Hypomyelinating leukodystrophies in adults: Clinical and genetic features

Eur J Neurol. 2021 Mar;28(3):934-944. doi: 10.1111/ene.14646. Epub 2020 Dec 3.


Background and purpose: Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among undefined leukoencephalopathies in adulthood.

Methods: We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near-normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy-targeted next generation sequencing panel.

Results: We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early-onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early-onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early-onset diseases with central hypomyelination/dysmyelination.

Conclusions: A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease-causing genes, including genes associated with severe early-onset HLDs, and genes causing peroxisome biogenesis disorders.

Keywords: genetic leukoencephalopathies; hypomyelination; leukodystrophies; peroxisome biogenesis disorders; spastic paraplegias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Demyelinating Diseases*
  • Female
  • Humans
  • Leukoencephalopathies* / diagnostic imaging
  • Leukoencephalopathies* / genetics
  • Magnetic Resonance Imaging
  • Microtubule-Associated Proteins
  • Mutation


  • Microtubule-Associated Proteins
  • TBCD protein, human