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

Authors

Hörtnagel K1,2, Krägeloh-Mann I3, Bornemann A4, Döcker M1, Biskup S1,2,5, Mayrhofer H3, Battke F2, du Bois G6, Harzer K7.
  1. Praxis für Humangenetik, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
  2. CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
  3. Department of Neuropediatrics and Neurometabolic Laboratory, Children’s Hospital of the University of Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.
  4. Department of Pathology, Division of Neuropathology, University of Tübingen, Calwer Str. 3, 72076, Tübingen, Germany.
  5. Hertie Institute of Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany.
  6. ‘genetikum Stuttgart’, Genetic Counselling and Diagnostics, Lautenschlagerstr. 23, 70173, Stuttgart, Germany.
  7. Department of Neuropediatrics and Neurometabolic Laboratory, Children’s Hospital of the University of Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany. harzer-rottenburg@t-online.de.

Abstract

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.