This chapter will focus on the more common and clinically important leukodystrophies. The prevalence of all leukodystrophies is approximately 1 in 7000. Leukodystrophies and genetic leukoencephalopathies comprise a clinically and radiographically heterogeneous group of disorders. These disorders share the common features of neurologic dysfunction and preferential involvement of central nervous system (CNS) white matter. The terminology can be confusing as the terms leukodystrophy and leukoencephalopathy are both used clinically and found interchangeably in the literature. Although white matter can be affected by many different processes, “leukodystrophy” is generally reserved for either abnormal formation of myelin or loss of previously formed myelin with an identified or presumed genetic basis. Genetic “leukoencephalopathies” are disorders with white matter changes secondary to other factors such as gray matter degeneration (lysosomal disorders, mitochondrial disorders) or congenital vascular disorders. The differential diagnosis also includes acquired causes of white matter dysfunction from infectious, inflammatory, nutritional, or neoplastic causes; medication; or a previous injury. When evaluating a patient with white matter changes on neuroimaging, these acquired disorders should be excluded based on the clinical history and specific testing; acquired causes require different management.
For many leukodystrophies, the underlying pathophysiology remains unknown. The primary mechanisms that are known are secondary to a loss of myelin, a demyelinating process versus hypomyelination, or abnormal formation of myelin involving mostly the oligodendrocytes and astrocytes. Oligodendrocytes and astrocytes are impaired either structurally or metabolically because of disruption of an intrinsic pathway or the buildup of toxic by-products that leads to a disruption of myelin.
Genetic etiologies arise from many types of inheritance patterns, including autosomal recessive, dominant, X-linked, and mitochondrial. Many of the leukodystrophies remain uncharacterized from a genetic perspective, suggesting that additional genes remain to be discovered. Overall, however, improvements in neuroimaging and genetic testing are uncovering new genetic etiologies for these previously unknown disorders.
Traditionally, a diagnosis of a leukodystrophy starts with the clinical history of global developmental delay and/or regression, as well as white matter changes on neuroimaging. Clinical presentations vary by age from severe neonatal/infantile-onset to milder adult-onset forms. The clinical presentations can also vary within a family for the same mutation in some disorders, for example, X-linked adrenoleukodystrophy (ALD). In the United States, some states are now including some leukodystrophies, such as Krabbe and ALD, in their newborn screening program in order to detect presymptomatic neonates because of emerging therapies. The varied presentations in severity and age can complicate the interpretation of newborn screening results.
Neuroimaging is the key for obtaining a diagnosis for patients with leukodystrophies. Brain magnetic resonance imaging (MRI) can help to distinguish genetic from acquired white matter disorders and between primary demyelinating and hypomyelinating disorders. Normally, myelination starts prenatally and continues at least into the third decade of life. Myelination generally proceeds in a caudal-to-rostral and central-to-peripheral ...