The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement

J Inherit Metab Dis. 2016 Nov;39(6):849-857. doi: 10.1007/s10545-016-9961-x. Epub 2016 Jul 29.


Vesicular protein sorting-associated proteins (VPS, including VPS11) are indispensable in the endocytic network, in particular the endosome-lysosome biogenesis. Exome sequencing revealed the homozygous variant p.Leu387_ Gly395del in the VPS11 gene in two siblings. On immunoblotting, the mutant VPS11 protein showed a distinctly reduced immunostaining intensity. The children presented with primary and severe developmental delay associated with myoclonic seizures, spastic tetraplegia, trunk and neck hypotonia, blindness, hearing loss, and microcephaly. Neuro-imaging showed severe hypomyelination affecting cerebral and cerebellar white matter and corpus callosum, in the absence of a peripheral neuropathy. Electron microscopy of a skin biopsy revealed clusters of membranous cytoplasmic bodies in dermal unmyelinated nerve axons, and numbers of vacuoles in eccrine sweat glands, similar to what is seen in a classic lysosomal storage disease (LSD). Bone marrow cytology showed a high number of storage macrophages with a micro-vacuolated cytoplasm. Biochemically, changes in urinary glycosphingolipids were reminiscent of those in prosaposin deficiency (another LSD). The clinical and neuro-imaged features in our patients were almost identical to those in some recently reported patients with another variant in the VPS11 gene, p.Cys846Gly; underlining the presumed pathogenic potential of VPS11 defects. A new feature was the morphological evidence for lysosomal storage in VPS11 deficiency: This newly characterised disease can be viewed as belonging to the complex field of LSD.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Base Sequence
  • Cataract / congenital
  • Cataract / genetics
  • Child
  • Demyelinating Diseases / genetics*
  • Endosomes / genetics
  • Female
  • Hereditary Central Nervous System Demyelinating Diseases / genetics
  • Humans
  • Lysosomal Storage Diseases / genetics
  • Lysosomes / genetics*
  • Male
  • Mutation / genetics
  • Vesicular Transport Proteins / deficiency*
  • Vesicular Transport Proteins / genetics*


  • VPS11 protein, human
  • Vesicular Transport Proteins

Supplementary concepts

  • Leukodystrophy, Hypomyelinating, 5