NOTE: THIS PUBLICATION HAS BEEN RETIRED. THIS ARCHIVAL VERSION IS FOR HISTORICAL REFERENCE ONLY, AND THE INFORMATION MAY BE OUT OF DATE.
Clinical characteristics: Leukodystrophies are heritable myelin disorders affecting the white matter of the central nervous system with or without peripheral nervous system myelin involvement. Involvement of the white matter tracts almost universally leads to motor involvement that manifests as hypotonia in early childhood and progresses to spasticity over time. This may lead to variable motor impairment, from mild spastic diplegia to severe spastic quadriplegia that limits purposeful movement. In addition, motor dysfunction is likely to significantly impair vital functions including swallowing, chewing, and (in some cases) respiration. Other findings that vary by disorder include extrapyramidal movement disorders (e.g., dystonia and/or dyskinesias), ataxia, seizures, and delay in cognitive development or change in cognitive function over time.
Diagnosis/testing: Establishing the specific leukodystrophy present in a given individual usually involves:
Obtaining a medical history and detailed family history
Performing a physical examination and neurologic examination
Review of brain MRI findings:
T2-weighted hyperintensity in the white matter is the MRI finding required for diagnosis of a leukodystrophy.
T1-weighted signal may be variable: iso- or hyperintense T1-weighted signal is consistent with a hypomyelinating leukodystrophy; hypointense T1-weighted signal is consistent with a demyelinating leukodystrophy.
Performing specialized laboratory testing, often including molecular genetic testing (either stepwise single-gene testing or use of a multigene panel targeted to the leukodystrophies).
Genetic counseling: Leukodystrophies with an identified genetic cause may be inherited in an autosomal dominant manner, an autosomal recessive manner, or an X-linked recessive manner. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Prenatal testing for pregnancies at increased risk is possible for some types of leukodystrophy if the pathogenic variant(s) in the family are known. Many leukodystrophies are still without an identified genetic cause; once a genetic cause is identified, other inheritance patterns may emerge.
Management: Treatment of manifestations: Treatment is symptomatic and ideally occurs in a multidisciplinary setting by specialists experienced in the care of persons with a leukodystrophy. Pharmacologic agents are used to manage muscle tone and block neuronal signaling to muscle (chemodenervation). Intensive physical therapy is used to improve mobility and function. Pharmacologic treatment of dystonia and dyskinesias may result in significant functional improvement. Treatment of ataxia, seizures, and cognitive issues is provided in the usual manner, depending on the needs of the individual.
Prevention of primary manifestations: In a few leukodystrophies primary disease manifestations can be prevented by hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) early in the disease course.
Surveillance: Routine assessment of growth and nutritional status; physical examination and/or serial x-rays of the hips and spine to monitor for orthopedic complications; and routine history regarding signs and symptoms of seizures.
Agents/circumstances to avoid: Mild head injuries and infection as these may exacerbate disease manifestations.
Evaluation of relatives at risk: When primary prevention of a leukodystrophy is possible (e.g., by HSCT or BMT), it is appropriate to offer testing to asymptomatic at-risk relatives who would benefit from early diagnosis and consideration of early treatment.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.