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Advanced Neurology Neurologic manifestation associated with an RYR2 variant

brain abnormalities, familial dysautonomia, and
mitochondrial dysfunction. The results revealed no large
deletions or known deleterious mutations. However,
genetic testing identified variants in both RYR2 and
leucine-rich repeat kinase 2 (LRRK2) genes. The patient
was confirmed to carry the same RYR2 (OMIM 18090)
variant (pAsn2517Ser) as his father. The genetic testing
documentation concluded that the RYR2 variant is the
most likely cause of the disease progression observed in
the patient, given the absence of other significant genetic
abnormalities.

3. Discussion
This case report highlights the association between a
novel RYR2 variant to a unique phenotype characterized
by Alzheimer’s-like cognitive dysfunction and global
autonomic dysregulation. The identified missense
Figure 1. Family pedigree of Patient 1 (the father). Patient 1 and Patient mutation, RYR2 pAsn2517Ser, results in an asparagine-
2 (Patient 1’s 19-year-old son) share the RYR2 pAsn2517Ser and LRRK2 to-serine substitution at amino acid 2517 in the cytosolic
mutation pMet1646Thr mutations. Patient’s 1 mother (deceased) had
moderately severe Alzheimer’s disease, diagnosed at the age of 64 – 65, domain of the RyR2 protein. This mutation, localized
and passed away at 67 due to gastrointestinal issues for which she refused to the BSolB region of RyR2, has not been previously
treatment. She was also treated for hypertension. During her illness, she characterized. Although unconfirmed, current theories
experienced sundowning at night and, toward the end of her life, developed suggest that mutations in this region may enhance
social phobias. An autopsy revealed moderate to severe atrophy in cortical sensitivity to sarcoplasmic reticulum luminal calcium or
and limbic structures. Patient 1’s Brother 1 (Uncle 1): No known medical 15
problems; Patient 1’s Brother 2 (Uncle) 2: Diagnosed with bipolar disorder. destabilize the closed conformation of the RyR2 channel.
Patient 1’s grandmother: Alzheimer’s presented at 84. Image created with: Both mechanisms could disrupt calcium homeostasis,
http://pedigrees.varphi.com/cgi-bin/pedigree.cgi contributing to the observed neurological and autonomic
manifestations.
intra-axial mass, or midline shift. A small focus of fluid- Calcium homeostasis plays a critical role in autonomic
attenuated inversion recovery and T2 signal hyperintensity stability. While this case does not involve calcium channel
was observed at the level of the right corona radiata, in antibodies, dysautonomia – particularly orthostatic
close proximity to the anterior limb of the right internal hypotension – has been documented in cases linked to
capsule, consistent with prior imaging findings. No calcium dysfunction. The destabilization of the RyR2
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significant changes were noted, and overall, the imaging function in this specific domain could provide a plausible
impression was unremarkable. mechanism for the son’s pathology.

On physical examination, the patient exhibited Although mutations in RyR2 account for up to 50% of
slowed processing speed and poor attention. Cranial CPVT cases, fewer studies have investigated their impact
nerve function was intact, and motor strength was 5/5 on extracardiac processes. The clinical presentations
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throughout. Reflexes were decreased at 1/4 across all tested in this case report suggest that the RYR2 mutation may
regions. Pinprick sensation was decreased bilaterally in the extend beyond cardiac phenotypes, influencing cognitive
mid-forearms and upper thighs. Gait was normal, though and autonomic functions. Temporal lobe atrophy observed
a mild postural tremor was observed. on imaging, combined with a family history of dementia,
Genetic testing was performed due to the early onset further supports the hypothesis of a connection between
of symptoms and the father’s diagnosed autonomic and this mutation and these clinical manifestations.
cognitive issues. Next-generation sequencing technology Emerging research suggests that RyR2 function is
was employed to analyze mitochondrial nuclear DNA essential for activity- and experience-dependent dendritic
from multiple sources, including peripheral blood, muscle, spine formation in the hippocampus, processes crucial for
liver, saliva, and urine. The analysis targeted known memory acquisition. Patients with Alzheimer’s disease
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variants in genes associated with autism, developmental exhibit downregulated RYR2 expression, which may
delay, dysautonomia, fatigue, gastrointestinal dysmotility, contribute to reduced dendritic spine density and impaired
hypotonia, migraine, seizures, ventricular tachycardia, memory. Alternatively, RyR2-mediated endoplasmic
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Volume 4 Issue 3 (2025) 119 doi: 10.36922/an.4509