Clinical Guidance

SSADH deficiency is caused by biallelic pathogenic variants and SSADH is an oligomeric protein; therefore, knowledge of the ALDH5A1 biallelic pathogenic variants is informative only if their resultant global molecular effect on the SSADH protein is elucidated. In general, individuals with pathogenic ALDH5A1 variants resulting in truncated SSADH or lack of SSADH altogether (as opposed to having single homotetramers or a mixed population of homo- and heterotetramers) or that lead to impairment in the SSADH catalytic sites (as opposed to impairments in its folding, stability, or oligomerization) have a more severe phenotype .

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"

Diagnostic Criteria

Suggestive Findings

Succinic semialdehyde dehydrogenase (SSADH) deficiency should be suspected in individuals with the following clinical, imaging, and supportive laboratory findings and family history. Clinical findings. Late-infantile to early-childhood onset, slowly progressive or static encephalopathy characterized by:

• Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit

• Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues

• Hypotonia

• Epilepsy

• Hyporeflexia

• Movement disorders, such as ataxia, dystonia, and exertional dyskinesia

• Sleep disturbances

Neuroimaging findings

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"

Differential Diagnosis

Disorder of gamma-aminobutyric acid (GABA) metabolism. 4-aminobutyrate aminotransferase (also known as GABA transaminase or GABA-T) deficiency (OMIM 613163) is characterized by psychomotor delay, hypotonia, hyperreflexia, lethargy, refractory seizures of neonatal or infantile onset, agenesis of the corpus callosum, and cerebellar hypoplasia. Free and total GABA concentration levels are elevated in the cerebrospinal fluid, without elevation in 4-hydroxybutyric acid (GHB). Biallelic pathogenic variants in ABAT are causative. Inheritance is autosomal recessive. Elevated glycine can be seen in glycine encephalopathy (i.e.

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"

Management Guidelines

Consensus clinical management guidelines for succinic semialdehyde dehydrogenase (SSADH) deficiency have been published .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SSADH deficiency, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval, incl assessments for ataxia movement disorders | • Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.

• An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.

Ataxia/

Movement disorder

| Orthopedics/ physical medicine rehab/ PT OT eval | To incl assessment of:

• Gross motor fine motor skills

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

Clinical Guidance

Vigabatrin could be a rational therapy in people with SSADH deficiency due to its property of gamma-aminobutyric acid transaminase (GABA-T) inhibition leading to decreased 4-hydroxybutyric acid (GHB) levels. However, it may result in elevated GABA and the exacerbation of manifestations, and its clinical utility has been inconsistent. For these reasons and its potential for retinal toxicity, vigabatrin is not generally recommended as an anti-seizure medication (ASM) for individuals with SSADH deficiency. Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency. Valproate may lead to inhibition of residual SSADH activity; however, its efficacy in individuals with SSADH deficiency has been occasionally described. Valproate is not recommended as a first-line ASM in those with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy .

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"

Therapies Under Investigation

Ongoing work on gene replacement therapy for people with SSADH deficiency involves disease-specific modeling, viral vector testing, and development of clinical biomarkers assessing indices of cortical inhibition such as transcranial magnetic stimulation . For disease modeling, a novel Aldh5a1 lox-STOP mouse enables gene restoration "on demand" and the assessment of successful phenotypic rescue. Current work is also focused on development of a custom-designed adeno-associated virus vector encompassing an ALDH5A1-specific promoter tethered with the human ALDH5A1 coding sequence . Additionally, human induced pluripotent stem cell models that are being established provide a meaningful human genomic testing platform. Search ClinicalTrials.

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 5.

Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations such as seizures, ataxia, or movement disorders.

| At each visit

Development

| Monitor developmental progress educational needs.

Neurobehavioral/

Psychiatric

| Assess for anxiety, ADHD, OCD, aggression.

Respiratory

| Monitor for evidence of sleep disturbance, such as excessive daytime sleepiness.

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder

Source: GeneReviews — "Succinic Semialdehyde Dehydrogenase Deficiency"