Assessing Autonomic Dysfunction in a Cohort of Giant Axonal Neuropathy Natural History Patients

Topic:

Other

Poster Number: 99

Author(s):

Eduardo Paredes BA, Gina Norato ScM, Tanya Lehky MD, Wadih Zein MD, Dimah Saade MD, Carsten Bönnemann MD, Diana Bharucha-Goebel MD

Institutions:

1. National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, 2. National Institutes of Health, Clinical Trials Unit, 3. National Institutes of Health, EMG Section, 4. National Institutes of Health, National Eye Institute, 5. National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, 6. NINDS/NIH, Bethesda, MD, 7. National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section

Giant Axonal Neuropathy (GAN) is an ultra-rare neuromuscular disorder with early-childhood onset caused by autosomal recessive mutations in the GAN gene. GAN is characterized by severe peripheral neuropathy and progressive central nervous system involvement. Despite reports of autonomic dysfunction in patients, GAN’s autonomic phenotype has yet to be clinically investigated.

To address this knowledge gap, we systematically evaluated autonomic dysfunction in the scope of an existing natural history study of 45 GAN patients seen at the NIH Clinical Center. Patient data were collected from 2013 to 2019, using the COMPASS 31 self-assessment questionnaire and targeted testing of sweat and tear production.

COMPASS 31, which assesses autonomic dysfunction across six autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor), was completed in 14 patients. Abnormalities in gastrointestinal (n=11, 78.6%), vasomotor (n=8, 57.1%), and pupillomotor domains (n=8, 57.1%) were most frequently reported, and the gastrointestinal domain, which contributed to 37.8% of the average COMPASS 31 score, was most severe.

Schirmer’s test of lacrimal secretion was completed in 23 individuals. Average measured lacrimation in the right eye (OD) was 10.8 mm (range 0 mm – 35 mm). 16 patients (69.6%) had moderate to severe reduction in lacrimation, while 7 patients (40.4%) had normal (> 15 mm) lacrimation. The quantitative sudomotor axon reflex test (Q-SWEAT) was completed in 11 individuals. Average sweat yield volume in the upper extremity was 0.106 mcl (range 0.000 mcl – 0.510 mcl). This value is lower than that of healthy male pediatric patients between 5-18 years old where the average forearm Q-SWEAT volume was 0.65 +/- 0.44 µL/mm2.

From an interim analysis, we infer that abnormalities in autonomic function are reported and observed in GAN. However, as these abnormalities occur independently of age or markers of disease severity, such as MFM32, a more robust evaluation of GAN’s autonomic phenotype is necessary.