Adrenoleukodystrophy (ALD) is an X-linked disorder that in hemizygotes involves mainly the nervous system white matter and the adrenal cortex. The hallmark of the disease is the accumulation of saturated very long chain fatty acids (VLCFA) due to the impaired capacity to degrade these substances. More than 1,100 women who are heterozygous for ALD have been identified and preliminary studies show that at least 50% have some degree of neurological disability. This disability ranges widely from subtle neurological abnormalities that do not cause overt symptoms to severe paraparesis and fatal cerebral involvement. The patients are often misdiagnosed as having multiple sclerosis, familial spastic paraparesis, or spinocerebellar degeneration. Precise diagnosis is important because of the 50% risk of affected offspring, and the likelihood that specific therapy will become available.
In Specific Aim 1 a systematic study of the neurological and endocrine function will be carried out in a large and representative sample of the ALD heterozygote population. This will yield precise knowledge about the frequency, type of defects, and clinical course, information that is essential for counseling and selection of therapeutic options.
Specific Aim 2 will determine if severe neurological disability is related to the degree of the biochemical and endocrine dysfunction and if it can be attributed to predominant inactivation of the normal X-chromosome, to uniparental disomy, or the action of cytokines or immune mechanisms.
Specific Aim 3 will study effects of 5-azacytidine on activation patterns of the X- chromosome in cultured skin fibroblasts as a prelude to therapeutic interventions that may be applicable to heterozygotes specifically.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046877-03
Application #
2146150
Study Section
Neurology C Study Section (NEUC)
Project Start
1993-01-21
Project End
1996-12-31
Budget Start
1995-02-01
Budget End
1995-12-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
DUNS #
167202410
City
Baltimore
State
MD
Country
United States
Zip Code
21205