What is Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency (SSADHD)?
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited disorder of GABA metabolism characterized by developmental delays and neurologic abnormalities that appear in infancy. Neurologic abnormalities usually appear by 1-2 years of age and include developmental delay and intellectual disability. Seizures may develop in infancy or later in childhood. The disorder is unique in the accumulation of two neuromodulatory species in the physiological fluids of patients, including the inhibitory neurotransmitter GABA and the GABA-analog, gamma-hydroxybutyric acid (GHB). The normal metabolic pathway of GABA includes two enzymes: GABA transaminase followed by SSADH. In the absence of SSADH, the intermediate succinic semialdehyde accumulates and is converted to GHB, a compound with complex and incompletely-defined roles in the central nervous system, but an agent with high-affinity binding sites.
The key symptoms of SSADHD include:
- Non-progressive encephalopathy (although a subset of patients may have a progressive phenotype)
- Decreased muscle tone in the arms and/or legs (hypotonia)
- Intellectual disability
- Striking absence of formalized speech
- Neuropsychiatric morbidity prominently occurring in late childhood through adolescence, including OCD and ADHD
- Accumulation of GABA and GHB in physiological fluids
How many people have SSADHD?
SSADHD is estimated to occur in 1 per 1,000,000 births worldwide, and is higher in certain geographic locations such as the Mideast, Turkey, and Greece. As of this writing, approximately 180 patients have been reported in the primary literature (Attri et al 2017). The figure indicates the panethnic nature of patients in terms of geographic locations. Diagnosis based upon clinical features is impossible (due to the nonspecific neurological features). The initial diagnosis is made through the detection of elevated urinary GHB achieved using routine organic acid analysis. This must be followed-up with either repeat urine organic acid analysis and, preferably, molecular diagnostics since GHB is employed in illicit settings, as well as in an increasing number of clinical situations, including narcolepsy, fibromyalgia, and other experimental uses.
What causes SSADHD?
SSADHD is caused by mutations (or changes) in the ALDH5A1 gene that makes the enzyme succinic semialdehyde dehydrogenase. SSADH is one of two enzymes active in the catabolism of the major inhibitory neurotransmitter, GABA. In the absence of SSADH, the accumulated succinic semialdehyde (the product of the GABA transaminase reaction) is converted to GHB. Mutations in ALDH5A1 result in an inactive SSADH enzyme and accumulation of GABA and GHB, and several other metabolites related to both compounds. Accumulation of neuromodulatory compounds, under a variety of permutations, is believed in turn to cause developmental delay and intellectual disability. Neurologic symptoms are associated with accumulation of neurotransmitters in the brain that can be seen on specialized MRI brain scans. SSADHD is an inherited autosomal recessive disorder. Affected individuals inherit two copies of the mutated or changed ALDH5A1 gene, one from each parent. Therefore the parents are "carriers" of SSADHD, meaning that they have one normal functioning copy and one nonfunctioning copy of the gene. With each pregnancy, carriers of SSADHD have a 1 in 4 or 25% chance of having a child with SSADHD.
How is SSADHD diagnosed?
The first step in diagnosis is the identification of increased GHB in the urine organic acid profile. This is subsequently confirmed by genetic testing of the ALDH5A1 gene. The potential for newborn screening through determination of bloodspot GABA levels in under active investigation.
What is the treatment for SSADHD?
There is no curative treatment for SSADHD and targeted therapeutics are lacking. Current medications are palliative (antiepileptics for seizures, various neuroleptics for OCD). Historically, the antiepileptic vigabatrin (SabrilR) has been employed as a first line intervention. As an irreversible inhibitor of GABA transaminase, vigabatrin is rational, yet it is predicted (and documented) to increase GABA in the central nervous system. The latter may be contraindicated in an already hyperGABAergic syndrome such as SSADHD.
OMIM: Succinic semialdehyde dehydrogenase (# 271980)
Associated Websites and Patient Support groups:
Ongoing Clinical Trials
Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
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- Chambliss KL, Hinson DD, Trettel F, Malaspina P, Novelletto A, Jakobs C, Gibson KM. Two exon-skipping mutations as the molecular basis of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria). Am J Hum Genet. 1998 Aug;63(2):399-408.
- Hogema BM, Gupta M, Senephansiri H, Burlingame TG, Taylor M, Jakobs C, Schutgens RB, Froestl W, Snead OC, Diaz-Arrastia R, Bottiglieri T, Grompe M, Gibson KM. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet. 2001 Oct;29(2):212-6.
- Gupta M, Greven R, Jansen EE, Jakobs C, Hogema BM, Froestl W, Snead OC, Bartels H, Grompe M, Gibson KM. Therapeutic intervention in mice deficient for succinate semialdehyde dehydrogenase (gamma-hydroxybutyric aciduria). J Pharmacol Exp Ther. 2002 Jul;302(1):180-187
- Vogel KR, Ainslie GR, Schmidt MA, Wisor JP, Gibson KM. mTOR Inhibition Mitigates Molecular and Biochemical Alterations of Vigabatrin-Induced Visual Field Toxicity in Mice. Pediatr Neurol. 2017 Jan;66:44-52.e1. doi: 10.1016/j.pediatrneurol.2016.09.016.
- Vogel KR, Ainslie GR, Gibson KM. mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism. J Inherit Metab Dis. 2016 Nov;39(6):877-886.
- Vogel KR, Ainslie GR, Pearl PL, Gibson KM. Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity? Clin Pharmacol Ther. 2016 Nov 19. doi: 10.1002/cpt.581. [Epub ahead of print]
- Attri SV, Singhi P, Wiwattanadittakul N, Goswami JN, Sankhyan N, Salomons GS, Roullet J-B, Hodgeman R, Parviz M, Gibson KM, Pearl PL. Incidence and Geographic Distribution of Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency. Inherit. Metab. Dis., Rep. 2016 Nov 5. [Epub ahead of print]
- Malaspina P, Roullet J-B, Pearl PL, Ainslie GR, Vogel KR, Gibson KM. Succinic semialdehyde dehydrogenase deficiency (SSADHD): Pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Int., 2016;99:72-84
- Schreiber JM, Pearl PL, Dustin I, Wiggs E, Barrios E, Wassermann EM, Gibson KM, Theodore WH. Biomarkers in a taurine trial for succinic semialdehyde dehydrogenase deficiency. JIMD Rep. 2016;30:81-87.
- Johansen SS, Wang X, Sejer Pedersen D, Pearl PL, Roullet J-B, Ainslie GR, Vogel KR, and Gibson KM. Gamma-Hydroxybutyrate (GHB) Content in Hair Samples Correlates Negatively with Age in Succinic Semialdehyde Dehydrogenase Deficiency. Inherit. Metab. Dis., 2017 Feb 18. doi: 10.1007/8904_2017_3. [Epub ahead of print]