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Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies

  • Original Article
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Journal of Inherited Metabolic Disease

Abstract

We present an update to the status of research on succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD), a rare disorder of GABA metabolism. This is an unusual disorder featuring the accumulation of both GABA and its neuromodulatory analog, gamma-hydroxybutyric acid (GHB), and recent studies have advanced the potential clinical application of NCS-382, a putative GHB receptor antagonist. Animal studies have provided proof-of-concept that enzyme replacement therapy could represent a long-term therapeutic option. The characterization of neuronal stem cells (NSCs) derived from aldehyde dehydrogenase 5a1−/− (aldh5a1−/−) mice, the murine model of SSADHD, has highlighted NSC utility as an in vitro system in which to study therapeutics and associated toxicological properties. Gene expression analyses have revealed that transcripts encoding GABAA receptors are down-regulated and may remain largely immature in aldh5a1−/− brain, characterized by excitatory as opposed to inhibitory outputs, the latter being the expected action in the mature central nervous system. This indicates that agents altering chloride channel activity may be therapeutically relevant in SSADHD. The most recent therapeutic prospects include mTOR (mechanistic target of rapamycin) inhibitors, drugs that have received attention with the elucidation of the effects of elevated GABA on autophagy. The outlook for novel therapeutic trials in SSADHD continues to improve.

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Acknowledgements

Supported in part by NIH NS 82286, NS 98856, NS 85369, and EY27476. We remain grateful for the ongoing support of the SSADH Association (www.ssadh.net).

Details of funding

Supported in part by NIH NS 82286, NS 98856, NS 85369, and EY27476.

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Authors and Affiliations

  1. Department of Neuroscience, University of Wisconsin, Madison, WI, USA

    Kara R. Vogel

  2. Theravance Biopharma Inc., South San Francisco, CA, USA

    Garrett R. Ainslie

  3. Department of Pharmacotherapy, College of Pharmacy, Washington State University, 412 E. Spokane Falls Blvd, Health Sciences Building Room 210, Spokane, WA, 99204, USA

    Dana C. Walters, Jean-Baptiste Roullet & K. Michael Gibson

  4. Speragen, Inc., Austin, TX, USA

    Alice McConnell

  5. Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Sameer C. Dhamne & Alexander Rotenberg

Authors
  1. Kara R. Vogel
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  2. Garrett R. Ainslie
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  3. Dana C. Walters
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  4. Alice McConnell
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  7. Jean-Baptiste Roullet
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  8. K. Michael Gibson
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Corresponding author

Correspondence to K. Michael Gibson.

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Conflict of interest

K.Vogel, G. Ainslie, J. Roullet, K. Gibson, D. Walters, A. McConnell, A. Rotenberg, and S. Dahmne declare that they have no conflict of interest

Additional information

Communicated by: Jaak Jaeken

Electronic supplementary material

ESM 1

Representative electrocorticographic recordings of seizure types in an aldh5a1−/− mouse. These data are representative of traces employed to generate the data of Table 2. (JPEG 101 kb)

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Vogel, K.R., Ainslie, G.R., Walters, D.C. et al. Succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism: an update on pharmacological and enzyme-replacement therapeutic strategies. J Inherit Metab Dis 41, 699–708 (2018). https://doi.org/10.1007/s10545-018-0153-8

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  • DOI: https://doi.org/10.1007/s10545-018-0153-8

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