# PRKAG2 Variant, Motor Neuron Disease, and Parkinsonism: Fortuitous Association or a Potentially Underestimated Pathophysiological Mechanism?

## TL;DR

A 72-year-old woman with Parkinson's disease and motor neuron symptoms was found to have a novel PRKAG2 gene variant, suggesting a possible link between cardiac and neurological conditions.

## Contribution

Identifies a novel PRKAG2 variant in a patient with overlapping motor neuron disease, parkinsonism, and cardiac preexcitation syndrome.

## Key findings

- The patient met diagnostic criteria for amyotrophic lateral sclerosis and parkinsonism.
- A novel heterozygous PRKAG2 variant (c.1247C > T) was identified through next-generation sequencing.
- The case highlights the need to consider PRKAG2 variants in complex neurological and cardiac presentations.

## Abstract

A 72-year-old Brazilian woman presented with a 4-year history of rest tremors of the hands, followed by slowness of movement, and a diagnosis of idiopathic Parkinson’s disease. She was started on dopamine agonists with significant improvement. After three years, she complained about slowly progressive dysphagia, dysphonia, quadriparesis, and cramps and fasciculations. A neurological examination disclosed distal-dominant quadriparesis, dysarthria, atrophy and fasciculation of the tongue, global brisk tendon reflexes, fasciculations, bilateral ankle clonus, and moderate spasticity of the lower limbs. She had also palpitations, dyspnea, and one episode of paroxysmal atrial fibrillation. Electrocardiography revealed a short PR interval, a widened QRS complex, and the delta wave, suggestive of Wolff–Parkinson–White syndrome. Brain and spine MR imaging, a cerebrospinal fluid analysis, and general serum lab exams were unremarkable. Needle electromyography disclosed chronic denervation involving cervical, thoracic, lumbosacral, and bulbar levels associated with acute denervation, including positive sharp waves, fasciculations, and fibrillation potentials. This patient fulfilled the diagnostic criteria for amyotrophic lateral sclerosis associated with parkinsonism. A broad next-generation sequencing-based panel disclosed the presence of the novel heterozygous variant c.1247C > T (p.Pro416Leu) in the PRKAG2 gene (NM_016203.4). Clinicians must be aware of the possibility of PRKAG2 variants in complex clinical scenarios associating cardiac arrhythmia, preexcitation syndromes, hypertrophic cardiomyopathy, motor neuron disease, and parkinsonism.