Succinic Semialdehyde Dehydrogenase (SSDH) Deficiency

SSADH deficiency was first reported as ᵞ-hydroxybutyric aciduria in 1981. It has been documented in at least 32 patients.

Clinical Presentataion Succinic Semialdehyde Dehydrogenase Deficiency 

The clinical presentation varies from mild to severe and comprises psychomotor retardation, delayed speech development, hypotonia, ataxia and less frequently, hyporeflexia, convulsions, aggressive behavior, hyperkinesis, oculomotor apraxia, choreoathetosis, and nystagmus. Ataxia, when present, may resolve with age.

Disorders of Neurotransmitters Diseases

Metabolic Derangement Succinic Semialdehyde Dehydrogenase Deficiency

The key feature is an accumulation of ᵞ-hydroxybutyric in urine, plasma, and CSF. ᵞ-hydroxybutyric is a neuropharmacologically active compound. Its accumulation in the body fluids tends to decrease with age. Metabolites indicative of the β and α- oxidation of ᵞ-hydroxybutyric acid may be variably detected in the urine of SSADH-deficient patients. The identification of other metabolites in the urine of SSADH-deficient patients related to pathways of fatty acid, pyruvate, and
glycine metabolism suggests that the deficiency has metabolic consequences beyond the pathway of GABA metabolism.

Disorders of Neurotransmitters Diseases

Diagnostic Tests Succinic Semialdehyde Dehydrogenase Deficiency

Diagnosis is made by organic acid analysismof urine, plasma, and/or CSF. ᵞ-hydroxybutyrate can be higher in CSF than in plasma and even be extremely increased. The enzyme deficiency can be demonstrated in lymphocytes and lymphoblasts. Patients typically show 0%-19% of residual activity in isolated lymphocytes or 0%-12% in cultured lymphocytes (0%-6% in lymphoblasts and 4%-12% in intact lymphoblasts), and parents have intermediate levels of enzyme activity.

SSADH activity is expressed in normal human liver, kidney and brain, and SSADH deficiency in these tissues was recently demonstrated. The prenatal diagnosis of an affected fetus has been reported: ᵞ-hydroxybutyrate was elevated in amniotic fluid, and SSADH activity was absent from cultured amniocytes and autopsied fetal brain, liver, and kidney.

Disorders of Neurotransmitters Diseases

Treatment and Prognosis Succinic Semialdehyde Dehydrogenase Deficiency

In an attempt to reduce the accumulation of ᵞ-hydroxybutyrate, we introduced a novel treatment principle, namely inhibition of the preceding enzymatic step GABA transaminase. This was realized by giving ᵞ-vinyl GABA (Vigabatrin), an irreversible inhibitor of this enzyme, in doses of 50-100 mg/kg per day.

This treatment was shown to reduce CSF ᵞ-hydroxybutyrate levels and improved cerebellar signs in five out of six patients. However longterm administration of vigabatrin should be monitored closely because this drug increases CSF (and probably also brain) GABA levels.

As for the prognosis, this disease can manifest a mild to severe neurological course. Some patients have died, although there was no evidence for metabolic acidosis or decompensation.

Disorders of Neurotransmitters Diseases

Genetics Succinic Semialdehyde Dehydrogenase Deficiency

The mode of inheritance is autosomal recessive.

Disorders of Neurotransmitters Diseases