Objective:

To encourage consideration of genetic diagnoses in patients whose antibody levels and response to treatment provide weak support for a diagnosis of Stiff-person syndrome.

Background:

Stiff-person syndrome (SPS) is a rare diagnosis affecting 1-2 people per million. Despite its rarity, awareness has increased since celebrity Céline Dion’s diagnosis. SPS is associated with GAD65 antibodies, which may be seen at lower levels in autoimmune diabetes.

Design/Methods:

NA

Results:

Case 1: A 34 year-old man recently diagnosed with diabetes and GAD65 antibody 0.06 nmol/L (NL≤0.02) was admitted for progressive lower extremity weakness and spastic paraparesis. SPS was considered based on symptoms and GAD65. Genetic testing was positive for ABCD1 X-linked adrenoleukodystrophy, followed by endocrine work-up, steroid initiation for adrenal insufficiency, and positive genetic testing in another family member.

Case 2: A 59 year-old woman was admitted for acute-on-chronic weakness and muscle spasms. Evaluation prior to admission involved intravenous immunoglobulin (IVIG) for presumed SPS, but symptoms progressed despite increasing IVIG doses. GAD antibody was 47.9IU/mL (NL≤5). She had a strong family history of similar symptoms. Genetic testing was positive for KIF5A variant associated with amyotrophic lateral sclerosis (ALS), and she was referred to an ALS clinic.

Case 3: A 30 year-old man presented for second opinion of progressive pain with stiffness and spastic gait, suspected to represent SPS, with prior GAD65 antibody 0.12nmol/L (NL≤0.02) and multiple years of IVIG. Repeat GAD65 testing was negative. Genetic testing was positive for two ZFYVE26 gene variants associated with autosomal recessive hereditary spastic paraplegia, leading to genetic testing in family.

Conclusions:

Patients with stiffness, weakness, and spastic gait may be diagnosed with SPS when GAD antibodies are positive. Patients without significantly elevated GAD levels should continue work-up for alternate diagnoses that may better explain their symptoms, particularly as genetic syndromes are treated differently and may have implications for family members.