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.

Signs and 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 intellectual disability. Nearly half of patients seen manifest ataxia, behavior problems, seizures, and hyporeflexia.

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.

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

Genetics

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.

Mechanism

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. In 2003, Ren and Mody et al. proved that repeated exposure of GHB to MAP kinase affected myelin expression. This is a critical finding since myelin is the electrical and insulating phospholipid layer that surrounds the axons of many neurons in the brain. Proper myelination is critical for carrying electrical signals, or data, from one nerve cell to the next. When myelin becomes damaged, it can cause numerous neurological problems, many of which are seen in patients with SSADH deficiency. 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.

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.

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.

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 hyporeflexia would be common.

Laboratory

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.

Treatments

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 thought 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.

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.

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