et al., 1982). This is the form of the illness that was originally described by Siemerling and Creutzfeldt (1923) and, until it was possible to make the biochemical diagnosis, it was the only form of the disease recognized as adrenoleukodystrophy. It is a rapidly progressive demyelinating condition affecting the cerebral white matter. It is by definition confined to boys who develop cerebral involvement before the age of 10 years. The boys are normal at birth and have unremarkable development. The mean age of onset is approximately 7 years. The disease usually manifests itself early with behavioral manifestations including inattention, hyperactivity, and emotional lability. It often becomes apparent through school difficulties. It progresses into visual symptoms, auditory processing difficulties, and motor incoordination. Once the neurologic manifestations appear, progression of the illness is tragically rapid and the child is often in a vegetative state within 1 to 2 years. Magnetic resonance imaging is often the first diagnostic study and shows a characteristic pattern of symmetric involvement of the posterior parietooccipital white matter in 85% of patients, frontal involvement in 10%, and an asymmetric pattern in the rest. - Adult/Adrenomyeloneuropathy Budka et al. (1976) reported a case they interpreted as an adult variant of adrenoleukodystrophy. At the time, a geneticist could raise the possibility of this form being the consequence of an allelic mutation, but phenotypic variability within families has subsequently been demonstrated. The neurologic picture was dominated by spastic paraplegia. Both clinically and pathologically, absence of diffuse cerebral involvement was noteworthy. The endocrinologic disorder was the particularly striking feature. Griffin et al. (1977) and Schaumburg et al. (1977) described a variant that they called adrenomyeloneuropathy. Hypogonadism was present in all cases appropriately studied. Adrenal insufficiency began in childhood and progressive spastic paraparesis in the third decade. Neurologic features included peripheral neuropathy, impotence, and sphincter disturbances. O'Neill et al. (1985) found biochemical characteristics of ALD in 2 brothers with spastic paraplegia of onset at age 40 and 50 years. Further study in the family revealed 2 nephews who were also affected as well as asymptomatic carriers in a typical X-linked pedigree pattern. None had symptoms of adrenal insufficiency. Cotrufo et al. (1987) reported the remarkable cases of an uncle and nephew who were completely asymptomatic at ages 25 and 10, respectively, but who showed levels of very long chain fatty acids in plasma consistent with the ALD hemizygote state. Both were found to have adrenocortical insufficiency as evidenced by compensatory high ACTH release. Uyama et al. (1993) described a man who had presenile onset (at age 51 years) of the cerebral form of ALD. The first manifestation was difficulty in recalling where he had placed things. Shortly thereafter, he had problems operating farm machinery and gradually developed difficulty seeing clearly and writing at normal speeds. He could dress himself but often put garments on backward or inside out. He later developed Balint syndrome and dementia. (Balint syndrome is an acquired visuospatial disorder characterized by psychic paralysis of visual fixation, optic ataxia, and disturbance of visual attention with relatively intact vision (Hecaen and De Ajuriaguerra, 1954).) MRI demonstrated demyelinating lesions in the bilateral posterior parietooccipital white matter involving the splenium of the corpus callosum. The patient could not move his eyes on command or follow a moving object. He had difficulty in maintaining central fixation. Optic ataxia was also shown by frequent errors when he attempted to grasp an object at which he was looking. The patient was bedridden by age 54 and died at age 55. Tests of adrenal function yielded normal results. Ratios of C26:0 to C22:0 in plasma and in erythrocyte membranes established the diagnosis of ALD in the proband and demonstrated that his mother was a heterozygote. Van Geel et al. (2001) studied the evolution of the disease in adults. They studied 129 men retrospectively, with a mean follow-up period of 10.1 +/- 5.0 years. Among 32 neurologically asymptomatic patients, 16 (50%) developed some neurologic involvement. Among 68 men with AMN without cerebral involvement, 13 (19%) developed clinically apparent cerebral demyelination. There was a high risk for adult neurologically asymptomatic patients to develop neurologic deficits and for AMN patients to develop cerebral demyelination. This had implications for the phenotype classification, search for modifying factors, and the development and evaluation of new therapies. Eichler et al. (2007) reviewed serial brain MRI scans of 56 adult patients with ALD and white matter abnormalities. Forty-two (75%) of these patients had corticospinal tract involvement, and 21 (50%) of the 42 showed lesion progression over a 3 to 5-year period. Disease progression was slower in adults compared to that previously observed in affected children. Only 3 adult patients showed isolated lesions in the genu or the splenium, all of which developed in childhood or adolescence. The findings suggested that progressive inflammatory demyelination can occur along with the known axonopathy of adulthood. Eichler et al. (2007) suggested that the vulnerability of specific fiber tracts in ALD changes with age. - Adrenal Insufficiency Addison disease in young males should prompt consideration of ALD as the underlying abnormality. See also Sadeghi-Nejad and Senior (1990). Laureti et al. (1996) performed biochemical analysis of very long chain fatty acids in 14 male patients (age ranging from 12-45 years at diagnosis) previously diagnosed as having primary idiopathic adrenocortical insufficiency. In 5 of the 14 patients, elevated levels of very long chain fatty acids (VLCFA) were found in plasma; none had adrenocortical antibodies. By electrophysiologic tests and magnetic resonance imaging, it was determined that 2 had cerebral ALD, 1 had adrenomyeloneuropathy with cerebral involvement, and 2 had preclinical AMN. Since the adrenal insufficiency may long precede neurologic manifestations and perhaps may occur alone, caution must be exercised in the interpretation of isolated X-linked Addison disease as a separate entity. Of course, autopsy-confirmed adrenal hypoplasia (300200) is a well-established entity. The achalasia-Addisonian syndrome (231550), which appears to be autosomal recessive, is another example of combined adrenal and neurologic (autonomic) involvement. The postperfusion syndrome is an uncommon event following open-heart surgery with extracorporeal circulation. It is associated with a young age at surgery (less than 1 year) and bypass lasting longer than 60 minutes. Luciani et al. (1997) observed the syndrome in an 18-year-old man who underwent transpulmonary patch repair of a ventricular septal defect with cardiopulmonary bypass for 50 minutes. Preoperatively, the patient exhibited a slight gait disorder and unremarkable EEG and laboratory findings. Twelve hours after surgery he developed hypotension and circulatory collapse. This was treated successfully, but 10 days after discharge the patient was admitted with findings suggesting Addison disease. He showed a worsening disturbance of gait, with ataxia and EEG abnormalities. The diagnosis of adrenoleukodystrophy was supported by MRI of the head and confirmed by increased plasma levels of very long chain saturated fatty acids. Thus, Luciani et al. (1997) concluded that this was a case of Addisonian crisis precipitated by surgery in a patient with previously unrecognized AMD. - Heterozygote Women who are carriers for the condition may develop spastic paraparesis with bowel and bladder difficulties. This appears to be partially a function of age. Heffungs et al. (1980) observed cerebral sclerosis and Addison disease in a previously healthy 14-year-old sister of an affected boy. They suggested that this was the first documented example of adrenoleukodystrophy in a heterozygote. Several other unusual examples have been published. Also see O'Neill et al. (1982). The patient reported by Noetzel et al. (1987) illustrates further the occurrence of a chronic nonprogressive spinal cord syndrome in women heterozygous for ALD. Hershkovitz et al. (2002) reported an 8.5-year-old girl who presented with declining school performance and diffuse frontal white matter demyelination. She was known to be at risk for heterozygosity because 2 maternal uncles had ALD. Levels of very long chain fatty acids were elevated. DNA analysis of the patient and her mother showed a cytosine insertion in codon 515 (515insC) of the ABCD1 gene, resulting in a frameshift after amino acid 171 (tyrosine). Immunocytochemical studies showed that ALDP reactivity was lacking in 99% of the fibroblasts analyzed. Cytogenetic analysis showed a deletion at Xq27.2-qter. Both parents were normal. She underwent bone marrow transplantation from a normal sister and at 18 months was stable. Hershkovitz et al. (2002) recommended that cytogenetic studies be performed in the 1% of heterozygotes who show evidence of cerebral involvement. Jung et al. (2007) reported 2 unrelated women with heterozygous mutations in the ABCD1 gene. The first patient was diagnosed at age 8 years with manic-hebephrenic disorder and subsequent psychotic episodes. She had spastic paraparesis at age 25 and developed cognitive deficits, cerebellar signs, and more severe spastic paraparesis at age 45. She died of pneumonia at age 52. Her brother had Addison disease at age 47, and later developed spastic paraparesis and polyneuropathy. The second patient developed inability to run at age 35 years, 1 year after her son died of ALD. She was wheelchair-bound by age 48. Later features included bilateral visual loss and mild polyneuropathy. She was cognitively intact. - Other--Spinocerebellar Kobayashi et al. (1986) described 2 adult male first cousins with spinocerebellar degeneration manifested by progressive limb and truncal ataxia, slurred speech, and spasticity of the limbs. Brain CT scans showed atrophy of the pons and cerebellum. Very long chain fatty acids were elevated in the plasma and red cell membranes of the affected patients and were increased to intermediate levels in the female carriers.
Moser et al. (1991) reported that their laboratory had identified more than 900 hemizygotes and 1,000 heterozygotes. Approximately 50% of the hemizygotes had a rapidly progressive childhood or adolescent form of the disease. In 25% of males, a ... Moser et al. (1991) reported that their laboratory had identified more than 900 hemizygotes and 1,000 heterozygotes. Approximately 50% of the hemizygotes had a rapidly progressive childhood or adolescent form of the disease. In 25% of males, a slowly progressive paraparesis was the clinical picture. The illness occasionally presented as Addison disease without apparent neurologic involvement. Approximately 15% of heterozygotes developed moderately severe spastic paraparesis. In studies of 30 Dutch kindreds, van Geel et al. (1994) phenotyped 77 affected males and found that 35 (46%) had adrenomyeloneuropathy and 24 (31%) had the childhood or adolescent cerebral ALD. These percentages differed significantly from previous reports in which 25 to 28% of the patients developed AMN and 53 to 57% developed childhood or adolescent cerebral ALD. In studies in Australasia and Spain, Kirk et al. (1998) and Ruiz et al. (1998), respectively, provided new information about the epidemiology of ALD and the relative frequency of ALD phenotypes. The first study originated from the unit that had served as the ALD Referral Center in Australasia for the previous 15 years. Based on the number of ALD cases identified during this period and the number of live births, they arrived at a minimum incidence of 1.6 per 100,000 live births, slightly higher than the 1.1 per 100,000 based on similar analyses in the United States (Moser et al., 1995) and considerably higher than the estimated 1 per 200,000 males in the Netherlands (van Geel et al., 1994). Of the 95 affected males studied by Kirk et al. (1998), 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison disease only, and 5 remained asymptomatic when last examined. Of the 60 patients belonging to 48 kindreds studied by Ruiz et al. (1998), 33% had childhood cerebral ALD plus adolescent cerebral ALD, 16% had adult cerebral ALD, 27% had adrenomyeloneuropathy, 12% had Addison disease only, and 12% had presymptomatic ALD. Bezman and Moser (1998) reviewed the relative frequency of phenotypes in 388 patients from 253 sibships from the United States and Canada in whom the genotype and phenotype of every male was known. This determination of every male eliminated the ascertainment bias introduced by other series in which ALD status was not known. When the proband was excluded, the phenotypic breakdown was 33% with childhood cerebral ALD, 26% with adrenomyeloneuropathy, 14% Addison only, 13% asymptomatic, 4% adolescent, and 2% adult cerebral. These numbers were very similar to the series from the Netherlands in which there was an attempt to identify everyone in the country with ALD. Bezman et al. (2001) determined the minimum frequency of hemizygotes in the United States to be 1:42,000 and that of hemizygotes and heterozygotes to be 1:16,800. In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (250100) (8.2%), Pelizaeus-Merzbacher disease (312080) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births.