About succinic semialdehyde dehydrogenase defi...

What is succinic semialdehyde dehydrogenase defi...?

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare inborn error of metabolism that is inherited as an autosomal recessive trait. In individuals with the disorder, deficient activity of the SSADH enzyme disrupts the metabolism of gamma-aminobutyric acid (GABA). GABA is a natural chemical known as a "neurotransmitter" that serves to inhibit the electrical activities of nerve cells (inhibitory neurotransmitter). SSADH deficiency leads to abnormal accumulation of the compound succinic semialdehyde, which is reduced or converted to 4-hydroxybutyric acid, also known as GHB (gamma-hydroxybutyric acid). GHB is a natural compound that has a wide range of effects within the nervous system. The "hallmark" laboratory finding associated with SSADH deficiency is elevated levels of GHB in the urine (i.e., 4-hydroxybutyric or gamma-hydroxybutyric aciduria), the liquid portion of the blood (plasma), and the fluid that flows through the brain and spinal canal (cerebrospinal fluid [CSF]).

SSADH deficiency leads to various neurological and neuromuscular symptoms and findings. These abnormalities may be extremely variable from case to case, including among affected members of the same families (kindreds). However, most individuals with SSADH deficiency are affected by mild to severe mental retardation, delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor retardation), and delays in language and speech development. In addition, in some cases, initial findings may include diminished muscle tone (hypotonia), an impaired ability to coordinate voluntary movements (ataxia), and/or episodes of uncontrolled electrical activity in the brain (seizures). Some affected individuals may also have additional abnormalities, such as decreased reflex reactions (hyporeflexia); involuntary, rapid, rhythmic eye movements (nystagmus); increased muscular activity (hyperkinesis); and/or behavioral abnormalities.



What are the causes for succinic semialdehyde dehydrogenase defi...?

Mutations in the ALDH5A1 gene cause succinic semialdehyde dehydrogenase deficiency. The ALDH5A1 gene provides instructions for producing the succinic semialdehyde dehydrogenase enzyme. This enzyme is involved in the breakdown of a chemical that transmits signals in the brain (neurotransmitter) called gamma-amino butyric acid (GABA). The primary role of GABA is to prevent the brain from being overloaded with too many signals.

A shortage (deficiency) of succinic semialdehyde dehydrogenase leads to an increase in the amount of GABA and a related molecule called gamma-hydroxybutyrate (GHB) in the body, particularly the brain and spinal cord (central nervous system). It is unclear how an increase in GABA and GHB causes developmental delay, seizures, and other signs and symptoms of succinic semialdehyde dehydrogenase deficiency.



What are the treatments for succinic semialdehyde dehydrogenase defi...?

Most management of succinic semialdehyde dehydrogenase deficiency is symptomatic, with the goal of treating seizures and neurobehavioral abnormalities. This illness has been treated with a wide range of antiepileptic medications.

1. While vigabatrin is a permanent inhibitor of GABA-transaminase and hence suppresses the synthesis of succinic semialdehyde, its efficacy in treating seizures linked with SSADH deficiency has been variable.
2. Methylphenidate, thioridazine, risperdal, fluoxetine, and benzodiazepines have all been used to treat anxiety, aggression, and inattention.
3. Physical and occupational therapy, sensory integration, nutrition, and/or speech therapy are examples of non-pharmacologic treatments.
4. Surveillance: As needed, regular neurologic and developmental examinations.
5. Agents and situations to avoid: Valproate may suppress residual SSADH enzyme activity; nonetheless, in patients with refractory epilepsy who have exhausted previous therapies, valproate may be considered.
6. Genetic counseling
SSADH deficiency is transmitted autosomally recessive. Each affected individual's sib has a 25% chance of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier at conception. If the pathogenic mutations have been discovered in the family, at-risk relatives can be tested for carriers. For carrier determination, biochemical testing is neither accurate nor dependable. Prenatal testing for a high-risk pregnancy is feasible by molecular genetic testing if pathogenic mutations have been detected in the family, or through biochemical analysis (either measurement of 4-hydroxybutyric acid in amniotic fluid.

Symptoms
Delayed gross motor development,Delayed mental development,Delayed fine motor skill development,Delayed speech and language development,Hypotonia
Conditions
Seizures,Hyporeflexia,Ataxia,Behavioral problems,Hyperkinesis
Drugs
Vigabatrin,Taurine



Is there a cure/medications for succinic semialdehyde dehydrogenase defi...?

Treatments
Several pharmaceutical treatments for succinic semialdehyde dehydrogenase deficiency have been proposed or tested for efficacy in Aldh5a1-/- animals and/or humans. The following is a tiny sample of the most prevalent treatments for patients with SSADH deficiency. Unfortunately, because few regulated studies have been undertaken in patients, there is very little data that supports the effectiveness of the following treatments.
Increased levels of GHB and GABA are two markers of SSADH disease. Potential biochemical and neurological corrective treatment techniques should seek to minimize one or both while without worsening the other.

1. Vigabatrin: The most commonly used treatment for SSADH deficiency is one that lessens GHB levels by inhibiting GABA transaminase. Vigabatrin is an irreversible blocker of GABA transaminases, resulting in lower GHB levels and higher GABA levels. Clinical outcomes range from enhanced ataxia and speech in some patients to negatively affecting symptoms in others.

2. Valproate: In humans, sodium valproate has been used to treat generalized and partial seizures caused by epilepsy and bipolar disorder. Valproate increases GABA synthesis and release, resulting in enhanced GABAergic functions in certain areas of the brain. Although there have been reports of successful valproate interventions, no clinical trials have been conducted to date.

3. Taurine: Taurine is a non-protein sulfur amino acid present in large amounts in human milk. It has been demonstrated that it has neuroprotective and neuromodulating characteristics. Although it is an inhibitory neurotransmitter, it has a limited ability to pass the blood-brain barrier.

Symptoms
Delayed gross motor development,Delayed mental development,Delayed fine motor skill development,Delayed speech and language development,Hypotonia
Conditions
Seizures,Hyporeflexia,Ataxia,Behavioral problems,Hyperkinesis
Drugs
Vigabatrin,Taurine



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