Leukodystrophy, adult onset

STR: ATN1_CAG

Comment on list classification: As reviewed by Luke Stuart, there are numerous individuals reported in literature with ATN1 CAG repeats and adult-onset Dentatorubral-Pallidoluysian Atrophy, which entails widespread white matter atrophy. Hence, this STR should be promoted to Green on Adult onset leukodystrophy.

Created: 24 Jul 2026, 1:05 p.m. | Last Modified: 24 Jul 2026, 1:05 p.m.

Panel Version: 7.5

Green List (high evidence)

The pathogenic ATN1 CAG repeat expansion causes Dentatorubral-Pallidoluysian Atrophy (DRPLA; OMIM #125370), an autosomal dominant neurodegenerative disorder with anticipation. Diffuse cerebral white matter abnormalities are a well-recognised feature of adult- and late-onset disease and are repeatedly observed across independent studies.

Evidence consistently shows that white-matter involvement is associated with later age at disease onset and longer disease duration. Uyama et al. 1995 (PMID 8586978) described elderly-onset family members with symmetrical T2 hyperintensities involving deep cerebral white matter, globus pallidus, thalamus and brainstem, findings not seen in younger-onset relatives. Suemaru et al. 1993 (PMID 8370212) and Ihara et al. 1991 (PMID 1837247) similarly reported diffuse white matter abnormalities in adult-onset patients, accompanied by subcortical dementia. GeneReviews cites Koide et al. 1997 (PMID 9409354) as further evidence that diffuse deep white matter T2 hyperintensities are observed in adults with long-standing DRPLA. Li et al. 2025 (PMID: 40298952) analysed 24 adult-onset DRPLA patients and identified widespread white matter atrophy and microstructural abnormalities on advanced MRI that correlated with both CAG repeat length and disease duration.

Neuropathological studies provide support for a primary degenerative leukoencephalopathy. Munoz et al. 2004 (PMID 15210537) demonstrated severe myelin pallor and white matter alterations (disproportionate to the degree of vascular changes seen) with relative axonal preservation, while Mizoi et al. 1994 (PMID 8167052) similarly concluded that observed white matter pathology could not be attributed to vascular or ischaemic mechanisms alone.

Conclusions: pathogenic ATN1_CAG expansions are associated with a leukodystrophy-like phenotype characterised by diffuse cerebral white matter disease in adult- and late-onset presentations. Evidence supports leukoencephalopathy as a recognised component of the adult-onset DRPLA phenotype and warrants inclusion of the ATN1_CAG repeat expansion on the adult-onset leukodystrophy panel.

Created: 24 Jul 2026, 11:23 a.m. | Last Modified: 24 Jul 2026, 11:23 a.m.

Panel Version: 7.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dentatorubral-pallidoluysian atrophy, 125370

Publications

• PMID: 8586978
• 8370212
• 1837247
• 9409354
• 40298952
• 15210537
• 8167052

Green List (high evidence)

National Inherited White Matter Disorders MDT requests that this STR is added to the R62 panel
Sources: NHS GMS

Created: 16 Jul 2026, 3:30 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this STR are reported as part of current diagnostic practice