Succinic semialdehyde dehydrogenase deficiency
Synonyms
4
Overview
Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydoxybutyric aciduria or gamma-hydoxybutyric aciduria, is a rare autosomal recessive disorder[1] 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.
Symptoms
The symptoms of SSADH deficiency fall into three primary categories: neurological, psychiatric, and ocular. The most constant features seen are developmental delay, hypotonia, and mental retardation. Nearly half of patients seen manifest ataxia, behavior problems, seizures, and hyporreflexia.[2] The age of onset ranges from newborn period to 25 years. Problems unique to neonates can include prematurity, lethargy, decreased sucking, respiratory difficulty and hypoglycemia. Gastrointestinal symptoms have been seen primarily in this population and are usually related to increased feeding. Ocular problems related to the disorder include strabismus, nystagmus, retinitis, disc pallor, and oculomotor apraxia.[4] Nearly 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.
Causes
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
Diagnosis
Neuroimaging Cranial computed topography, magnetic resonance imaging, and flurodeoxyglucose positron emission topography are just some of the neuroimaging modalities that have been used to diagnose patients with SSADH deficiency. On the basis of 29 previously published cases that had imaging results available, there were some common abnormalities found. These included increased T2-weighted signal abnormalities involving the globus pallidi bilaterally and symmetrically as well as the presence of subcortical white matter. Similar abnormalities have been identified in the brainstem and cerebellar dentate nucleus. [2] Signal intensity on a T2 image may be a result of edema or an inflammatory response. Because this type of imaging is a water detecting sequence, any form of calcification or mineralization would also appear dark, thus explaining why accumulation of extra blood or fluid would appear bright on a T2 image. 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 hyporreflexia would be common.
Treatment
A number of pharmacological treatments have been suggested or tested for efficacy on Aldh5a1-/- mice and/or humans. Below is a small sampling of the most common treatments though to be therapeutic to patients with SSADH deficiency. Unfortunately, there is very little data to support the benefit of the following treatments since few controlled studies have been conducted in patients. [edit] Vigabatrin 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. [9] [edit] Sodium Valproate Sodium valproate has been used for the treatment of generalized and partial seizures in humans for both epilepsy and bipolar disorder. Valproate enhances GABA synthesis and release leading to augmented GABAergic functions in some areas of the brain. Successful interventions with valproate have been noted, but no clinical trials have been conducted thus far.[9] However, Valproate is usually contraindicated as it may inhibit residual SSADH enzyme activity [14] [edit] GABA(B) receptor antagonist: CGP-35348 The GABA(B) 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. [9] [edit] GABA(B) agonist: Baclofen Baclofen (β-p-chlorophenyl-GABA) has some analgesic properties and has been traditionally used for spasticity. Its pharmacological effects primarily take place via presynaptic GABA(B) receptors in the spinal cord, simultaneously releasing excitatory neurotransmitters onto motor neurons. Because the number and function of GABA(B) receptors has been shown to progressively diminish in Aldh5a1-/- mice, such a therapy may prove to be useful. However, no data on the efficacy of baclofen on Aldh5a1-/- mice or human patients has been reported. [9] [edit] Taurine Taurine is a non-protein sulfur amino acid that is found in high concentrations in human milk. It has been shown to have neuroprotective and neuromodulating properties. While it is an inhibitory neurotransmitter, its ability to cross the blood brain barrier is limited. There is a lot of literature that indicates that taurine acts as antagonist at GABA(A) and GABA(B) receptors which may further enhance its ability to treat patients with SSADH deficiency, but further pharmacological studies are yet to be conducted to see if taurine could serve a therapeutic purpose. [9] [edit] Ketogenic Diet 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. [15] In a recent study conducted at the Hospital for Sick Children in Canada in 2007, 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. [16] These effects were in conjunction with “…a significant restoration of GABAergic synaptic activity and region-specific restoration of GABA(A) receptor associated chloride channel binding.” [16] Ultimately, the data seen in the study indicated that a ketogenic diet may work in its ability to restore GABAergic inhibition. But further studies on murine models need to be conducted, ultimately leading to the possibility of conducting a controlled study on humans afflicted with the disorder. [edit] Other Interventions Other therapeutic interventions [9] include: * ethosuximide and other epileptic drugs * GHB receptor antagonist NCS-382 * GABA(A) receptor modulators * uridine * acamprosate * dopaminergic agents * dextromethorphan * glutamine * antioxidants * Lamotrigine[17]