Hyperkalemic periodic paralysis: Difference between revisions
Ozzie10aaaa (talk | contribs) Add: bibcode. | You can use this tool yourself. Report bugs here. |
No edit summary |
||
| Line 26: | Line 26: | ||
'''Hyperkalemic periodic paralysis''' ('''HYPP''', '''HyperKPP''') is an [[genetic disease|inherited]] [[autosomal]] [[dominance relationship|dominant]] disorder that affects [[ion channels|sodium channel]]s in [[muscle]] cells and the ability to regulate [[potassium]] levels in the [[blood]]. It is characterized by muscle hyperexcitability or weakness which, exacerbated by [[potassium]], heat or cold, can lead to uncontrolled shaking followed by [[paralysis]]. Onset usually occurs in early childhood, but it still occurs with adults. |
'''Hyperkalemic periodic paralysis''' ('''HYPP''', '''HyperKPP''') is an [[genetic disease|inherited]] [[autosomal]] [[dominance relationship|dominant]] disorder that affects [[ion channels|sodium channel]]s in [[muscle]] cells and the ability to regulate [[potassium]] levels in the [[blood]]. It is characterized by muscle hyperexcitability or weakness which, exacerbated by [[potassium]], heat or cold, can lead to uncontrolled shaking followed by [[paralysis]]. Onset usually occurs in early childhood, but it still occurs with adults. |
||
The [[mutation]] which causes this disorder is [[dominant gene|dominant]] on SCN4A with linkage to the [[sodium channel]] expressed in [[muscle]]. The mutation causes single [[amino acid]] changes in parts of the channel which are important for inactivation. |
The [[mutation]] which causes this disorder is [[dominant gene|dominant]] on SCN4A with linkage to the [[sodium channel]] expressed in [[muscle]]. The mutation causes single [[amino acid]] changes in parts of the channel which are important for inactivation. These mutations impair "ball and chain" fast inactivation of SCN4A following an action potential. |
||
==Signs and symptoms== |
==Signs and symptoms== |
||
| Line 43: | Line 43: | ||
Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Na<sub>v</sub>1.4. Mutations have been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.<ref>{{cite journal |vauthors=Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH |title=A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis |journal=Nature |volume=354 |issue=6352 |pages=387–9 |date=December 1991 |pmid=1659668 |doi=10.1038/354387a0 |bibcode=1991Natur.354..387R }}</ref><ref>{{cite journal |vauthors=Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ |title=Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5 |journal=Neurology |volume=58 |issue=8 |pages=1266–72 |date=April 2002 |pmid=11971097 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11971097 |doi=10.1212/wnl.58.8.1266}}</ref> |
Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Na<sub>v</sub>1.4. Mutations have been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.<ref>{{cite journal |vauthors=Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH |title=A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis |journal=Nature |volume=354 |issue=6352 |pages=387–9 |date=December 1991 |pmid=1659668 |doi=10.1038/354387a0 |bibcode=1991Natur.354..387R }}</ref><ref>{{cite journal |vauthors=Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ |title=Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5 |journal=Neurology |volume=58 |issue=8 |pages=1266–72 |date=April 2002 |pmid=11971097 |url=http://www.neurology.org/cgi/pmidlookup?view=long&pmid=11971097 |doi=10.1212/wnl.58.8.1266}}</ref> |
||
In patients with mutations in SCN4A, |
The pathological mechanism of SCN4A mutations in hyperkalemic periodic paralysis is complex, but explains the autosomal dominant and hyperkalemia-related aspects of the disease<ref>{{cite journal |last1=Cannon |first1=Stephen C. |title=Sodium Channelopathies of Skeletal Muscle |journal=Voltage-gated Sodium Channels: Structure, Function and Channelopathies |date=2018 |pages=309–330 |doi=10.1007/164_2017_52 |url=https://doi.org/10.1007/164_2017_52 |publisher=Springer International Publishing |language=en}}</ref>. In patients with mutations in SCN4A, not all copies of the channel inactivate following the action potential. This results in a sodium leak and failure to return to the original resting membrane potential. In the presence of hyperkalemia, which causes an additional chronic depolarization of the membrane potential, this sodium leak raises the membrane potential to the point that all sodium channels, including channels produced from the wild-type allele and mutant channels that did inactivate, fail to be release from inactivation (enter depolarization block). Since the motor end plate is depolarised, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell to repolarise it to the [[resting potential]]. This further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.<ref>{{cite journal |vauthors=Rüdel R, Lehmann-Horn F, Ricker K, Küther G |title=Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters |journal=Muscle Nerve |volume=7 |issue=2 |pages=110–20 |date=February 1984 |pmid=6325904 |doi=10.1002/mus.880070205 }}</ref><ref>{{cite journal |vauthors=Jurkat-Rott K, Lehmann-Horn F |title=Muscle channelopathies and critical points in functional and genetic studies |journal=J. Clin. Invest. |volume=115 |issue=8 |pages=2000–9 |date=August 2005 |pmid=16075040 |pmc=1180551 |doi=10.1172/JCI25525 }}</ref> |
||
==Treatment== |
==Treatment== |
||
Revision as of 00:14, 19 January 2020
| Hyperkalemic periodic paralysis | |
|---|---|
| Other names | Gamstorp episodic adynamy |
| Specialty | Neurology |
Hyperkalemic periodic paralysis (HYPP, HyperKPP) is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood. It is characterized by muscle hyperexcitability or weakness which, exacerbated by potassium, heat or cold, can lead to uncontrolled shaking followed by paralysis. Onset usually occurs in early childhood, but it still occurs with adults.
The mutation which causes this disorder is dominant on SCN4A with linkage to the sodium channel expressed in muscle. The mutation causes single amino acid changes in parts of the channel which are important for inactivation. These mutations impair "ball and chain" fast inactivation of SCN4A following an action potential.
Signs and symptoms
 |
Hyperkalemic periodic paralysis causes episodes of extreme muscle weakness, with attacks often beginning in childhood.[1] Depending on the type and severity of the HyperKPP, it can increase or stabilize until the fourth or fifth decade where attacks may cease, decline, or, depending on the type, continue on into old age. Factors that can trigger attacks include rest after exercise, potassium-rich foods, stress, fatigue, weather changes, certain pollutants (e.g., cigarette smoke) and fasting. Muscle strength often improves between attacks, although many affected people may have increasing bouts of muscle weakness as the disorder progresses (abortive attacks). Sometimes with HyperKPP those affected may experience degrees of muscle stiffness and spasms (myotonia) in the affected muscles. This can be caused by the same things that trigger the paralysis, dependent on the type of myotonia.
Some people with hyperkalemic periodic paralysis have increased levels of potassium in their blood (hyperkalemia) during attacks. In other cases, attacks are associated with normal blood potassium levels (normokalemia). Ingesting potassium can trigger attacks in affected individuals, even if blood potassium levels do not rise in response.
In contrast to HyperKPP, hypokalemic periodic paralysis (noted in humans) refers to loss-of-function mutations in channels that prevent muscle depolarisation and therefore are aggravated by low potassium ion concentrations.
Genetics
In humans, the most common underlying genetic cause is one of several possible point mutations in the gene SCN4A.[2] This gene codes for a voltage-gated sodium channel Nav1.4 found at the neuromuscular junction. This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause it.
Action potentials from the central nervous system cause end-plate potentials at the NMJ which causes sodium ions to enter by Nav1.4 and depolarise the muscle cells. This depolarisation triggers the entry of calcium from the sarcoplasmic reticulum to cause contraction (tensing) of the muscle. To prevent the muscle from being perpetually contracted, the channel contains a fast inactivation gate that plugs the sodium pore very quickly after it opens. This prevents further entry of sodium. In time, potassium ions will leave the muscle cells, repolarising the cells and causing the pumping of calcium away from the contractile apparatus to relax the muscle.
Mutations altering the usual structure and function of this sodium channel therefore disrupt regulation of muscle contraction, leading to episodes of severe muscle weakness or paralysis. Mutations have been identified in residues between transmembrane domains III and IV which make up the fast inactivation gate of Nav1.4. Mutations have been found on the cytoplasmic loops between the S4 and S5 helices of domains II, III and IV, which are the binding sites of the inactivation gate.[3][4]
The pathological mechanism of SCN4A mutations in hyperkalemic periodic paralysis is complex, but explains the autosomal dominant and hyperkalemia-related aspects of the disease[5]. In patients with mutations in SCN4A, not all copies of the channel inactivate following the action potential. This results in a sodium leak and failure to return to the original resting membrane potential. In the presence of hyperkalemia, which causes an additional chronic depolarization of the membrane potential, this sodium leak raises the membrane potential to the point that all sodium channels, including channels produced from the wild-type allele and mutant channels that did inactivate, fail to be release from inactivation (enter depolarization block). Since the motor end plate is depolarised, further signals to contract have no effect (paralysis). The condition is hyperkalemic because a high extracellular potassium ion concentration will make it even more unfavourable for potassium to leave the cell to repolarise it to the resting potential. This further prolongs the sodium conductance and keeps the muscle contracted. Hence, the severity would be reduced if extracellular (serum) potassium ion concentrations are kept low.[6][7]
Treatment
- Glucose or other carbohydrates can be given during an attack and may reduce the severity.[1]
- Intravenous calcium decreases activity of sodium channels. It may stop sudden attacks.[1]
- Diuretics such as furosemide may be needed to stop sudden attacks;[1] acetazolamide and thiazide diuretics such as chlorothiazide are also effective.[1]
- Intravenous glucose and insulin stimulates potassium uptake into the cell by the Na-K ATPase and may reduce weakness without a loss of total body potassium.[1]
- A high-carbohydrate diet may be recommended.[1]
- Avoidance of other known attack triggers.[8]
References
- ^ a b c d e f g MedlinePlus: Hyperkalemic periodic paralysis Update Date: 7/25/2006. Updated by: David M. Charytan, M.D., M.Sc., Department of Medicine, Division of Nephrology, Brigham and Women's Hospital, Boston, MA.
- ^ Online Mendelian Inheritance in Man (OMIM): Hyperkalemic Periodic Paralysis; HYPP - 17050
- ^ Rojas CV, Wang JZ, Schwartz LS, Hoffman EP, Powell BR, Brown RH (December 1991). "A Met-to-Val mutation in the skeletal muscle Na+ channel alpha-subunit in hyperkalaemic periodic paralysis". Nature. 354 (6352): 387–9. Bibcode:1991Natur.354..387R. doi:10.1038/354387a0. PMID 1659668.
- ^ Bendahhou S, Cummins TR, Kula RW, Fu YH, Ptácek LJ (April 2002). "Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5". Neurology. 58 (8): 1266–72. doi:10.1212/wnl.58.8.1266. PMID 11971097.
- ^ Cannon, Stephen C. (2018). "Sodium Channelopathies of Skeletal Muscle". Voltage-gated Sodium Channels: Structure, Function and Channelopathies. Springer International Publishing: 309–330. doi:10.1007/164_2017_52.
- ^ Rüdel R, Lehmann-Horn F, Ricker K, Küther G (February 1984). "Hypokalemic periodic paralysis: in vitro investigation of muscle fiber membrane parameters". Muscle Nerve. 7 (2): 110–20. doi:10.1002/mus.880070205. PMID 6325904.
- ^ Jurkat-Rott K, Lehmann-Horn F (August 2005). "Muscle channelopathies and critical points in functional and genetic studies". J. Clin. Invest. 115 (8): 2000–9. doi:10.1172/JCI25525. PMC 1180551. PMID 16075040.
- ^ Lee, GM; Kim, JB (June 2011). "Hyperkalemic periodic paralysis and paramyotonia congenita caused by a de novo mutation in the SCN4A gene". Neurology Asia. 16 (2): 163–6.
- National Library of Medicine. Hyperkalemic periodic paralysis