Periodic Paralysis Across the Life Course: Age-related Phenotype transition and sarcopenia overlap, 2024, Suetterlin et al

[duncan]

Interesting study that explores RYR1 gene variations and their import to things like muscle weakness and ATP and mitochondrial function, and how these change with age in healthy individuals vs those with channelopathies. RYR1 variations have been tied into ME/CFS before.

This study parses down on RYR1 variations and compares different age groups of healthy individuals and the pathophysiology of major categories of periodic paralysis. It highlights ionic homeostasis vs gradual degradation and the implications to muscle weakness and energy depletion.

I thought there might be some insight into potential mechanisms involved in ME/CFS.

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1507485/full

 

[Hutan]

Abstract

In Periodic Paralysis (PP), a rare inherited condition caused by mutation in skeletal muscle ion channels, the phenotype changes with age, transitioning from the episodic attacks of weakness that give the condition its name, to a more degenerative phenotype of permanent progressive weakness and myopathy. This leads to disability and reduced quality of life.

Neither the cause of this phenotype transition, nor why it occurs around the age of 40 is known. However, 40 is also the age of onset of ‘normal’ age-related physiological decline when we consider (a) muscle mass and strength (b) physical function at the world class level and (c) age-related mitochondrial dysfunction. Elevated Na+, mitochondrial dysfunction and sarcoplasmic Ca2+ leak via the skeletal muscle ryanodine receptor (RyR1) have been implicated in both periodic paralysis myopathy and skeletal muscle ageing. We suggest this combination may trigger a negative spiral ultimately leading to progressive muscle failure.

Understanding the interaction between ageing physiology and disease phenotype will provide a window into the healthy ageing process but also help understand how, and why PP phenotype changes with age. Understanding the mechanism underlying PP phenotype-transition and its link with ageing physiology, not only has the potential to identify the first disease modifying therapies for PP, but also to identify novel and potentially tractable mechanisms that contribute to sarcopenia, the pathological loss of muscle mass and function with age.

 

[Hutan]

The primary periodic paralyses are rare inherited conditions caused by skeletal muscle ion channel mutations. These disorders are broadly divided into Hyperkalaemic Periodic Paralysis (HyperPP), Hypokalaemic Periodic Paralysis (HypoPP) and Andersen Tawil Syndrome (ATS). HyperPP and HypoPP, as their names suggest, are associated with high or low serum potassium levels, respectively.

HyperPP is caused by mutations in the skeletal muscle voltage-gated sodium gene (SCN4A). HypoPP, in Caucasian populations, is most commonly caused by mutations in the voltage-gated calcium channel gene (CACNA1S (HypoPP I)), whilst in Chinese populations HypoPP secondary to mutations in SCN4A (HypoPP II) is more common (1). Andersen Tawil Syndrome is caused by mutations in the inwardly rectifying potassium channel encoded by KCNJ2 and, in contrast to Hyper and HypoPP, has extra-muscular manifestations of cardiac conduction abnormalities and dysmorphism.

Classically, the phenotype of PP is characterized by episodic bouts of weakness with normal or near-normal inter-ictal muscle function (2). However, a consistent, yet unexplained, feature is an age-related transition from episodic weakness to fixed progressive weakness with signs of muscle degeneration (Figure 1A) (3–5). The pathophysiology of episodic bouts of weakness in PP is well understood (6–8), but neither the mechanisms that underlie the progressive, fixed weakness, nor the trigger for phenotype transition are known. Furthermore, whilst there are effective treatments to help manage episodic weakness in PP, disease-modifying therapies to prevent progressive, fixed weakness are lacking.

 

[Hutan]

Skeletal muscle is one of the main regulators of lipid metabolism in the body (15). However, it also consumes nearly 80% of available glucose and regulates both basal metabolic rate and whole body energy expenditure (16, 17) so in addition to its role enabling movement, skeletal muscle is a key metabolic organ. Maintenance of the transmembrane ion gradients necessary for action potential initiation and propagation and skeletal muscle contraction and relaxation is a major energy cost. Maintaining the transmembrane Na+ gradient uses 7% of skeletal muscle ATP whilst Ca2+ reuptake into the sarcoplasmic reticulum accounts for 35% (16). This means that ionic homeostasis accounts for just under half of total skeletal muscle ATP use (16).

Given that mitochondrial dysfunction is a key hallmark of skeletal muscle ageing (18), this suggests that ionic homeostasis may be compromised in older muscle. In support of this, skeletal muscle sodium content, as measured by Magnetic Resonance Spectroscopy, increases exponentially in men over age 40 (19). A phenomenon is also seen in wild-type mice where skeletal muscle sodium is elevated from middle age and continues to increase into old age (20). In cardiac tissue, Na+ overload reversibly inhibits mitochondrial ATP synthesis and increases free radical production (21). If the same were true for skeletal muscle, Na+ overload would itself exacerbate mitochondrial dysfunction further (Figure 2).

Additional evidence of a change in ionic homeostasis and skeletal muscle excitability with age comes from human Muscle Velocity Recovery Cycles (MVRCs). MVRCs are a specialised electromyography technique that use post-impulse change in conduction velocity, known as supernormality, as an indirect measure of skeletal muscle excitability and ion channel function in vivo (22) MVRCs are sensitive enough to detect the genetic ion channel dysfunction associated with periodic paralysis and can distinguish HyperPP from HypoPP (23). Life course studies of human MVRCs in periodic paralysis have not been performed. However, MVRCs do demonstrate change with age in healthy muscle membrane properties. These changes consist of an increase in muscle relative refractory period and a decrease in supernormality that would be most consistent with a relative depolarisation of the resting membrane potential and/or increased inactivation of the skeletal muscle voltage-gated sodium channel with age (24).

 

[Hutan]

HyperPP is caused by mutations in the skeletal muscle voltage-gated sodium gene (SCN4A).

We have some discussion about variants of other SCN genes e.g. SCN9a variant and dysautonomia

The SCN genes are the voltage-gated sodium channel genes (SCN1-SCN11)

From Gene variant effects across sodium channelopathies predict function and guide precision therapy

Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign.

 

[Hutan]

HypoPP, in Caucasian populations, is most commonly caused by mutations in the voltage-gated calcium channel gene (CACNA1S (HypoPP I)), whilst in Chinese populations HypoPP secondary to mutations in SCN4A (HypoPP II) is more common

@forestglip found that CACNA1E was the gene closest to a region of interest in DecodeME - here
and @Andy posted a paper about a CACNA1S variant being the cause of a myalgic myopathy in a family - here

(edit- corrected the reference to CACNA1E)

 

[forestglip]

@forestglip found that CACNA1S was the gene closest to a region of interest in DecodeME - here

I think CACNA1E is the gene from DecodeME. Note also this other gene in the same family:

Ultra-rare variant in CACNA1B found in two siblings with PANS, and the same variant was previously found in a woman with ME/CFS+anorexia.