Succinic semialdehyde dehydrogenase deficiency

Rare disorder involving deficiency in GABA degradation

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive disorder of the degradation pathway of the inhibitory neurotransmitter γ aminobutyric acid, or GABA. The disorder has been identified in approximately 350 families, with a significant proportion being consanguineous families. 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. SSADH deficiency is caused by an enzyme deficiency in GABA degradation. Under normal conditions, SSADH works with the enzyme GABA transaminase to convert GABA to succinic acid. Succinic acid can then be utilized for energy production via the Krebs cycle. However, because of the deficiency, the final intermediate of the GABA degradation pathway, succinic semialdehyde, accumulates and cannot be oxidized to succinic acid and is therefore reduced to gamma hydroxybutyric acid (GHB) by gamma hydroxybutyric dehydrogenase. This causes elevations in GHB and is believed to be the trademark of this disorder and cause for the neurological manifestations seen. Over half of the patients with SSADH deficiency have seizures. These include absence, tonic clonic, and convulsive status epilepticus. It is unclear whether decreased levels of GABA or elevated levels of GHB are responsible for these seizures but alterations in these neurotransmitters and their receptor binding or neurotransmitter transport is hypothesized to play a role in the pathogenesis of the seizures in this population. Symptoms associated with SSADHD may be mild, moderate or severe and often vary greatly from case to case. The symptoms of SSADH are caused by the accumulation of GHB in the brain and include the following manifestations (Defined as: common, > 70% of patients; frequent 30 70% of patients;unusual, < 30% of patients):

Common manifestations include:
Delayed gross motor development
Delayed mental development
Delayed fine motor skill development
Delayed speech and language development
Hypotonia

Frequent manifestations include:
Seizures
Hyporeflexia
Ataxia
Behavioral problems
Hyperkinesis

Unusual manifestations include:
Neonatal problems
EEG abnormalities
Psychoses
MRI or X ray computed tomography abnormalities
Oculomotor apraxia
Microcephaly
Macrocephaly
Hyperreflexia
Somnolence
Choreoathetosis
Myopathy

SSADH deficiency is inherited in an autosomal recessive fashion. Such diseases are caused by an error in a single DNA gene. Because the disease is autosomal, the defective gene is found on an autosome (chromosome 6), rather than the sex linked 23rd chromosome. Being a recessive disorder, the disease can only be inherited from both parents since the disorder can only occur when a person has two copies of the gene. It is believed that the genetic basis for SSADH deficiency resides in the SSADH human ALDH5A1 gene, which maps to chromosome 6p22. More than 47 disease causing mutations have been identified for the disorder, all of which lead to absence of functional proteins through missense, nonsense, or splicing errors; no hotspots have been identified. Consanguinity is frequent; this suggests the rare occurrence of disease causing alleles in the general population.

GABA is a major inhibitory neurotransmitter in the central nervous system. It modulates the activity of several neurotransmitters including dopamine, serotonin, and norepinephrine. GABA is synthesized in a single step from its precursor glutamate by glutamic acid decarboxylase. GABA is metabolized by successive transamination and oxidation to yield succinic semialdehyde and succinic acid respectively via the catalyzing effects of GABA transaminase. The succinic semialdehyde can be converted into either succinic acid by SSADH or to GHB by the enzyme succinic semialdehyde reductase. The absence of SSADH leads to a 30 fold increase of GHB and a 2 4 fold increase of GABA in the brains of patients with SSADH deficiency as compared to normal brain concentrations of the compounds. Elevations of GHB have been shown to induce spike and wave activity similar to that seen in generalized absence epilepsy in animal models as well, which has motivated researchers to increase their knowledge on the relationship between GHB and the neurological manifestations seen in SSADH deficiency. GABA acts via binding to its receptors which include the ligand gated ion channels, GABAA and GABAC and the G protein couple receptors GABAB. The GABAB receptor has been found to be the most important of the three receptors for this disorder as it is vital in both GABA and GHB release. This receptor mediates the release through presynaptic effects through a voltage dependent inhibition of high voltage activation of calcium channels. 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. 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. Glutamine metabolism may also play a role in the pathophysiology of SSADH deficiency. The major ionotropic glutamate receptors include the N methyl D aspartate (NMDA) and alpha amino 3 hydroxy 5 methylisoxazole 4 propionic acid (AMPA)/kainite receptor. 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. Decreased glutamine, coupled with elevated GABA, has also suggested disruption of the glutamine–glutamate shuttle which ultimately provides for astrocytic glutamine as a precursor for neuronal glutamate and GABA. 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. Finally, additional mitochondrial processes may also be affected by SSADH deficiency. Succinate semialdehyde is considered a reactive carbonyl and may lead to increased oxidative stress. 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. Additionally, oxidative stress may be responsible for loss of striatal dopamine which may contribute to pathophysiology of the disease. Another explanation for signal intensity may be demyelination since the globus pallidi are traversed by a number of myelinated axons, thus confirming Ren and Mody's 2003 work proving that repeated exposure of GHB to MAP kinase affected myelin expression, thus causing the numerous neurological dysfunctions seen in SSADH deficiency patients. 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.

Detection of the disorder is possible with an organic acid analysis of the urine. Patients with SSADH deficiency will excrete high levels of GHB but this can be difficult to measure since GHB has high volatility and may be obscured on gas chromatography or mass spectrometry studies by a high urea peak. Other GABA metabolites can also be identified in urine such as glycine. Finally, succinic semialdehyde dehydrogenase levels can be measured in cultured leukocytes of the patient. This occurs due to the accumulation of 4,5 dihydroxyhexanoic acid which is normally undetectable in mammalian tissues but is characteristic of SSADH deficiency. This agent can eventually compromise the pathways of fatty acid, glycine, and pyruvate metabolism, and then become detectable in patients' leukocytes. Such enzyme levels can also be compared to non affected parents and siblings. Two hallmarks of SSADH disorder are the increased levels of both GHB and GABA. Potential treatment modalities into biochemical and neurological correction should aim to reduce one or both while not exacerbating the other.

The most common therapeutic agent available for SSADH deficiency is one that reduces the levels of GHB via inhibition of GABA transaminase. Vigabatrin is an irreversible inhibitor of GABA transaminases which leads to decreased levels of GHB and elevation of GABA. Clinical results after use are diverse, ranging from improved ataxia and speech in some patients to worsening of symptoms in others. Lower doses (30–50 mg/kg per day) is associated with fewer side effects and greater improvement of clinical features at high doses of the therapeutic. Although vigabatrin has not been consistently successful in patients with SSADH deficiency, it has shown enhanced survival of Aldh5a1 / mice at very high doses.

The GABAB antagonist CGP 35348 (3 amino propyl (diethoxymethyl) phosphinic acid) has been used in Aldh5a1 / mice with strong results. It has shown to reduce the frequency of absence seizures, though there have been some cases in which it worsened convulsive seizures.

During prolonged periods of fasting, ketone bodies serve as the primary energy source for the brain. In 2006, Henderson et al. showed that there is a therapeutic effect of maintaining a ketogenic diet – a diet consisting of high fat/low carbohydrate meals – in children with epilepsy. Ketogenic diets have also been shown to have some neuroprotective effects in models of Parkinson's disease and hypoxia as well. 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. These effects were in conjunction with " a significant restoration of GABAergic synaptic activity and region specific restoration of GABAA receptor associated chloride channel binding." The GABA(B) receptor antagonist, SGS 742, is currently being tested as a potential therapeutic in an NIH phase II clinical trial (NCT02019667).

While SSADH deficiency has been studied for nearly 30 years, knowledge of the disorder and its pathophysiology remains unclear. 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. Both have contributed significant efforts to finding appropriate therapies for SSADH deficiency and have specifically spent most of their recent efforts into understanding the efficacy of the ketogenic diet for patients with SSADH deficiency. In addition, a lot of the research that was published in 2007 examined the pathogenesis for the disorder by examining the role of oxidative stress on tissues in various cerebral structures of Aldh5a1 / mice. Ultimately, the metabolic pathway of SSADH deficiency is known, but how the enzyme deficiency and accumulation of GABA and GHB contribute to the clinical phenotype is not. For the future however, treatment strategies should focus on both decreasing the total production of GHB and increasing the total concentration of GABA and further assessing whether the effects of these changes influences the neurological manifestations seen in patients afflicted with SSADH deficiency. Response to treatment is variable and the long term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

Several scientists have developed murine models of SSADH (Aldh5a1 / ) by typical gene methodology to create a uniform absence of the SSADH enzyme activity as well as accumulations of GHB and GABA in tissues and physiological fluids. The mice are born at the expected Mendelian frequencies for an autosomal recessive disorder. Most of the models include distinctive neurological phenotypes and exhibit hypotonia, truncal ataxia, generalized tonic clonic seizures associated with 100% mortality. The mice uniformly die at 3–4 postnatal weeks. While this model is considered to be more severe than the phenotypes seen in humans, currently, it is the most highly regarded, valid, metabolic model to study potential therapeutic interventions for the disorder. Studies have shown that alterations of both the GABAA receptor and the GABAB receptor early in the life of the Aldh5a1 / mice can increase levels of GHB and enhance GABA release. 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." Other studies have confirmed the relationship between elevated levels of GHB and MAP kinase in mutant animals contribute to profound myelin abnormalities.