Succinic Semialdehyde Dehydrogenase Deficiency

Excerpt

Clinical characteristics: Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been observed.

Diagnosis/testing: Increased gamma-hydroxybutyric aciduria (GHB) on a urinary organic acid analysis is suggestive of the condition; however, the diagnosis of SSADH deficiency is established in a proband with consistent analyte findings and/or suggestive clinical features by identification of biallelic pathogenic variants in ALDH5A1 by molecular genetic testing.

Management: Treatment of manifestations: Many anti-seizure medications (ASMs) may be effective for seizures; none has been demonstrated effective specifically for this disorder. In general, valproate is avoided except in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective. Vigabatrin is not generally recommended. Standard treatment for ataxia/movement disorder, sleep disturbance, developmental delay / cognitive issues, and neurobehavioral and psychiatric issues.

Surveillance: At each visit, monitor those with seizures as clinically indicated; assess for new manifestations such as seizures, ataxia, or movement disorders; monitor developmental progress and educational needs; assess for anxiety, ADHD, OCD, and aggression; monitor for evidence of sleep disturbances, such as excessive daytime sleepiness.

Agents/circumstances to avoid: Vigabatrin may result in elevated gamma-aminobutyric acid (GABA) and exacerbation of manifestations, and its clinical utility has been inconsistent. Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency. Valproate is not recommended as a first-line ASM in people with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy.

Genetic counseling: SSADH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALDH5A1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the ALDH5A1 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for SSADH deficiency are possible.