Succinic Semialdehyde Dehydrogenase Deficiency

Etiology

The etiology of SSADH deficiency is the absence of SSADH due to mutations in the gene ALDH5A1.[2] This gene has been mapped on 6p22.3 and comprises 42,341 bases. The protein codified by the ALDH5A1 gene has 535 amino acids with a molecular mass of 57215 Da, and the metric structure is a homotetramer with a quaternary structure. The genetic variants reported include missense, nonsense, and splicing mutations, deletions, and insertions.[2] 

Studies analyzing the structural and functional consequences of some of these variants have shown a profound effect on SSADH enzyme activity. The mRNA expression has been identified in the brain, liver, and biliary system, as well as the reproductive system (Leydig cells, testicular interstitium), upper gastrointestinal tract (duodenum), and endocrine system (thyroid gland and parathyroid glands). The brain sites of SSADH expression include the hippocampus, cerebellum, cerebral cortex, and lateral ventricles.[3] These locations are particularly important for the relationship to the increased electrical activity that may be detected in patients affected with SSADH deficiency.

Epidemiology

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder. Approximately 450 patients are reported in the literature.[2] The exact prevalence is not known. Because of the non-specific nature of the clinical features, the disorder is often underdiagnosed. The most common presentation is during childhood, but rarely the onset of symptoms can occur in adolescence or adulthood.[4] There is no gender or geographic predilection, and the disorder has been reported worldwide.

Pathophysiology

The impairment of the function of the SSADH enzyme leads to a disruption of the metabolism of gamma-aminobutyric acid (GABA), which is a naturally occurring amino acid that functions as an inhibitory neurotransmitter in the brain. SSADH deficiency leads to an abnormal accumulation of the compound succinic semialdehyde, which in turn is converted to 4-hydroxybutyric acid (4-HBA), which is also known as gamma-hydroxybutyric (GHB). Both GABA and gamma-hydroxybutyric acid contribute to pathophysiology. However, the relative contribution of each of these compounds to the pathophysiology remains unknown.[5] 

Both experiments in murine knockout models and humans have suggested a role for down-regulated gamma-aminobutyric acid type-A receptor (GABAAR) and gamma-aminobutyrate type-B receptor (GABABR) function in epileptogenesis in SSADH deficiency.[4] Indirect effects that result in organelle dysfunction or impairment of signaling have been suggested to contribute to SSADH deficiency. Mitochondrial dysfunction oxidative damage and autophagy are additional pathogenetic mechanisms postulated.[2] 

In SSADH deficiency, mitochondrial dysfunction may take place as GABA degradation is coupled to the Krebs cycle. Thus, it is linked to the respiratory chain through succinate and alpha-ketoglutarate.[6] Molecular pathology studies involving the ALDH5A1-/- mutant mice seem to exhibit a decrease in the activities of respiratory chain complexes I-IV in the hippocampus. This finding is often seen with decreased glutathione. Both findings seem to suggest a mitochondrial dysfunction and an increase in oxidative stress.

Histopathology

Neuropathological findings in SSADH deficiency have been described in a single report.[3] The patient was considered to have died of sudden unexpected death in epilepsy (SUDEP) and later confirmed to have SSADH deficiency. The most prominent finding was striking bilateral sharply circumscribed discoloration of the basal ganglia, specifically of the globus pallidus, which corresponds to the site of the most consistent abnormality visible on neuroimaging.

The other findings included congestion of the vessels in the leptomeninges, globus pallidum, and superior colliculus. Granular perivascular calcifications were present in globus pallidi, cerebellar dentate nuclei, and hippocampus. They have been attributed to chronic progressive excitotoxic injury.[3][7] There were no changes attributed to hypoxia in the CA1 section of the hippocampus, the area most vulnerable to hypoxia and ischemia.

Toxicokinetics

Lee et al. studied the SSADH in the rat brain.[8] They used anti-SSADH antibodies and targeted the distribution of brain SSADH in the rodent brain. They found in the lobus frontalis, immunophenotypically positive cells in the lateral areas of the septum pellucidum, ventral portion of the pallidum, as well as in the reticular nucleus thalami, which is closely related to 'sleeping,' the basal nuclei of Meynert, and the very crucial hypothalamic nuclei.

The basal nuclei of Meynert are associated with Alzheimer disease. Finally, immunoreactivity was detected in raphe nuclei of the reticular formation of the midbrain, cerebellum, and inferior olivary nuclei of the medulla oblongata. Immunophenotypically reactive cells were markedly observed in the areas, which were linked with both the formatio reticularis and the limbic system of the rodent brain.

History and Physical

The clinical features of SSADH deficiency are often non-specific and variable. SSADH deficiency typically presents in late infantile period and early childhood but may be diagnosed occasionally in adulthood. The disorder often has a slowly progressive or static course. The clinical features are characterized by developmental delay and later intellectual impairment, with prominent expressive language delays, hypotonia, ataxia, movement disorder, and seizures.

Neuropsychiatric features: Prominent neuropsychiatric symptoms occur, especially in the older age group, and are disabling. These include irritability, easy agitation, anxiety, hallucinations, disabling obsessive-compulsive disorder, inattention, hyperactive behavior, and autistic-like behavior.[9]

Seizures are seen in approximately 50% of patients. Generalized seizures are commonly seen, of which generalized tonic-clonic seizures predominate, followed by myoclonic seizures and atypical absences.[10] 

Sleep disorders are common and increasingly seen as age advances. Excessive day time somnolence and other disorders of initiating or maintaining sleep have been reported.[11]

Episodic deterioration or encephalopathy is generally not seen as it is in other metabolic disorders. However, a rare presentation with a metabolic stroke following diarrheal illness has been reported.[12]. Intrafamilial variability in symptoms has been observed rarely.

Evaluation

The diagnosis of SSADH deficiency is initially made by the presence of 4-hydroxy butyric acid excretion in urine, which is identified by special ion monitoring gas chromatography-mass spectrometry. Magnetic resonance imaging of the brain shows bilateral symmetrical hyperintense signal changes in globus pallidum and often raises diagnostic suspicion of SSADH in an appropriate clinical setting.[4] The lesions show restricted diffusion. Bilateral hyperperfusion of the globus pallidus has been demonstrated on arterial spin-labeling perfusion MR imaging.[13] Pallidal abnormalities are rarely asymmetric. Other changes include hyperintense signal changes in the brainstem, cerebellar dentate nucleus, subthalamic nuclei, as well as atrophy of the cerebellum and cerebrum. Rarely, the involvement of the thalami and neostriatum can occur.[14][15]

Specialized magnetic resonance spectroscopy protocols that allow editing for small molecules have shown elevated levels of GABA and related compounds in patients with SSADH deficiency.[16]

Electroencephalography shows background slowing and epileptiform abnormalities. The epileptiform abnormalities are usually generalized and sometimes multifocal. Rarely photo paroxysmal response and electrographic status epileptics of slow-wave sleep have been reported.[10]

The diagnosis is established by the identification of biallelic pathogenic variations in ALDH5A1. The molecular testing approach could be either single-gene sequencing or multigene panel testing.

Treatment / Management

Similar to other pediatric neurodegenerative disorders, there is no curative treatment for SSADH deficiency currently. However, there are some symptomatic and supportive management options [2]. Treatment approaches are directed at seizure control and control of neurobehavioral symptoms and also include physiotherapy, occupational therapy, and speech therapy. 

Anti-seizure medications: Broadspectrum anticonvulsants are advised though sodium valproate is contraindicated because of the inhibition of the SSADH enzyme.[17] However, magnesium valproate has been shown efficacious in one patient with SSADH deficiency and refractory seizures, possibly secondary to limbic encephalitis.[18] Also, vigabatrin, which is an irreversible inhibitor of GABA transaminase, has been shown to have a beneficial effect on dystonia in one patient.[19] It inhibits the subsequent formation of SSA. However, the results are often inconsistent, and critical side effects, especially retinal toxicity, have been recorded.[20](B3)

Neuropsychiatric symptoms: Various antidepressants, anti-anxiety, and antipsychotic medications and cerebral stimulants have been used to treat behavioral symptoms in SSADH deficiency.[21] These include benzodiazepines, risperidone, fluoxetine, and methylphenidate.(B3)

There are a number of pharmacological and enzyme replacement therapeutic options that are currently being evaluated, including GABA and GHB receptor antagonists and mTOR inhibitors.[5] Enzyme replacement therapy and gene therapy are valid options for the future and hopes for both families and patients. New molecular biology tools, including gene editing (e.g., CRISPR-Cas9), have been suggested that may play a role in the current decade of the 21st century.

Differential Diagnosis

The differential diagnoses of SSADH deficiency include other disorders of GABA metabolism, which include GABA transaminase deficiency and homocarnosinosis. GABA transaminase deficiency results from mutations in the ABAT gene and the clinical features are characterized by developmental delay, hypotonia, hypersomnolence, movement disorder, and seizures.[22] The free and total GABA levels in cerebrospinal fluid (CSF) are elevated. There is no elevation in GHB levels. The MRI findings include cerebellar hypoplasia and agenesis of the corpus callosum. Magnetic resonance spectroscopy demonstrates elevated levels of GABA and related compounds similar to SSADH deficiency. The other related disorder homocarnosinosis, is extremely rare.  

Another important consideration is other disorders causing bilateral symmetrical signal changes in the globus pallidum. These disorders include organic acidemias, especially methylmalonic academia, mitochondrial disorders, pyruvate dehydrogenase deficiency, and pantothenate kinase-associated neurodegeneration. Late-onset isolated sulfite oxidase deficiency (ISOD) is another disorder with globus pallidus signal changes.[23] All these disorders can be differentiated from SSADH deficiency by appropriate biochemical and genetic studies.

Prognosis

SSADH deficiency is a lifelong disorder, and the clinical features evolve over time. Longitudinal studies have shown that compulsive behavior, sleep disturbances, and seizures are more commonly seen in adolescence or the adult age group compared to a lower proportion of those with hypotonia.[24] There is also a high risk of SUDEP in adult patients. This shows that there is a worsening of epilepsy, neuropsychiatric features, sleep disturbances, and a higher risk of SUDEP with advancing age in patients with SSADH deficiency.

Complications

The complications include progressive neurological disorder and neuropsychiatric problems, including seizures and a high incidence of SUDEP in adult patients.[24]