Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder[1] of the degradation pathway of the inhibitory neurotransmitter γ-aminobutyric acid, or GABA.

[2] The first case was identified in 1981 and published in a Dutch clinical chemistry journal that highlighted a number of neurological conditions such as delayed intellectual, motor, speech, and language as the most common manifestations.

Later cases reported in the early 1990s began to show that hypotonia, hyporeflexia, seizures, and a nonprogressive ataxia were frequent clinical features as well.

[citation needed] Ocular problems related to the disorder include strabismus, nystagmus, retinitis, disc pallor, and oculomotor apraxia.

Many experiments have been able to show that it is the increased levels of both GABA and GHB that seem to alter the function of GABAB receptor, which may further play a role in the tonic-clonic seizures that are often seen in patients with the disorder.

[9] In terms of intracellular signaling, GHB inhibits mitogen activated protein (MAP) kinase action via the GABAB receptor mechanism.

MAP kinase is imperative for numerous physiological changes including regulation of cell division and differentiation, thus, down-regulation of this pathway may occur during the presence of too much GHB as found in SSADH deficiency.

[9] In 2003, Ren and Mody et al. proved that repeated exposure of GHB to MAP kinase affected myelin expression.

Thus, Ren and Mody's work in the relationship between increased levels of GHB and myelin expression may further show the significance of this pathway in terms of the neurological deficits seen in SSADH deficiency.

High levels of GHB have been shown to depress both the NMDA and AMPA/kainite receptor mediated functions and may also alter glutamatergic excitatory synaptic transmission as well.

This disruption has the potential to impair glutamate homeostasis and may lead to uncoupling of the normal balance between glutamatergic excitatory activity and GABAergic inhibition, and may be responsible for the convulsive seizures that are observed in this disorder.

[13] This stress is believed to contribute to the formation of free radicals in the brain tissue of animal models induced with SSADH deficiency, which further leads to secondary cell damage and death.

These included increased T2-weighted signal abnormalities involving the globus pallidi bilaterally and symmetrically as well as the presence of subcortical white matter.

Ultimately, because the globus pallidus is intimately linked with the basal ganglia and thalamus, it would be expected that some of the motor dysfunctions seen in SSADH patients such as ataxia and hyporeflexia would be common.

This agent can eventually compromise the pathways of fatty acid, glycine, and pyruvate metabolism, and then become detectable in patients' leukocytes.

Its pharmacological effects primarily take place via presynaptic GABAB receptors in the spinal cord, simultaneously releasing excitatory neurotransmitters onto motor neurons.

[9] Taurine has been successfully used in a single case open study in a child with SSADH deficiency; with resolving of brain lesions, and improvement in coordination and gait.

[20] In a 2007 study conducted at the Hospital for Sick Children in Canada, researchers found that a ketogenic diet prolonged the lifespan of Aldh5a1-/- mice by greater than 300%, along with the normalization of ataxia and some improvement in various seizure types seen in SSADH deficient murine models.

[citation needed] There is speculation that a ketogenic diet may be harmful for humans with SSADH deficiency as it may cause elevated levels of GHB in the bloodstream.

However, the progress that has been made with both murine and human models of the disorder have provided a lot of insights into how the disease manifests itself and what more can be done in terms of therapeutic interventions.

Much of the current research into SSADH has been led by a dedicated team of physicians and scientists, including Phillip L. Pearl, MD of the Boston Children's Hospital at Harvard Medical School and K. Michael Gibson, PhD of Washington State University College of Pharmacy.

Most of the models include distinctive neurological phenotypes and exhibit hypotonia, truncal ataxia, generalized tonic-clonic seizures associated with 100% mortality.

Besides these effects, it has also been shown that "...a developmental down-regulation of GABAA receptor mediated neurotransmission in Aldh5a1-/- mice likely contributes to the progression of generalized convulsive seizures seen in mutant animals.

"[9] Other studies have confirmed the relationship between elevated levels of GHB and MAP kinase in mutant animals contribute to profound myelin abnormalities.