Original Article
Adrenomyeloneuropathy Presenting as Addison's Disease in Childhood
N Engl J Med 1990; 322:13-16January 4, 1990
- Abstract
- Abstract
Adrenoleukodystrophy, a sex-linked peroxisomal disorder that results in the impaired oxidation of long-chain saturated fatty acids and causes neurologic impairment, is a rare cause of Addison's disease in children. Adrenomyeloneuropathy is the name given to a biochemically identical but milder and more slowly progressive variant of adrenoleukodystrophy that affects young adults, in whom adrenal insufficiency may long precede nervous system dysfunction. The transmission of adrenomyeloneuropathy, like that of most cases of adrenoleukodystrophy, is sex-linked.
Because of a preponderance of male patients among a group of patients with the onset of adrenal failure in childhood, we questioned whether this condition might be the initial manifestation of adrenomyeloneuropathy. We therefore measured the plasma concentrations of very-long-chain saturated fatty acids in eight patients with adrenal insufficiency; of these, five had elevated plasma hexacosanoic acid concentrations (range, 2.42 to 6.43 μmol per liter; mean normal level [±SD], 0.83±0.45), confirming the presence of adrenomyeloneuropathy. Magnetic resonance imaging showed clear evidence of brain involvement in all five patients. Reexploration of the family histories revealed additional missed cases.
We conclude that the possibility of adrenomyeloneuropathy should be considered in any boy with Addison's disease. (N Engl J Med 1990; 322:13–6.)
Article Activity
- Article
THE most common cause of Addison's disease (primary adrenal failure) is autoimmune adrenal disease. In adults, metastatic tumors, amyloidosis, and tuberculosis and other infectious processes account for most of the remaining cases. In children, adrenoleukodystrophy is an additional, genetically determined, rare cause of Addison's disease.1 One form of adrenoleukodystrophy in infants is transmitted as an autosomal recessive trait; the disorder in older patients is sex-linked.2 , 3
The basic defect in adrenoleukodystrophy is one of peroxisomal dysfunction, which results in the impaired oxidation of very-long-chain saturated fatty acids, particularly hexacosanoic acid (C26:0).3 , 4 The accumulation of these fatty acids in the brain, adrenal glands, and other organs is believed to be responsible for the clinical manifestations of the disease.3 The neurologic features of the illness —progressive and severe dementia and deterioration of vision, speech, and gait — dominate the clinical picture in adrenoleukodystrophy, permitting the differentiation of children with this disease from those with adrenal failure due to other causes.
Adrenomyeloneuropathy is the name given to a milder and more slowly progressive form of adrenoleukodystrophy. Like that of adrenoleukodystrophy, its transmission is sex-linked, and the affected persons have the same biochemical abnormalities. Both disorders may occur in the same family. The onset of adrenomyeloneuropathy usually occurs in adolescence and early adulthood rather than childhood. The initial findings commonly include weakness, spasticity, and sensory disturbances of the legs.5 In one reported variant of adrenomyeloneuropathy, adrenal insufficiency was the initial feature, and the neurologic symptoms appeared many years later.5
Because of a marked preponderance of male patients among those with Addison's disease in our clinic, we wondered whether any might have adrenal insufficiency as an early manifestation of adrenomyeloneuropathy. This report describes the results of our search for adrenomyeloneuropathy among these patients.
Methods
We studied all eight male patients who had presented with Addison's disease in childhood and were being followed up at the Pediatric Endocrine–Metabolic Clinic of the New England Medical Center. Patients with multiple endocrine-gland failure were excluded. Two patients were siblings; the others were unrelated. The initial clinical findings included cyclic vomiting, asthenia, salt craving, and hyperpigmentation. In all patients the administration of adrenocorticotropin (ACTH) had failed to increase the plasma cortisol concentration, and all had responded to replacement therapy with cortisol and mineralocorticoid. The patients' laboratory data and ages at the onset of symptoms and at the diagnosis of adrenal failure are shown in Table 1Table 1
Summary of Clinical and Laboratory Results in Eight Male Patients with Addison's Disease.. None of the patients had any symptoms or signs of neurologic dysfunction.Plasma cortisol and ACTH concentrations were measured by standard competitive-protein-binding and immunoassay methods, respectively. We measured the plasma concentrations of very-long-chain saturated fatty acids by capillary-gas chromatography. The five patients who were found to have elevated plasma hexacosanoic acid (C26:0) concentrations then underwent magnetic resonance imaging of the brain.
We further explored the family histories of the patients found to have increased plasma hexacosanoic acid concentrations. In these families we sought additional information that the parents had not volunteered or had not been aware of at the time their sons were found to have adrenal insufficiency. We also measured the plasma hexacosanoic acid concentrations in some family members.
Results
Strikingly elevated plasma concentrations of hexacosanoic acid (C26:0) were found in five of the eight patients, confirming the presence of adrenomyeloneuropathy (Table 1). In these five patients, the symptoms of adrenal insufficiency seemed to have progressed more slowly than in the other three patients, delaying the recognition of their disease. Otherwise, these five patients were indistinguishable from the others in terms of the clinical and biochemical findings of adrenal insufficiency.
One patient (Patient 5) remained well for 15 years after the diagnosis of adrenal insufficiency. He wrestled competitively, married, and fathered a son, and he had only recently noted delayed ejaculation as well as paresthesias of the soles of his feet. Neurologic symptoms developed in a second patient (Patient 4) within a year after he was found to have adrenal insufficiency. The remaining three patients were in apparently good health.
Magnetic resonance imaging of the brain in patients with adrenoleukodystrophy reveals characteristic abnormalities of the T-l and T-2 signal intensity of the white matter, particularly in the periventricular regions.6 In all five patients who had elevated plasma hexacosanoic acid concentrations, magnetic resonance imaging showed unequivocal evidence of brain involvement.
Reexploration of the family histories of the five patients with adrenomyeloneuropathy revealed additional hemizygous and heterozygous family members and a multitude of neurologic disorders (Fig. 1Figure 1
Pedigrees of the Five Patients with Addison's Disease and Adrenomyeloneuropathy or Adrenoleukodystrophy (AMN/ALD).). Among the male family members who had died in the four families represented, one (family of Patient 5, Generation II) had amyotrophic lateral sclerosis, one (family of Patient 4, Generation II) had multiple sclerosis, one (family of Patient 1, Generation III) had Wilson's disease, one (family of Patient 4, Generation III) had dementia and seizures, one (family of Patient 3, Generation II) had questionable poliomyelitis, and one (family of Patient 3, Generation III) had questionable encephalitis. Two (families of Patient 1, Generation IV, and Patient 3, Generation III) were said to have Schilder's disease, an eponymous name once used for adrenoleukodystrophy. Female carriers are prone to have progressive spastic paraparesis.3 In our four families, four older heterozygous women had gait disturbances, and one (family of Patient 4, Generation II) had been given a diagnosis of multiple sclerosis.Discussion
Among these eight male patients with Addison's disease, the only difference between the five with adrenomyeloneuropathy and the other three was the longer time from the onset of symptoms of adrenal insufficiency to its diagnosis. If valid, this difference could reflect the basic pathophysiology of the disorder. The deposition of very-long-chain fatty acids in the adrenal gland increases membrane microviscosity and decreases responsiveness to ACTH, presumably by reducing the availability of receptors.7 The result might well be a more insidious development of adrenal insufficiency than occurs with the autoantibody-induced destruction of the adrenal glands.
The unusual findings in the family histories were not only the number of previously unsuspected cases uncovered but also the variability in the expression of the disorder. The ages at the time of the development of neurologic abnormalities ranged from early childhood to well into adult life. The neurologic disturbances included dementia, motor abnormalities, and sensory abnormalities. We do not know whether adrenomyeloneuropathy was the underlying disease in each family member who had a neurologic disorder, but the findings are compatible with that diagnosis, and the family trees show that each was a potential candidate for the disorder.
With such phenotypic variability, it is not surprising that different names, such as Schilder's disease, adrenoleukodystrophy, and adrenomyeloneuropathy, have been used for the same disorder. The use of a single term, such as adrenoneuropathy, might make it easier to recognize this pleiotropic disease in the future.
Attempts at therapy have included restricting the dietary intake of saturated, very-long-chain fatty acids, but presumably because of endogenous synthesis, such restriction has had little effect on plasma concentrations.8 Increasing the dietary intake of oleic acid seems more promising. The addition of this monounsaturated fatty acid to cell cultures diminished the rate of synthesis of hexacosanoic acid, and dietary supplementation with oleic acid combined with a decreased intake of very-long-chain fatty acids has lowered the plasma levels of very-long-chain fatty acids.9 , 10 This effect is thought to occur because the monounsaturated oleic acid competes with saturated fatty acids for the microsomal fatty acid chain-elongation system, thereby impeding the production of very-long-chain saturated fatty acids. Nerve-conduction measurements have shown some improvement in two patients who were so treated.10
From this small study one cannot determine exactly what proportion of boys with adrenal insufficiency have adrenoneuropathy, but the number is clearly not negligible. Because of the prognostic implications, the need for genetic counseling, and the potential benefit of therapeutic intervention, such patients need to be identified promptly. Accordingly, we suggest that any boy with Addison's disease should be tested for adrenoneuropathy.
Presented in part at the annual meetings of the American Pediatric Society—Society for Pediatric Research, Washington, D.C., May 1 to 4, 1989, and the Endocrine Society, Seattle, June 21 to 24, 1989.
We are indebted to Dr. Hugo Moser (Kennedy Institute, Baltimore) for measuring the plasma concentrations of very-long-chain fatty acids.
Source Information
From the Department of Pediatrics, Tufts University School of Medicine, and the Pediatric Endocrine–Metabolic Service, New England Medical Center (Floating Hospital for Infants and Children), Boston. Address reprint requests to Dr. Senior at Box 346, 750 Washington St., Boston, MA 02111.
- References
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- Citing Articles (14)
Citing Articles
1
Lynda E. Polgreen, Saydi Chahla, Weston Miller, Steven Rothman, Jakub Tolar, Teresa Kivisto, David Nascene, Paul J. Orchard, Anna Petryk. (2011) Early diagnosis of cerebral X-linked adrenoleukodystrophy in boys with Addison’s disease improves survival and neurological outcomes. European Journal of Pediatrics 170:8, 1049-1054
CrossRef2
Peter A. Hogan. 2011. Cutaneous Manifestations of Endocrine Disease. , 172.1-172.31.
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Bornstein, Stefan R., . (2009) Predisposing Factors for Adrenal Insufficiency. New England Journal of Medicine 360:22, 2328-2339
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Esra Arun Ozer, Aysun Kaya, Munevver Yildirimer, Ozlem Guler, Sule Can, Halil Aydinlioglu. (2009) A novel DAX1 gene mutation in a Turkish infant with X-linked adrenal hypoplasia congenita. European Journal of Pediatrics 168:3, 367-369
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WALTER L. MILLER, JOHN C. ACHERMANN, CHRISTA E. FLÜCK. 2008. The Adrenal Cortex and Its Disorders. , 444-511.
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Bijayeswar Vaidya, Simon Pearce, Pat Kendall-Taylor. (2000) Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure. Clinical Endocrinology 53:4, 403-418
CrossRef7
Peter Heim, Matthias Claussen, Béatrice Hoffmann, Ernst Conzelmann, Jutta Gärtner, Klaus Harzer, Donald H. Hunneman, Wolfgang Köhler, Gerhard Kurlemann, Alfried Kohlschütter. (1997) Leukodystrophy incidence in Germany. American Journal of Medical Genetics 71:4, 475-478
CrossRef8
H. W. Moser. (1995) Adrenoleukodystrophy: natural history, treatment and outcome. Journal of Inherited Metabolic Disease 18:4, 435-447
CrossRef9
Paula Jorge, Dulce Quelhas, Pedro Oliveira, Rui Pinto, António Nogueira. (1994) X-linked adrenoleukodystrophy in patients with idiopathic addison disease. European Journal of Pediatrics 153:8, 594-597
CrossRef10
H. W. Moser, A. B. Moser, K. D. Smith, A. Bergin, J. Borel, J. Shankroff, O. C. Stine, C. Merette, J. Ott, W. Krivit, E. Shapiro. (1992) Adrenoleukodystrophy: Phenotypic variability and implications for therapy. Journal of Inherited Metabolic Disease 15:4, 645-664
CrossRef11
B. H. Holmberg, E. Hägg, M. Duchek, L Hagenfeldt. (1992) Screening of patients with hereditary spastic paraparesis and Addison's disease for adrenoleukodystrophy/adrenomyeloneuropathy. Acta Neurologica Scandinavica 85:2, 147-149
CrossRef12
B. H. HOLMBERG, E. HÄGG, L. HAGENFELDT. (1991) Adrenomyeloneuropathy-report on a family. Journal of Internal Medicine 230:6, 535-538
CrossRef13
Patrick Aubourg, Jean-Louis Chaussain. (1991) Adrenoleukodystrophy presenting as addison's disease in children and adults. Trends in Endocrinology & Metabolism 2:2, 49-52
CrossRef14
Menkes, John H., . (1990) The Leukodystrophies. New England Journal of Medicine 322:1, 54-55
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