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Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a degenerative disorder of the sheath covering nerve fibers, known as myelin. A type of leukodystrophy, the victims of ALD are typically male, as the disease is usually inherited in a sex-linked manner on the X chromosome. Leukodystrophies are disorders that affect the growth and/or development of myelin, a complex fatty neural tissue that insulates many nerves of the central and peripheral nervous systems. Without myelin, nerves are unable to conduct an impulse, leading to increasing disability as myelin destruction increases and intensifies. more...

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Leukodystrophies are different from demyelinating disorders such as multiple sclerosis, in which myelin is formed normally, but is lost by immunologic dysfunction or other reasons.

Symptoms

The clinical presentations is largely dependent on the age of onset of the disease. The most frequent type is the childhood-onset one, which normally occurs in males between the ages of 5 and 10 and is characterized by failure to develop, seizures, ataxia, adrenal insufficiency and degeneration of visual and auditory function.

In the adolescent-onset form, the spinal cord dysfunction is more prominent and therefore is called adrenomyeloneuropathy or "AMD". The patients usually present with weakness and numbness of the limbs and urination or defecation problems. Most victims of this form are also males, although female carriers rarely exhibit symptoms similar to AMD.

Adult and neonatal (which tend to affect both males and females and be inherited in an autosomal recessive manner) forms of the disease also exist but they are extremely rare. Some patients may present with sole findings of adrenal insufficiency (Addison's disease).

Diagnosis

The diagnosis is established by clinical findings and the detection of serum long chain fatty acid levels. MRI examination reveals white matter abnormalities, and neuroimaging findings of this disease are quite reminiscent of the findings of multiple sclerosis. Genetic testing for the analysis of the defective gene is available in some centers.

Pathophysiology

The most common form of ALD is X-linked (the defective gene is on the X chromosome, location Xq28), and is characterized by excessive accumulation of very long chain fatty acids (VLCFA) - fatty acids chains with 24-30 carbon atoms (particularly hexacosanoate, C26) in length (normally less than 20). This was originally described by Moser et al in 1981.

The gene (ABCD1 or "ATP-binding cassette, subfamily D, member 1") codes for a protein that transfers fatty acids into peroxisomes, the cellular organelles where the fatty acids undergo β-oxidation (Mosser et al 1993). A dysfunctional gene leads to the accumulation of long-chain fatty acids.

The precise mechanisms through which high VLCFA concentrations cause the disease are still (2005) unknown, but accumulation is severe in the organs affected.

The prevalence of X-linked adrenoleukodystrophy is approximately 1 in 20,000 individuals. This condition occurs with a similar frequency in all populations.

Treatment

While there is no cure for the disease, some dietary treatments, for example, Lorenzo's oil in combination with a diet low in VLCFA, have been used with limited success, especially before disease symptoms appear. A recent study by Moser et al (2005) shows positive long-term results with this approach.

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Adrenoleukodystrophy
From Archives of Pathology & Laboratory Medicine, 1/1/03 by Chen, Xia

Adrenoleukodystrophy (ALD) is a rare genetic metabolic disorder. It is characterized by progressive dysfunction of the adrenal gland and demyelination of nerve cells in the brain due to impaired peroxisomal function. Peroxisomes are intracellular organelles that contain enzymes necessary for lipid metabolism.1

Adrenoleukodystrophy encompasses 2 rare and distinct genetic disorders, X-linked ALD (an X-linked recessive disorder) and neonatal ALD (an autosomal recessive disorder). In both forms of ALD, high levels of very long chain fatty acids accumulate in various organs due to the absence of peroxisomes. This accumulation is most severe in the brain and adrenal glands, and results in a variety of neurologic problems and endocrine dysfunction.

Impairment of more than one peroxisomal function can lead to a subgroup of even rarer diseases including Zellweger syndrome. This syndrome is an autosomal recessive disorder characterized by facial dysmorphism, neonatal hypotonia, psychomotor retardation, and hepatomegaly, and it is usually fatal in infancy.1 In genetic terms, Zellweger syndrome overlaps neonatal ALD: both disorders are caused by abnormalities of the same genes.

In patients with ALD, the adrenal glands are of normal shape, but small. Each gland usually weighs less than 2 g,2,3 but its architecture is preserved. The diminutive size of the adrenal gland in ALD has been attributed to an (as yet incompletely explained) "adrenalytic" process,2 referring to the dystrophy implied in the term ALD.

Histologically, the adrenal cortex shows changes mainly in the zona fasciculata and zona reticularis. These changes consist of variably enlarged cortical cells, with abundant striations and macrovacuoles in the cytoplasm. The "balboning" of cells, considered pathognomonic for ALD, is a result of accumulation of smooth endoplasmic reticulum and lipid material. The ballooned cells may form nodules. The nucleus may be either vesicular or hyperchromatic. The zona glomerulosa and adrenal medulla are minimally affected in ALD.

The accompanying images are of an adrenal gland affected by ALD, from the autopsy of a male infant diagnosed with Zellweger syndrome. The infant was the only child of a homeless mother. He had failed to thrive since birth and had developed seizure disorder, hypotonia, jaundice, and hepatosplenomegaly. The diagnosis was made based on this constellation of clinical manifestations. The infant died of sepsis and respiratory failure 10 weeks after birth.

Autopsy showed the presence of abnormal adrenal glands and multiple congenital abnormalities. Both left and right adrenal glands were small, with normal shape, and weighed 0.3 and 0.2 g, respectively (Figure A; bar, 1 nun). Histologic examination of the adrenal gland showed nodules composed of variably enlarged cortical ballooned cells with abundant waxy cytoplasm that were arranged in a pseudotubular pattern in the inner portion of the cortex (Figures B, C, and D show progressively higher-power magnifications of the affected adrenal glands, hematoxylin-eosin stain). Normal zonation of the gland was not evident. The adrenal medulla was not affected (Figure B).

The other abnormalities found at autopsy included simian creases, low-set ears, and frontal bossing. We also noted thymic hypoplasia, bilateral undescended testis, hepatosplenomegaly, intrahepatic paucity of bile ducts, and extrahepatic biliary atresia with marked cholestasis. We rendered a postmortem diagnosis of ALD, in the setting of Zellweger syndrome.

References

1. Moser HW, Moser AB, Chen WW, Watkins PA. Adrenoleukodystrophy and Zellweger syndrome. Prog Clin Biol Res. 1990;321:511-535.

2. Powers JM, Schaumburg HH. The adrenal cortex in adrenoleukodystrophy. Arch Pathol. 1973;96:305-310.

3. Lloyd RV, Douglas BR, Young WF. Endocrine Diseases. Washington DC: Armed Forces Institute of Pathology; 2002:203-205. Atlas of Non-tumor Pathology.

Xia Chen, MD; Ronald A. DeLellis, MD; Syed A. Hoda, MD

Accepted for publication July 22, 2002.

From the Departments of Pathology, New York Presbyterian Hospital & Weill Medical College of Cornell University, New York, NY (Drs Chen and Hoda) and Rhode Island Hospital, Brown University School of Medicine, Providence, RI (Dr DeLellis).

Reprints: Xia Chen, MD, New York-Presbyterian Hospital & Weill Medical College of Cornell University, Starr 1028, Box 93, 525 E 68th St, New York, NY 10021 (e-mail: xiachen@nyp.org).

Copyright College of American Pathologists Jan 2003
Provided by ProQuest Information and Learning Company. All rights Reserved

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