Leukodystrophy and Leukoencephalopathy, Adult Onset Panel

Adult onset leukodystrophies and leukoencephalopathies are rare groups of inherited heterogeneous disorders progressively leading to degeneration of white matter in the brain with or without peripheral nervous system involvement. The primary pathology of classical leukodystrophy involves the myelin sheath, whereas the pathology of genetic leukoencephalopathy results from neuronal or systemic defects. When white matter tracts are affected, motor impairment nearly always occurs. Common features of adult-onset leukodystrophies and leukoencephalopathies are progressive cognitive impairment, neuropsychiatric changes, spasticity, apraxia, ataxia and seizures (Vanderver et al. 2015. PubMed ID: 25649058; Kevelam et al. 2016. PubMed ID: 27564080; Lynch et al. 2017. PubMed ID: 28334938; Lynch et al. 2019. PubMed ID: 30467211). Other features vary depending on the specific disorder. Overall incidence is not precisely known. To our knowledge, there are no known differences between males and females.

MRI studies are very useful in the diagnosis of patients with leukoencephalopathies. They may facilitate the diagnosis of specific etiologic entities (Schiffmann and van der Knaap. 2009. PubMed ID: 19237705).

As adult onset leukodystrophy and leukoencephalopathy can be caused by abnormalities in a number of genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image study only. An accurate diagnosis is critical for treatment, prognosis, prediction of recurrence risk, as well as future family plans.

This panel includes genes which are involved in adult onset or late onset leukodystrophies and leukoencephalopathies. However, defects in some of the genes can lead to both early onset and adult onset leukodystrophy and leukoencephalopathy. Examples include the 5 genes that code for the heteropentameric protein EIF2B and CSF1R (Konno et al. 2017. PubMed ID: 27680516; Rannikmäe et al. 2015. PubMed ID: 25653287; Finnsson et al. 2015. PubMed ID: 26053668; Lynch et al. 2017. PubMed ID: 28334938; Lynch et al. 2019. PubMed ID: 30467211). Adult onset leukodystrophy and leukoencephalopathy can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. The covers the following adult onset leukodystrophies and leukoencephalopathies:

(1) hereditary diffuse leukoencephalopathy with spheroids (CSF1R)

(2) adult onset leukodystrophy, autosomal dominant (LMNB1)

(3) cerebral autosomal dominant /recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL, CARASIL) (NOTCH3, HTRA1)

(4) brain small vessel disease (COL4A1 and COL4A2)

(5) leukoencephalopathy, progressive, with ovarian failure (AARS2)

(6) leukoencephalopathy with vanishing white matter disease (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5)

(7) X linked adrenoleukodystrophy (ABCD1)

(8) metachromatic leukodystrophy (ARSA)

(9) Alexander disease (GFAP)

(10) Hypomyelinating disorders (PLP1, GJC2, NKX6-2, POLR3A, POLR3B, TUBB4A, CLCN2)

(11) Aicardi-Goutieres syndrome 1 (TREX1)

(12) Mitochondrial disorders (POLG, TYMP)

(13) several other genes for which late onset cases have been reported (CBS, CYP27A1, GLA, GBE1, GALC, CTSA, DARS2, MTHFR, PSAP, RNF216, TREM2, TYROBP).

Treatments are currently available for a few of these disorders, for example, cerebrotendinous xanthomatosis (CYP27A1), and methylenetetrahydrofolate reductase deficiency (MTHFR).

A wide variety of causative variants in these genes have been reported including missense, nonsense, splicing, small insertions/deletions, large deletions/duplications and complex rearrangements (Human Gene Mutation Database). De novo pathogenic variants are common in some of the genes such as CSF1R, COL4A1 and COL4A2.

See individual gene summaries for detailed information about molecular biology of gene products and spectra of pathogenic variants.

This panel contains genes which are causative for adult onset leukodystrophy and leukoencephalopathy. Sensitivity is variable depending on different disorders. The Queen Square Adult Leukodystrophy Group (QSALG) investigated 116 patients with a wide variety of white matter syndromes and found that the most common causes are small vessel disease (11 patients), followed by CSF1R pathogenic variants (9 patients), mitochondrial diseases (4 patients) and adrenoleukodystrophy (4 patients) (supplementary figure 1 in Lynch et al. 2019. PubMed ID: 30467211).

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

This panel typically provides 99.5% 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).