Age-related phenotype and biomarker changes in SSADH deficiency

Abstract

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 T₃ 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.

Figure 1

Proportion of comorbid clinical symptoms with age. Compulsive behaviors, sleep disturbances, hypotonia, and seizures show a statistically significant difference in proportion with age when comparing age the pediatric cohort to the adolescent/adult cohort.

Figure 2

Box plot of age of onset versus seizure type in SSADH deficiency. Box plot of age of onset for type of seizures. The median age of onset is indicated by the solid black line inside the box (absence = 2 years old, GTC = 12 years old). The box signifies the 1st quartile (Q1) and the 3rd quartile (Q3). The vertical lines (whiskers) indicate the minimum and maximum values (range). Data falling well outside the Q1 and Q3 range are plotted as outliers of the data; the circle and asterisk indicate outliers. The circle represents an age of onset of absence seizures at 6.7 years, which is outside the Q3 value but still within age group <12 years. The asterisk represents an age of onset of absence seizures at 30 years old, which was reported during an EEG.

Figure 3

Correlations between thyroid hormones and total GABA in patient plasma (A and B) and thyroid hormones as a function of patient age (C and D). Dotted lines indicate 95th percentile. Confidence intervals (statistical analysis, Spearman correlation). Samples were derived from an archival collection of SSADH‐deficient plasma samples maintained at −80°C.

Figure 4

Schematic representation of potential interactions between the thyroid and GABA and the GABA catabolic pathway. Enzymes represented numerically: E1 and E2, glutaminase and glutamine synthetase; E3, glutamic acid decarboxylase; E4, GABA‐transaminase; E5, succinic semialdehyde dehydrogenase, site of the defect in patients with SSADH deficiency (crossed‐hatched box); and E6, aldo‐keto reductase 7a2. Additional abbreviations: GABA, γ‐aminobutyrate; GHB, γ‐hydroxybutyrate; TRH, thyrotropin releasing hormone; TSH, thyroid stimulating hormone; T₃, liothyronine; T₄, thyroxine. Plus (+) and minus (−) symbols refer to stimulation and inhibition, respectively. GABA is believed to downregulate thyroid activity at all levels of the hypothalamic‐pituitary‐thyroid endocrine axis, most likely effected via vagal innervation. Changes in plasma T₃/T₄ appear to differentially stimulate or depress GABAergic systems in brain and thyroid gland. Both GABA and GHB are elevated in brain of SSADH‐deficient patients and null mice. Plasma GABA concentrations did not correlate with circulating TSH (not shown). Also shown in the brain are the use‐dependent effects of GABA and GABA_B subunit expression, as demonstrated in thalamus and hippocampus of SSADH‐deficient mice.9, 10 Downregulation of both receptor subtypes has been confirmed as well in SSADH‐deficient patients. (Figure adapted from Ref. 15). GHB, gamma hydroxybutyric acid; GABA, gamma‐amino butyric acid.