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Advanced Neurology Neurologic manifestation associated with an RYR2 variant

implicated in catecholaminergic polymorphic ventricular performance within the average range, although he
tachycardia (CPVT) and right ventricular dysplasia Type 2 exhibited persistent deficits in executive functioning,
(AVRD2). 1 particularly in phonemic fluency, verbal set-shifting, and
The RYR2 gene encodes a 105-exon, 565 kDa visuomotor integration.
monomer that assembles into homotetrameric proteins, In reference to Figure 1, the patient’s family history was
incorporating four 12 kDa FK-506 binding proteins. The notable for multiple neurologic and psychiatric disorders,
6
RyR2 protein contains a large cytosolic N-terminal domain including a brother with bipolar disorder, a mother
(approximately 4,300 residues) and a smaller C-terminal with early-onset Alzheimer’s disease, and a maternal
transmembrane domain (approximately 500 residues) that grandmother with dementia. More distant relatives
spans the channel pore. Most regulatory components of the reportedly had behavioral problems, obsessive–compulsive
channel are located in the cytosolic domain, with mutations disorder, and seizures.
predominantly occurring in four conserved regions of the On physical evaluation, the patient’s blood pressure was
RyR2 protein: domain 1 (amino acids 77 – 466, domain 2 elevated at 159/117 mmHg. Cognitive assessment revealed
(amino acids 2246 – 2534), domain 3 (amino acids 3777 – impairment, with a Montreal Cognitive Assessment
4201), and domain 4 (amino acids 4497 – 4959). 7 score of 22/30. Cranial nerve function was intact, and
While RyR2 mutations have been extensively studied motor strength was graded at 5/5 bilaterally in the arms
in the context of cardiac physiology and disease, recent and elsewhere. Reflexes were normal, and coordination
research has begun to investigate their associations with was intact. However, pinprick sensation was decreased
adverse neurological outcomes. These neurological bilaterally above the elbows and on the left leg to the mid-
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outcomes include sudden unexplained death in epilepsy, calf. He also exhibited mild balance difficulties during
benign epilepsy of childhood, and Alzheimer’s disease, tandem gait testing.
as well as Alzheimer’s-like signaling changes in the brain The patient was prescribed propranolol to manage
following COVID-19 infection. Studies in murine his hypertension and migraines. Magnetic resonance
9,10
models have revealed that RyR2 mutations affect glutamate imaging revealed mild atrophy of the temporal lobes at the
release and reduce the spreading depolarization potential Sylvian fissure bilaterally and an empty sella. Following the
in the dorsal medulla, a critical control center for the initiation of propranolol, the patient reported a resolution
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respiratory rhythm. These findings suggest a link between of headaches and blurred vision, but his cognitive
RyR2 mutations and extracardiac manifestations. difficulties persisted. Over the subsequent 6 months, his
In particular, RYR2 mutant mice have demonstrated symptoms progressed to include worsening remote and
increased spreading depolarization across the neocortex recent memory deficits, impulsive behaviors, and mood
and the dorsal medulla’s autonomic microcircuits, a swings. He was started on donepezil, which stabilized
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phenomenon implicated in heightened seizure activity. his cognitive scores, and additional mood-stabilizing
Consequently, RYR2 mutations are now considered a medication was introduced, yielding positive effects.
potentially novel neurocardiac calcium channelopathy, Genetic testing, prompted by his family history of
with relevance to epilepsy, Alzheimer’s disease, and early-onset Alzheimer’s disease, identified a novel RYR2
autonomic dysfunction. 13,14 variant (pAsn2517Ser). In addition, the patient was found
2. Case presentation to have intermediate enzymatic activity for catechol-O
methyltransferase, methylenetetrahydrofolate reductase,
2.1. Patient 1: The Father and cytochrome P450 2D6.
A 54-year-old man was referred for evaluation of 2.2. Patient 2: The Son
neurological symptoms, including headaches and
cognitive difficulties. He reported experiencing headaches The second patient in this case report is the 19-year-old son
up to 3 times/week, accompanied by blurred vision, of Patient 1. He has a complex medical history that includes
dizziness on standing, progressive weakness in the arms seizures, migraines, severe episodic dysautonomia, and
and legs, and depression. His hypertension was identified post-traumatic stress disorder. His dysautonomia was
as a contributing factor to his headaches. His past medical characterized by orthostatic hypotension and postural
history included obstructive sleep apnea with inconsistent tachycardia, with episodes accompanied by headaches,
adherence to continuous positive airway pressure treatment confusion, and increasing agitation.
and post-concussive syndrome following a motor vehicle Magnetic resonance imaging revealed no evidence
collision. Neuropsychological testing indicated cognitive of acute territorial infarct, intracranial hemorrhage,

Volume 4 Issue 3 (2025) 118 doi: 10.36922/an.4509