Objective: Scapuloperoneal spinal muscular atrophy (SPSMA) is a rare autosomal dominant disease caused by transient receptor potential cation channel (TRPV4) gene, involving scapular and peroneal muscle weakness. SPSMA is a rare Genetic disorder, with more than 30 affected individuals worldwide. We report a 63-year-old male with SPSMA with Parkinson’s disease (PD) due to heterozygous missense variation in exon 5 of the TRPV4 gene. To the best of our knowledge, the SPSMA with TRPV4 phenotype with Parkinson’s disease has not been reported in literature.

Background: –

Method: 63 years gentleman presented with hand tremors, bradykinesia and rigidity since 5 years. He had a history of difficulty in walking since childhood associated with muscle wasting in legs. No similar family history. He had atrophy of legs, moderate proximal and distal weakness in limbs, scapular winging, absent deep tendon reflexes with waddling gait. He also had bilateral resting and postural tremors, bradykinesia, and cogwheel rigidity. His CPK was elevated. Nerve conduction study and MRI brain were normal. TRODAT CT brain confirmed presynaptic Parkinson’s disease. whole-exome sequence revealed a heterozygous missense variation in exon 5 of the TRPV4 gene that results in (p.Arg269His) suggestive of SPSMA. He was started on Levodopa with modest benefit noted.

Results: –

Conclusion: Our patient had childhood-onset sporadic SPSMA with PD. SPSMA is a rare autosomal dominant disorder caused by TRPV4 gene, characterized by progressive scapuloperoneal atrophy and weakness of limbs. A TRPV4 mutation can cause nine different diseases ranging from SPSMA, Charcot-Marie-Tooth neuropathy type 2C (CMT2C), and, Congenital distal spinal muscular atrophy. 
TRPV4 gene mutations that cause gain of function are linked to some congenital neuropathies involving motor and sensory neurons.¹ Transient Receptor Potential (TRP) channel-related Ca2+ mediated excitotoxicity and oxidative stress-induced dopaminergic, inflammation leading to neuronal death in PD has highlighted the possible role in affecting the other molecular mechanisms associated with PD mechanism.^2,3
The understanding of TRPV Channel molecular mechanism will enlighten the role of TRPV4 in SPSMA and PD leading to ER stress and inflammatory pathways, inducing the loss of dopaminergic (DA) neurons in the substanitia nigra to confirm it is causative or coincidental.

References: 1. Tjaša O., Kolmančič K., Tratnjek L., Živin A., Živin M. (2016). “Immunohistochemical Staining of Trpv4 Channels in Rat Parkinson Disease Model,” in Proceedings of the MEi: CogSci Conference 2016, (Bratislava: Comenius University; ).
2. Liu N, Bai L, Lu Z, Gu R, Zhao D, Yan F, Bai J. TRPV4 contributes to ER stress and inflammation: implications for Parkinson’s disease. J Neuroinflammation. 2022 Jan 29;19(1):26. doi: 10.1186/s12974-022-02382-5. PMID: 35093118; PMCID: PMC8800324.
3. Vaidya B, Sharma SS. Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson’s Disease: An Insight Into Role of Pharmacological Interventions. Front Cell Dev Biol. 2020 Nov 20;8:584513. doi: 10.3389/fcell.2020.584513. PMID: 33330461; PMCID: PMC7714790.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/trpv4-mutation-related-parkinsons-disease-with-scapuloperoneal-spinal-muscular-atrophy/