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.

• Authors: Melissa L DiBacco, Jean-Baptiste Roullet, Kush Kapur, Madalyn N Brown, Dana C Walters, K Michael Gibson, Phillip L Pearl
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 6 Issue 1 Pg. 114-120 (01 2019) ISSN: 2328-9503 [Print] United States
• PMID: 30656189 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• Hydroxybutyrates
• Thyroid Hormones
• gamma-Aminobutyric Acid
• Succinate-Semialdehyde Dehydrogenase

Topics

• Adolescent
• Adult
• Age Factors
• Amino Acid Metabolism, Inborn Errors (blood, complications, epidemiology)
• Biomarkers (blood)
• Child
• Child, Preschool
• Developmental Disabilities (blood, complications, epidemiology)
• Female
• Humans
• Hydroxybutyrates (blood)
• Infant
• Longitudinal Studies
• Male
• Middle Aged
• Succinate-Semialdehyde Dehydrogenase (blood, deficiency)
• Thyroid Hormones (blood)
• Young Adult
• gamma-Aminobutyric Acid (blood)