What is Succinic Semialdehyde Dehydrogenase Deficiency?

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare genetic disorder that interferes with the breakdown of a particular brain chemical called gamma-aminobutyric acid (GABA), which helps control nervous system activity. This condition is caused by changes in a particular gene known as ALDH5A1, and has been diagnosed in about 450 patients worldwide. As the name suggests, the problem is due to a lack of an enzyme named succinic semialdehyde dehydrogenase, which is necessary for breaking down the GABA chemical.

The main mark of this disorder is a buildup of GABA in the body’s fluids. People with SSADH deficiency show different and non-specific symptoms related to the nervous system, so it can be difficult to diagnose. However, typical changes in the body’s chemistry and brain imaging can often raise suspicion of this disorder, helping in choosing specific tests that measure body chemicals and gene tests.

What Causes Succinic Semialdehyde Dehydrogenase Deficiency?

SSADH deficiency is caused by the lack of the enzyme SSADH due to changes or mutations in a gene known as ALDH5A1.[2] Genes are like instructions for our bodies, and are located on something called chromosomes – the ALDH5A1 gene is found on a specific place (number 6p22.3) and is made up of 42,341 bases (the building blocks of genes). The ALDH5A1 gene instructs the body to make a protein that has 535 building blocks known as amino acids.

The ALDH5A1 gene can experience a variety of changes such as missense, nonsense, and splicing mutations, as well as deletions, and insertions.[2] All these are different types of defect that occur in the gene instructions.

Research has shown that these changes can severely affect the activity of the SSADH enzyme. In other words, these changes can prevent the SSADH enzyme from doing its job correctly. This enzyme is usually found in places like the brain, liver, reproductive system, upper gastrointestinal tract (like the small intestine), and endocrine system (which includes the thyroid and parathyroid glands).

The enzyme is especially present in parts of the brain like the hippocampus, cerebellum, cerebral cortex, and lateral ventricles.[3] This is of particular importance since these areas are linked to the increase in electrical activity often seen in patients with SSADH deficiency. This means that the lack of this enzyme could lead to abnormal nerve signals in the brain, which might explain some of the symptoms of SSADH deficiency.

Risk Factors and Frequency for Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disease that many people may not recognize because its symptoms are not very specific. It’s often not diagnosed because of this. The disease often shows up in childhood, but sometimes it can start affecting people during adolescence or adulthood. It affects males and females equally, and there are cases of it from all over the world. However, we’re not sure how common it is overall, but around 450 cases have been recorded in medical literature.

Signs and Symptoms of Succinic Semialdehyde Dehydrogenase Deficiency

SSADH deficiency is a disorder that usually starts showing symptoms in late infancy or early childhood, but sometimes it can also be diagnosed in adults. It is typically a slow-progressing condition with symptoms that can vary greatly from person to person. These symptoms typically include developmental and intellectual delays, particularly with expressing language, muscle weakness (hypotonia), difficulty with coordination (ataxia), movement disorders, and seizures.

Symptoms related to mental health (neuropsychiatric symptoms) may also be noticeable, particularly in older individuals. These might include:

Irritability
Agitation
Anxiety
Hallucinations
Obsessive-compulsive disorder
Inattention
Hyperactive behavior
Autism-like behavior

About half of the individuals with SSADH deficiency experience seizures, with generalized tonic-clonic seizures being the most common, followed by myoclonic seizures and atypical absences.

Sleep disorders are another common symptom, and they may become more dominant as the individual ages. Excessive daytime sleepiness and trouble starting or maintaining sleep have been reported.

Unlike many other metabolic disorders, SSADH deficiency does not typically cause episodic worsening or encephalopathy. However, a rare presentation may include a metabolic stroke following diarrheal illness. There can also be variability in symptoms within family members.

Testing for Succinic Semialdehyde Dehydrogenase Deficiency

SSADH deficiency is a rare health condition. Its diagnosis begins with the detection of a chemical called 4-hydroxy butyric acid in the urine. This is identified through a sophisticated test known as gas chromatography-mass spectrometry.

The next step involves capturing images of the brain through a technique called Magnetic Resonance Imaging (MRI). In SSADH deficiency, the MRI often shows abnormal signals —bright spots— in a part of the brain called the globus pallidus. These abnormalities sort of act as a red flag, hinting towards the possibility of SSADH deficiency.

Beside the globus pallidus, the MRI can highlight abnormalities in other parts of the brain, including the brainstem, cerebellar dentate nucleus, subthalamic nuclei. It can also signal atrophy, a form of gradual wasting, in the cerebellum and cerebrum. In rare cases, similar abnormalities may show up in the thalami and neostriatum – other specific regions of the brain.

In addition to MRIs, using Magnetic Resonance Spectroscopy (MRS), a special variant of MRI, it’s possible to detect other chemical changes linked to the deficiency. This method can pick up increased levels of GABA, a chemical messenger in the brain, and other related compounds.

An electroencephalogram (EEG), a test that measures electrical activity in the brain, is another key diagnostic tool. In cases of SSADH deficiency, the EEG typically unveils slowed brain activity and abnormal electrical discharges. Most of these abnormal discharges are widespread throughout the brain, although in some cases they might be multiple points of origin. Occasionally, they might be provoked or worsened by exposure to flashing lights – a phenomenon known as photo paroxysmal response. In rare cases, an EEG during sleep might show continuous seizure activity.

Finally, to confirm the diagnosis, doctors may undertake specific genetic testing to identify harmful changes or variations in a gene called ALDH5A1, which are unique to SSADH deficiency. The testing could either focus solely on this gene (single-gene sequencing) or involve a panel of multiple genes (multigene panel testing).

Treatment Options for Succinic Semialdehyde Dehydrogenase Deficiency

SSADH deficiency is a type of pediatric neurodegenerative disorder, for which there currently isn’t a cure. However, there are several treatments available that can help manage symptoms and improve the patient’s quality of life.

Treatment methods mostly aim at controlling seizures and managing neurobehavioral symptoms. Patients can also benefit from physiotherapy, occupational therapy, and speech therapy.

When it comes to controlling seizures, doctors typically recommend a variety of anticonvulsant medications. However, a drug called sodium valproate is not recommended because it can hinder the function of the SSADH enzyme, which is already lacking in patients with this deficiency. On the other hand, the drug magnesium valproate has been effective in controlling seizures in one patient, likely due to an associated condition called limbic encephalitis. Another medication, vigabatrin, has shown to help reduce muscle contractions, or dystonia, in a patient.

That said, the effectiveness of these drugs can vary and some may have significant side effects like retinal toxicity (damage to the eye).

For managing neurobehavioral symptoms, doctors might recommend a variety of medications like antidepressants, anti-anxiety drugs, antipsychotics and cerebral stimulants. Some examples of these medications include benzodiazepines, risperidone, fluoxetine, and methylphenidate.

Currently, researchers are investigating new potential therapies to treat SSADH deficiency, including various medications and enzyme replacement therapy. Additionally, gene therapy, which aims to replace or correct the defective gene causing the condition, is another treatment option that holds a lot of promise in the future. Tools for gene editing, such as a technique called CRISPR-Cas9, may play a crucial role in advancing these treatments.

When trying to diagnose SSADH deficiency, doctors often have to consider other conditions that have similar symptoms. These could include conditions related to GABA (a neurotransmitter) metabolism abnormalities. Two of these conditions are:

GABA transaminase deficiency: This is caused by mutations in the ABAT gene and typically results in developmental delay, low muscle tone, excessive sleepiness, movement disorders, and seizures. There’s an increase in free and total GABA levels in the spinal fluid, but no increase in GHB levels. MRI scans might show an undeveloped cerebellum, the absence of the corpus callosum, and high levels of GABA and other compounds similar to SSADH deficiency.
Homocarnosinosis: This condition is extremely rare.

Doctors also have to consider other disorders that cause bilateral symmetrical changes in the globus pallidus, a part of the brain. These could include:

Organic acidemias, especially methylmalonic academia
Mitochondrial disorders
Pyruvate dehydrogenase deficiency
Pantothenate kinase-associated neurodegeneration
Late-onset isolated sulfite oxidase deficiency

All of these conditions can be distinguished from SSADH deficiency by undertaking the right biochemical and genetic studies.

What to expect with Succinic Semialdehyde Dehydrogenase Deficiency

SSADH deficiency is a lifelong condition that changes over time. Studies have found that as patients with this illness age into adolescence and adulthood, they tend to experience increased compulsive behavior, sleep problems, and seizures. These symptoms are less commonly seen when the patients are younger.

The risk of SUDEP (Sudden Unexpected Death in Epilepsy) is also higher in adult patients. This signals that the frequency and intensity of symptoms like epilepsy, psychiatric issues, sleep disorders, and the risk of SUDEP can increase with age in patients having SSADH deficiency.

Possible Complications When Diagnosed with Succinic Semialdehyde Dehydrogenase Deficiency

The complications from this condition can get worse over time and may involve neurological and mental health problems. These can include seizures and a heightened risk of sudden unexpected death in epilepsy in adult patients.

Common Complications:

Progressive neurological disorder
Neuropsychiatric problems
Seizures
High incidence of sudden unexpected death in epilepsy in adults

Preventing Succinic Semialdehyde Dehydrogenase Deficiency

Patients, their parents, and caregivers need to be well informed about the diagnosis of SSADH deficiency, the likely progress of the condition, and any expected complications. It’s important to also understand how the condition might affect certain mental health symptoms as the patient gets older. Genetic counseling should be offered to those who either are or could potentially be carriers of the condition.

SSADH deficiency is an autosomal recessive disorder, a type of condition that arises when a person inherits one copy of a faulty gene from each parent. This pattern is referred to as ‘Mendelian inheritance’.

So, if a child has SSADH deficiency, it means their parents each carry one copy of the faulty gene, even though they might not show symptoms themselves. These parents are known as ‘heterozygote carriers’. If two carriers – in this case, the father and the mother – have a child, there’s a 25% chance that their child will have SSADH deficiency. But there’s also a 25% chance that their child will not have the condition at all. The remaining 50% chance is that their child will be a carrier of the condition, just like them. Carriers do not usually show any symptoms, but they can potentially pass the condition on to their children.