Human genetic disorders of sphingolipid biosynthesis
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Monogenic defects of sphingolipid biosynthesis have been recently identified in human patients. These enzyme deficiencies affect the synthesis of sphingolipid precursors, ceramides or complex glycosphingolipids. They are transmitted as autosomal recessive or dominant traits, and their resulting phenotypes often replicate the abnormalities seen in murine models deficient for the corresponding enzymes. In quite good agreement with the known critical roles of sphingolipids in cells from the nervous system and the epidermis, these genetic defects clinically manifest as neurological disorders, including paraplegia, epilepsy or peripheral neuropathies, or present with ichthyosis. The present review summarizes the genetic alterations, biochemical changes and clinical symptoms of this new group of inherited metabolic disorders. Hypotheses regarding the molecular pathophysiology and potential treatments of these diseases are also discussed.
KeywordsCeramides Hereditary Spastic Paraplegia Sphingoid Base Ceramide Synthases GBA2 Mutation
Autosomal recessive congenital ichthyosis
Hereditary sensory and autonomic neuropathy
Magnetic resonance imaging
This work was supported by INSERM, Université Paul Sabatier, ANR (SphingoDR program), RITC, LNCC (Equipe Labellisée 2013), CHU Toulouse, and the Vaincre les Maladies Lysosomales Foundation (for TL’s group), and the Gebert Rüf Foundation, the Center for Integrative Human Physiology (ZIHP, University of Zurich), “radiz” – Rare Disease Initiative Zurich, Clinical Research Priority Program for Rare Diseases, University of Zurich, and the European Commission (LSHM-CT-2006-037631) (for TH’s group).
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Conflict of Interest
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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