Possible mechanisms for sensorineural hearing loss and deafness in patients with propionic acidemia

Abstract

Propionic acidemia is an inborn error of metabolism caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase. Sensorineural deafness and severe hearing loss have been described as long-term complications of this disease, however, the mechanism has not yet been elucidated. We have recently shown by patch clamping experiments and Western blots that acute and chronic effects of accumulating metabolites such as propionic acid, propionylcarnitine and methylcitrate on the KvLQT1/KCNE1 channel complex cause long QT syndrome in patients with propionic acidemia by inhibition of K⁺ flow via this channel. The same KvLQT1/KCNE1 channel complex is expressed in the inner ear and essential for luminal potassium secretion into the endolymphatic space. A disruption of this K⁺ flow results in sensorineural hearing loss or deafness. It can be assumed that acute and chronic effects of accumulating metabolites on the KvLQT1/KCNE1 channel protein may similarly cause the hearing impairment of patients with propionic acidemia.

Keywords: Hearing loss; Inner ear; KCNE1; KvLQT1; Long QT syndrome; Propionic acidemia; Propionic aciduria; Sensorineural deafness; Voltage-gated potassium channel.

Fig. 1

a. Propionic acid effects on I_Ks current in KCNQ1/KCNE1-CHO cells. Representative whole cell current traces at baseline, after the application of PA (5 mM, blue), and after brief wash-out (grey), demonstrating an acute reduction of I_Ks by 50%. Voltage clamp protocol is shown in the inset. b. Propionic acid effects on action potential in human iPSC-CMs. Superimposed representative AP traces at baseline and after PA (5 mM, blue), indicating an AP-prolongation

Fig. 2

Proposed pathophysiologic mechanism of long QT syndrome and sensoneurinal hearing loss in propionic acidemia. Accumulating metabolites such as propionic acid, methylcitrate and propionylcarnitine cause dysfunction of the KvLQT1/KCNE1 channel by acute blocking effects as well as reduced expression of the channel protein