Age‐related phenotype and biomarker changes in SSADH deficiency

OBJECTIVE: Succinic Semialdehyde Dehydrogenase (SSADH) deficiency is a disorder of elevated gamma‐amino butyric acid (GABA) and gamma hydroxybutyric acid (GHB) and a complex neuropsychiatric profile. Adult reports suggest worsening epilepsy and high SUDEP risk. METHODS: Subjects with confirmed SSADH deficiency were recruited into a longitudinal study. Plasma thyroid hormone and total GABA/GHB were quantified by standard clinical chemistry methodologies and mass spectrometry, respectively. RESULTS: A total of 133 subjects with SSADH deficiency are enrolled in the registry; 49 participated in the longitudinal study. The age range of the population is 8 weeks to 63 years (median 7.75 year; 44% male). There is a significant difference in proportions among the age groups in subjects affected with hypotonia, compulsive behavior, sleep disturbances, and seizures. Epilepsy is present in 50% of the total population, and more prevalent in subjects 12 years and older (P = 0.001). The median age of onset for absence seizures was 2 years, and 12 years for generalized tonic‐clonic seizures (P < 0.01). The SUDEP rate in adults was 12% (4/33). There was a significant age‐dependent negative correlation between GABA and T(3) levels. INTERPRETATION: There is an age‐dependent association with worsening of epilepsy, behavioral disturbances including obsessive‐compulsive behavior, and sleep disturbances with age in SSADH deficiency. There is a high risk of SUDEP. We have observed more absence seizures in younger patients, compared to tonic‐clonic in the older cohort, which correlates with age‐related changes in GABA and GHB concentration and thyroid function, as well as the natural history of seizures in the murine model.