Leukodystrophy and Leukoencephalopathy Panel

Leukodystrophies are a group of inherited heterogeneous disorders affecting the white matter of the central nervous system with or without peripheral nervous system involvement. These disorders are often characterized by glial cell or myelin sheath abnormalities. Neuropathology often reveals involvement of oligodendrocytes, astrocytes, and other non-neuronal cell types. Of note, the term leukoencephalopathy is a more neutral term for any brain white matter disorder including genetic or acquired causes. Leukodystrophies are present with highly variable phenotypes and disease onset at all ages due to different etiologies and pathogenic mechanisms. When white matter tracts are affected, it almost universally leads to motor impairment. The major features include hypotonia in early childhood, which progresses to spasticity over time. Motor dysfunction may involve swallowing, chewing, or respiration in certain cases. Other features include extrapyramidal movement dysfunction (for example, dystonia or dyskinesias), ataxia, seizures, and delay in cognitive development or cognitive impairment (Vanderver et al. 2015. PubMed ID: 25649058; Kevelam et al. 2016. PubMed ID: 27564080). MRI studies are extremely useful in the diagnosis of patients with leukoencephalopathies. MRI facilitates the diagnosis of specific etiologic entities (Schiffmann and van der Knaap. 2009. PubMed ID: 19237705).

This panel covers many well-characterized genes involved in classical leukodystrophies and other genetic leukoencephalopathies that have significant white matter involvement, such as certain inborn errors of metabolism, disorders in lysosomes, peroxisomes, mitochondria, vascular disorders, and diseases with primary involvement of neurons in the cerebral cortex or other gray matter structures (Vanderver et al. 2015. PubMed ID: 25649058).

The genetic etiology of leukodystrophy and leukoencephalopathy is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms. Leukodystrophy and leukoencephalopathy can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner or with complex inheritance.

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

This panel includes genes causative for leukodystrophy and leukoencephalopathy. The sensitivity is variable depending on different disorders. For example, this panel can identify pathogenic variants in more than 90% of individuals who have leukoencephalopathy with vanishing white matter and characteristic MRI findings (Schiffmann et al. 2010. PubMed ID: 20301435).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).