Author: owner

Adult-onset ATP1A3-related cerebellar ataxia with sensorineural hearing loss as the initial presentation— A Case report
Shannon Mangat, Michael Benedict , Michael Bonello

Introduction
ATP1A3 mutations are associated with a clinical spectrum of neurological disease. The most recognised condition being Dystonia-12. Presentation commonly occurs in childhood, with encephalopathy secondary to a triggering event like febrile illness. Varying neurological decompensation and sequalae are reported (1).

Case Report
A 50-year old gentlemen presented with disequilibrium on a background of ataxia, sensorineural hearing loss and visual abnormalities.
During his work as a bus cleaner episodes of unsteadiness were precipitated when standing from cleaning under bus seats. There was associated oscillopsia, auditory distortion and autonomic features of facial flushing and diaphoresis.
Normal development was reported. Dyslexia was diagnosed in adulthood. At 20 years hearing impairment developed with bilateral sensorineural hearing loss later diagnosed. Gait abnormalities developed aged 47 years. With recent blurred vision when reading. There was a family history of idiopathic late-onset cerebellar disease, with his mother diagnosed aged 61 years.
On examination postural hypertension was demonstrated only when replicating the postural change associated with symptoms. Subtle cerebellar signs included; impaired tandem walking, upper limb dysmetria and an intention tremor. Cranial nerves demonstrated left homonymous hemianopia and sensorineural hearing loss. There was symmetrical hyperreflexia of the lower limbs with bilateral extensor Babinski responses. Proprioception was impaired bilaterally to the ankles. The patient also had pes cavus.
A novel heterozygous missense mutation in the ATP1A3 gene (c.823 G>A p.A275T) was identified.

The structure of the Na+/K+ ATPase
The α3 isoform of the Na+/K+ ATPase is encoded by the ATP1A3 gene. The Na+/K+ ATPase pump is made up of α, β and γ subunits. The α-subunit is the catalytic site of ATP hydrolysis and transports Na+ and K+ across the membrane to maintain the electrochemical gradient. The α3 isoform is exclusively expressed in neurones, with areas of high expression including the optic nerve, the cochlear and the cerebellar cortex. The α3 isoform exhibits a lower affinity for Na+ when compared to the α2 isoform and that property is thought to be important in rapid repolarisation after intense depolarisation (3).

Conclusions
This case adds to the phenotypic variation of ATP1A3-mutations. There was no triggering encephalopathy. Sensorineural hearing loss was the initial presentation with the slow accumulation of neurological symptoms over decades. Although ATP1A3-mutations may still represent rare neurological diseases, genomic evaluation in clinically relevant patients may expand identification of this channelopathy, supporting research and treatment developments.

References
1. Fernandes C, Mikati MA. The expanding spectrum of ATP1A3 related disease. Eur J Paediatr Neurol. 2019;23(3):345-6.
2. Carecchio M, Zorzi G, Ragona F, Zibordi F, Nardocci N. ATP1A3-related disorders: An update. Eur J Paediatr Neurol. 2018;22(2):257-63.
3. Clausen MV, Hilbers F, Poulsen H. The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. Front Physiol. 2017;8:371-