Current treatments in familial dysautonomia

Abstract

Introduction: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (ELP-1) (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception result in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss.

Areas covered: This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene-modifying agents.

Expert opinion: Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to the risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression.

Keywords: future directions; hereditary autonomic neuropathy; hypertensive surges; nausea; splicing modification therapy.

Conflict of interest statement

Conflicts of interest: JAP: receives research support from the Dysautonomia Foundation, Inc.

LNK: receives research support from the National Institutes of Health (U54NS065736) and the Dysautonomia Foundation, Inc.

CFM: receives research support from the Dysautonomia Foundation, Inc.

CMS: receives research support from the Dysautonomia Foundation, Inc.

LP: receives research support from the Dysautonomia Foundation, Inc.

HK: serves receives research support from the National Institutes of Health (U54NS065736 [PI]) 1U01NS078025-01, the FDA (FD-R-3731-01 [PI]), and the Dysautonomia Foundation, Inc; has received compensation as a consultant/advisory board member for Lundbeck, Eli Lilly, Pfizer, and Astra Zeneca.

Figures

Figure 1. Organs and systems affected in familial dysautonomia

The involvement of cardiovascular, gastrointestinal, respiratory, orthopedic, renal, and neurological systems contributes to morbidity and mortality.

Figure 2. Cardiovascular autonomic phenotype

(A) Shows representative ambulatory blood pressure monitoring in a patient with FD. Red arrow notes onset of hypertensive-vomiting crisis. (B) Shows exaggerated blood pressure variability in patients with FD (n=15) and age/sex matched healthy controls (n=12). (C) Shows cardiovascular autonomic changes during a dysautonomic crisis. Note, increase in blood pressure accompanied by release of dopamine and norepinephrine spillover into the circulation. BP, blood pressure; SD, standard deviation; SBP, systolic blood pressure; DA, dopamine; NE, norepinephrine. Modified with permission from Norcliffe-Kaumann et al. and Norcliffe-Kaufmann et al.

Figure 3. Progression of renal disease

(A) Shows the cumulative probability of reaching the end point of a 50% decline in estimated glomerular filtration rate or progression to end-stage renal disease in patients stratified for the severity of hypertension in childhood. Note, patients with severe childhood hypertension (above AHA stage III) were more likely to progress to poor renal outcomes. (B) Shows change in eGFR over 5 years in adolescent patients treated empirically with fludrocortisone (mean dose 0.2 mg/day, n=20) vs. matched untreated FD patients (n=20). Of note, patients treated with high dose fludrocortisone had a faster decline in renal function. Starting eGFR and severity of orthostatic hypotension were similar in both groups (data not shown). (C) Retrospective review showing more excessive blood pressure variability (24-h ambulatory monitoring) was associated with a faster rate of decline in eGFR overtime (13-year follow-up). Figure B reproduced with permission from Norcliffe-Kaufmann et al.

Figure 4. Effect of carbidopa on nausea, retching and dopamine output

(A) Shows significant reduction in nausea and retching outcomes in a double-blind randomized placebo controlled clinical trial of carbidopa in patients with FD. (B) Shows significant reduction in dopamine output on active carbidopa. PRO, patient reported outcome scale. Modified with permission from Norcliffe-Kaufmann et al.