Knowledge on rare diseases and orphan drugs

Approximately 450 cases have been reported in the literature to date.

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.

The main differential diagnoses include gamma-aminobutyric acid transaminase deficiency and homocarnosinosis (see these terms).

Prenatal diagnosis is possible in families with a known disease causing mutation.

SSADH deficiency is inherited in an autosomal recessive fashion. Genetic counseling is recommended.

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.

The prognosis varies. Although most patients live until adulthood, neuropsychiatric symptoms can be disabling, decreasing quality of life. Early mortality, including sudden unexpected death in epilepsy patients (SUDEP), has been reported.

Last update: February 2016 - Expert reviewer(s): Dr Mahsa PARVIZ - Dr Phillip PEARL