, Volume 28, Issue 3, pp 247-265

Gamma-hydroxybutyric aciduria: A biochemist’s education from a heritable disorder of GABA metabolism

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Summary

In keeping with the theme of the 41st Annual Symposium (Metabolic Encephalopathies), the current report provides an overview of a quarter century of research investigating a rare inborn error of GABA metabolism, succinic semialdehyde dehydrogenase (SSADH) deficiency (also referred to as gamma-hydroxybutyric aciduria). The clinical phenotype, treatment challenges, pathomechanistic concepts, as well as metabolic, enzymatic and molecular characteristics, of the disorder are summarized. In addition, important features of a recently developed murine model are presented, with discussion of how this model has broadened thinking about, and treatment approaches to, the clinical disease. In addition, a brief scientific history of the author is provided, and an account of how serendipitous circumstances brought him together with other colleagues to begin delineating the aetiological mechanisms in SSADH deficiency. The evolution of research on SSADH deficiency re-establishes the classical approach beginning at clinical characterization, evolving to enzyme and metabolite identification as well as molecular characterization, and eventually to model development and preclinical treatment approaches. This scientific evolution admirably supports the life and ideals of Dr George Komrower, in whose honour this lecture is named.