Succinic Semialdehyde Dehydrogenase Deficiency

Excerpt

Clinical characteristics: Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described.

Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T₂ hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized.

Diagnosis/testing: The diagnosis of SSADH deficiency is established by the identification of biallelic pathogenic variants in ALDH5A1.

Management: Treatment of manifestations: Management is most often symptomatic, directed at the treatment of seizures and neurobehavioral disturbances. A broad spectrum of antiepileptic medication has been used to treat this condition. While vigabatrin is an irreversible inhibitor of GABA-transaminase and thus inhibits the formation of succinic semialdehyde, it has shown inconsistent results in treatment of seizures associated with SSADH deficiency. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for treatment of increased anxiety, aggressiveness, and inattention. Additional, non-pharmacologic treatments may include physical and occupational therapy, sensory integration, feeding and/or speech therapy.

Surveillance: Regular neurologic and developmental assessments as indicated.

Agents/circumstances to avoid: Valproate may inhibit residual SSADH enzyme activity; however, valproate may be considered in individuals with refractory epilepsy who have failed other treatments.

Genetic counseling: SSADH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives is possible if the pathogenic variants have been identified in the family. Biochemical testing is not accurate or reliable for carrier determination. Prenatal testing for a pregnancy at increased risk is possible using molecular genetic testing if the pathogenic variants have been identified in the family, or using biochemical testing (either measurement of 4-hydroxybutyric acid in amniotic fluid or assay of SSADH enzyme activity in chorionic villus tissue and cultured amniocytes).