Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare neurometabolic disorder of gamma-aminobutyric acid (GABA) metabolism with a nonspecific clinical presentation (ranging from mild to severe) with the most frequent symptoms being cognitive impairment with prominent deficit in expressive language, hypotonia, ataxia, epilepsy, and behavioral dysregulation.
The mean age of onset is 11 months. Contrary to what is seen in many metabolic encephalopathies, patients do not present with hypoglycemia, hyper-ammonemia, or intermittent lethargy. Infants usually present with a slowly progressive or static encephalopathy manifesting with hypotonia, hyporeflexia, ataxia and delayed acquisition of motor and language developmental milestones in the first two years of life. Seizures occur in more than half of all affected individuals and are usually generalized tonic-clonic or atypical absence. Intellectual disability, psychiatric manifestations (i.e. attention deficit hyperactivity disorder and aggression in early childhood, obsessive-compulsive disorder and anxiety in adolescence and adulthood) and sleep disturbances are commonly observed. Hyperkinetic behavior, self-injurious behaviors and hallucinations are reported in half of all cases. A more fulminating, early-onset presentation occurs in up to 10% of patients and is characterized by extrapyramidal signs and sometimes a progressive disease course.
SSADH deficiency is due to mutations in the ALDH5A1 gene (6p22), encoding mitochondrial succinate-semialdehyde dehydrogenase, a protein involved in amino-acid degradation. A deficiency of SSADH enzyme activity impairs degradation of GABA, the brain's major inhibitory neurotransmitter, and thereby results in elevated concentrations of a putative toxic metabolite, gamma-hydroxybutyric acid (GHB), which is detectable in physiological fluids including blood, urine, and cerebrospinal fluid.
The key laboratory diagnostic test suggestive of SSADH deficiency is urine organic acid analysis with results of elevated GHB. Findings from plasma analysis include elevated GHB and lymphocytes will display low SSADH enzymatic activity. In cerebrospinal fluid analysis, GHB and GABA will be elevated. Cranial magnetic resonance imaging shows increased bilateral and usually symmetrical T2-weighted signal involving the globus pallidi, as well as the cerebellar dentate nuclei and subthalamic nuclei. Electroencephalogram findings include mainly generalized background slowing and spike discharges. Molecular genetic testing revealing a mutation in the ALDH5A1 gene confirms diagnosis.
SSADH deficiency is inherited in an autosomal recessive fashion. Genetic counseling is recommended.
Management and treatment
As there is no treatment currently available to effectively address the underlying disorder, long-term management of the phenotype focuses on pharmacologically controlling the most debilitating manifestations (typically seizures and neurobehavioral disorders). Carbamazepine and lamotrigine are effective in controlling seizures. Anxiety, aggressiveness, inattention, and hallucinations may be treated with benzodiazepines, methylphenidate, thioridazine, risperidone or fluoxetine. Physical and occupational therapy, sensory integration, and/or speech therapy may be beneficial in some cases.