title: The second report of a new hypomyelinating disease due to a defect in the VPS11 gene discloses a massive lysosomal involvement.
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.
authors.affiliation: Praxis für Humangenetik, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.|CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Hörtnagel
authors.affiliation: Department of Neuropediatrics and Neurometabolic Laboratory, Children's Hospital of the University of Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Krägeloh-Mann
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Tübingen, Calwer Str. 3, 72076, Tübingen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.affiliation: Praxis für Humangenetik, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Döcker
authors.affiliation: Praxis für Humangenetik, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.|CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.|Hertie Institute of Clinical Brain Research, University of Tübingen, Otfried-Müller-Str. 27, 72076, Tübingen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.affiliation: Department of Neuropediatrics and Neurometabolic Laboratory, Children's Hospital of the University of Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Mayrhofer
authors.affiliation: CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Battke
authors.affiliation: 'genetikum Stuttgart', Genetic Counselling and Diagnostics, Lautenschlagerstr. 23, 70173, Stuttgart, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: du Bois
authors.affiliation: 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.
authors.forename: Klaus
authors.initials: K
authors.lastname: Harzer
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002386:Cataract / Q000151:congenital / Q000235:genetics; D002648:Child; D003711:Demyelinating Diseases / Q000235:genetics*; D011992:Endosomes / Q000235:genetics; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics; D008247:Lysosomes / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000172:deficiency* / Q000235:genetics*
chemical_list: C424438:VPS11 protein, human; D033921:Vesicular Transport Proteins