Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes

Brugnoni, Raffaella; Canioni, Eleonora; Filosto, Massimiliano; Pini, Antonella; Tonin, Paola; Rossi, Tommaso; Canavese, C; Eoli, Marica; Siciliano, Gabriele; Lauria, Giuseppe; Mantegazza, Renato; Maggi, Lorenzo

doi:10.1007/s10048-021-00673-2

Cited by 14 publications

(8 citation statements)

References 36 publications

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“…Our case series included 108 men and 11 women, for a gender ratio of about 10:1. This gender disparity could be explained by females' lower penetrance, which is consistent with previous findings ( 18 , 22 , 23 ). Though without substantial variation, female patients (45.5%) were more likely than male patients (26.9%) to receive a molecular diagnosis.…”

Section: Discussionsupporting

confidence: 92%

“…Both rates were significantly lower than previous studies conducted in the USA and China ( 11 , 12 ). In terms of hypoPP, the diagnostic rate was 26.2%, which was also much lower than in several western countries (64.3–89.2%) ( 12 , 18 – 20 ), but higher than in a Taiwan study (12.5%) ( 21 ) ( Table 2 ). In contrast, 18 out of 25 (72.0%) patients with FPP received a molecular diagnosis, showing a much higher yield than patients with SPP (17.0%; p < 0.0001).…”

Section: Discussionmentioning

confidence: 60%

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Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan

Yuan

Higuchi²,

Hashiguchi³

et al. 2023

Front. Neurol.

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IntroductionGenetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan.MethodsWe obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted.ResultsFrom 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25).DiscussionThe low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 60%

Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan

Yuan

Higuchi²,

Hashiguchi³

et al. 2023

Front. Neurol.

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“…CACNA1S mutations are associated with MH and some forms of congenital myopathies ( Monnier et al, 1997 ; Schartner et al, 2017 ; Mauri et al, 2021 ). CACNA1S mutations identified in MH affect residues located in the S4 voltage-sensing domain, while those identified in congenital myopathies are associated with a decrease in CACNA1S protein expression and impairment of E-C coupling ( Maggi et al, 2021 ; Brugnoni et al, 2022 ). More severe cases were reported with fetal akinesia or cognitive delay ( Yis et al, 2019 ; Ravenscroft et al, 2021 ).…”

Section: Ryr1 -Related Myopathiesmentioning

confidence: 99%

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

Rossi

Catallo

Pierantozzi

et al. 2022

Journal of General Physiology

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In skeletal muscle, Ca2+ necessary for muscle contraction is stored and released from the sarcoplasmic reticulum (SR), a specialized form of endoplasmic reticulum through the mechanism known as excitation–contraction (E-C) coupling. Following activation of skeletal muscle contraction by the E-C coupling mechanism, replenishment of intracellular stores requires reuptake of cytosolic Ca2+ into the SR by the activity of SR Ca2+-ATPases, but also Ca2+ entry from the extracellular space, through a mechanism called store-operated calcium entry (SOCE). The fine orchestration of these processes requires several proteins, including Ca2+ channels, Ca2+ sensors, and Ca2+ buffers, as well as the active involvement of mitochondria. Mutations in genes coding for proteins participating in E-C coupling and SOCE are causative of several myopathies characterized by a wide spectrum of clinical phenotypes, a variety of histological features, and alterations in intracellular Ca2+ balance. This review summarizes current knowledge on these myopathies and discusses available knowledge on the pathogenic mechanisms of disease.

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“…In addition, the SCN4A , SCN5A , and SCN10A genes that encode the skeletal muscle Na V 1.4, the cardiac Na V 1.5 and the PNS Na V 1.8 channels, respectively, are associated with other channelopathies ( England and de Groot, 2009 ; Fouda et al, 2022 ). For example, SCN4A mutants cause various neuromuscular disorders ( Brugnoni et al, 2022 ), SCN5A mutants are responsible for cardiac syndromes ( Verkerk et al, 2018 ) and pain-related conditions are associated with mutations in SCN9A and SCN10A ( Shen et al, 2022 ). Therefore, compounds that modify sodium-channel function may have therapeutic efficacy in these various channelopathies.…”

Section: Introductionmentioning

confidence: 99%

Beyond CBD: Inhibitory effects of lesser studied phytocannabinoids on human voltage-gated sodium channels

Milligan

Anderson²,

McGregor³

et al. 2023

Front. Physiol.

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Introduction: Cannabis contains cannabidiol (CBD), the main non-psychoactive phytocannabinoid, but also many other phytocannabinoids that have therapeutic potential in the treatment of epilepsy. Indeed, the phytocannabinoids cannabigerolic acid (CBGA), cannabidivarinic acid (CBDVA), cannabichromenic acid (CBCA) and cannabichromene (CBC) have recently been shown to have anti-convulsant effects in a mouse model of Dravet syndrome (DS), an intractable form of epilepsy. Recent studies demonstrate that CBD inhibits voltage-gated sodium channel function, however, whether these other anti-convulsant phytocannabinoids affect these classic epilepsy drug-targets is unknown. Voltage-gated sodium (NaV) channels play a pivotal role in initiation and propagation of the neuronal action potential and NaV1.1, NaV1.2, NaV1.6 and NaV1.7 are associated with the intractable epilepsies and pain conditions.Methods: In this study, using automated-planar patch-clamp technology, we assessed the profile of the phytocannabinoids CBGA, CBDVA, cannabigerol (CBG), CBCA and CBC against these human voltage-gated sodium channels subtypes expressed in mammalian cells and compared the effects to CBD.Results: CBD and CBGA inhibited peak current amplitude in the low micromolar range in a concentration-dependent manner, while CBG, CBCA and CBC revealed only modest inhibition for this subset of sodium channels. CBDVA inhibited NaV1.6 peak currents in the low micromolar range in a concentration-dependent fashion, while only exhibiting modest inhibitory effects on NaV1.1, NaV1.2, and NaV1.7 channels. CBD and CBGA non-selectively inhibited all channel subtypes examined, whereas CBDVA was selective for NaV1.6. In addition, to better understand the mechanism of this inhibition, we examined the biophysical properties of these channels in the presence of each cannabinoid. CBD reduced NaV1.1 and NaV1.7 channel availability by modulating the voltage-dependence of steady-state fast inactivation (SSFI, V0.5 inact), and for NaV1.7 channel conductance was reduced. CBGA also reduced NaV1.1 and NaV1.7 channel availability by shifting the voltage-dependence of activation (V0.5 act) to a more depolarized potential, and for NaV1.7 SSFI was shifted to a more hyperpolarized potential. CBDVA reduced channel availability by modifying conductance, SSFI and recovery from SSFI for all four channels, except for NaV1.2, where V0.5 inact was unaffected.Discussion: Collectively, these data advance our understanding of the molecular actions of lesser studied phytocannabinoids on voltage-gated sodium channel proteins.

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Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes

Cited by 14 publications

References 36 publications

Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan

Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

Beyond CBD: Inhibitory effects of lesser studied phytocannabinoids on human voltage-gated sodium channels

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