A Familial Analysis of Stiff-Person Spectrum Disorder utilizing the Utah Population Database
Justin Abbatemarco1, Paul Crane2, Jonathan Galli3, Stefanie Rodenbeck4, Zhe Yu5, Ankita Date5, Jennifer West5, Alison Fraser5, Myke Madsen5, Ka-Ho Wong6, John Greenlee3, Stacey Clardy3
1Mellen Center, Cleveland Clinic, 2Neurology, University of Utah, 3University of Utah, 4Neurology, Indiana University, 5Huntsman Cancer Institute, 6U of U Neurology Clinic
Objective:
To describe the clinical and immunologic findings of a large cohort of patients with
stiff-person spectrum disorder (SPSD) while exploring for potential familial clustering within the Utah Population Database (UPDB).
Background:
There is limited understanding of the pathophysiology of SPSD. The common co-occurrence of autoimmune diseases in these patients suggests a shared genetic predisposition.
Design/Methods:
We performed a retrospective review of all confirmed SPSD patients diagnosed and managed in the Autoimmune Neurology Clinic at the University of Utah. Using the UPDB, a population-based genealogic resource containing medical and demographic information of over 11 million individuals, we identified high-risk pedigrees with excess familial aggregation of SPSD using the Familial Standardized Incidence Ratio (FSIR). Unaffected subjects were identified and matched 10:1 to SPSD patients by age, birth year, and pedigree structure in the UPDB. Familial risk analyses were performed to estimate the heritability of SPSD separately using multivariate logistic regression adjusting for sex, birth year, race, and ethnicity.
Results:
We identified a total of 46 patients with a SPSD. The median age was 52 years old (SD 14 years), and 78% were female and 93% self-identified as White. A total of 22 (47%) had classical SPS, 16 (34%) had SPS with an overlapping with ataxia, epilepsy, or encephalitis. The majority (95%) had glutamic acid decarboxylase (GAD65) antibodies, 11 (24%) had α1-subunit of the glycine receptor (GlyR) antibodies (8 with concomitant GAD65 antibodies), and one patient tested negative for all antibodies. Twenty-eight patients had a comorbid autoimmune disorder with the most frequent being insulin-dependent diabetes (30%) and autoimmune thyroid disease (17%).
Conclusions:
SPSD is a complex group of disorders predominantly defined by GAD65 and GlyR antibodies. The co-occurrence of autoimmune diseases and potential familial clustering suggests that genetic, inherited factors may play a role in SPSD.