Severe prognosis in a large family with hypokalemic periodic paralysis

Caciotti, Anna; Morrone, Amelia; Domenici, R; Zammarchi, Enrico

doi:10.1002/mus.10298

Cited by 25 publications

(13 citation statements)

References 30 publications

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“…These MHS mutations are distinct from those in Ca V 1.1 associated with HypoPP, and none of these patients had episodes of periodic paralysis. Conversely, there is a lack of agreement about whether HypoPP carries a slightly increased risk of MHS (24, 135, 155). …”

Section: Calcium Channelopathies Of Skeletal Musclementioning

confidence: 99%

Channelopathies of Skeletal Muscle Excitability

Cannon

2015

Comprehensive Physiology

176

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Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics.

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Section: Calcium Channelopathies Of Skeletal Musclementioning

confidence: 99%

Channelopathies of Skeletal Muscle Excitability

Cannon

2015

Comprehensive Physiology

176

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“…The long-term prognosis is generally good, and crises may decrease in midlife. However, severely affected families were reported, and involvement of respiratory muscles may lead to death [7]. The discovery of single missense CACNA1S mutations in humans with HPP-1 which still allow expression of a full-length Ca v 1.1 α1 subunit protein suggested that changes in channel gating or channel expression on the cell surface may account for altered skeletal muscle function.…”

Section: Cav11 Channelopathies (Cacna1s Gene)mentioning

confidence: 99%

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Striessnig

Bolz

Koschak

2010

Pflugers Arch - Eur J Physiol

130

140

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Voltage-gated Ca2+ channels couple membrane depolarization to Ca2+-dependent intracellular signaling events. This is achieved by mediating Ca2+ ion influx or by direct conformational coupling to intracellular Ca2+ release channels. The family of Cav1 channels, also termed L-type Ca2+ channels (LTCCs), is uniquely sensitive to organic Ca2+ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca2+ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Cav1.1 α1), incomplete congenital stationary night blindness (CSNB2; Cav1.4 α1), and Timothy syndrome (Cav1.2 α1; reviewed separately in this issue). Cav1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca2+ channelopathies affecting non-LTCCs, such as Cav2.1 α1 in tottering mice. Ca2+ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function.

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“…CACNA1S is composed of four homologous domains (DI-DIV), each of them consisting of six transmembrane segments (S1-S6) [9]. Three specific mutations have been identified in the CACNA1S gene in families with HypoPP: Arg528His in DIIS4, and Arg1,239His and Arg123Gly in DIVS4 [3,[10][11][12][13][14][15][16][17][18][19][20]. These mutations are all missense mutations where an arginine residue is replaced by either a histidine or sometimes a glycine residue.…”

Section: Introductionmentioning

confidence: 99%

Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family

Wang

Liu

et al. 2005

J Mol Med

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Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disorder which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. The skeletal muscle calcium channel α-subunit gene CACNA1S is a major disease-causing gene for HypoPP, however, only three specific HypoPP-causing mutations, Arg528His, Arg1,239His and Arg1,239Gly, have been identified in CACNA1S to date. In this study, we studied a four-generation Chinese family with HypoPP with 43 living members and 19 affected individuals. Linkage analysis showed that the causative mutation in the family is linked to the CACNA1S gene with a LOD score of 6.7. DNA sequence analysis revealed a heterozygous C to G transition at nucleotide 1,582, resulting in a novel 1,582C→G (Arg528Gly) mutation. The Arg528Gly mutation co-segregated with all affected individuals in the family, and was not present in 200 matched normal controls. The penetrance of the Arg528Gly mutation was complete in male mutation carriers, however, a reduced penetrance of 83% (10/12) was observed in female carriers. No differences were detected for age-at-onset and severity of the disease (frequency of symptomatic attacks per year) between male and female patients. Oral intake of KCl is effective in blocking the symptomatic attacks. This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease.

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Severe prognosis in a large family with hypokalemic periodic paralysis

Cited by 25 publications

References 30 publications

Channelopathies of Skeletal Muscle Excitability

Channelopathies of Skeletal Muscle Excitability

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family

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