Alternative titles; symbols
ORPHA: 681; DO: 14452;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | Hypokalemic periodic paralysis, type 1 | 170400 | Autosomal dominant | 3 | CACNA1S | 114208 |
A number sign (#) is used with this entry because hypokalemic periodic paralysis type 1 (HOKPP1) is caused by heterozygous mutation in the CACNL1A3 gene (CACNA1S; 114208) on chromosome 1q32.
See also HOKPP2 (613345), which is caused by mutation in the SCN4A gene (603967). Mutations in the SCN4A gene can also cause hyperkalemic periodic paralysis (HYPP; 170500). Mutation in the ATP1A2 gene (182340) may also cause a similar phenotype (AHC1; 104290).
There are 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, that are distinguished by the changes in serum potassium levels during paralytic attacks. In contrast to HYPP, myotonia is usually not present in HOKPP (Jurkat-Rott et al., 2000). Hypokalemic periodic paralysis may also occur as a rare complication of thyrotoxicosis (see TTPP1, 188580), a disorder with a high frequency in individuals of Asian descent (Kung, 2006).
The classic picture of HOKPP is episodic weakness accompanied by low serum potassium levels. The attacks are aborted by administration of potassium or by exercise and are precipitated by insulin or glucose administration. Hypokalemic periodic paralysis shows markedly reduced penetrance in females, although penetrance is 100% in males. For this reason, some pedigree patterns have suggested X-linked recessive inheritance (Sagild, 1959). Ropers and Szliwowski (1979) described a family in which an unaffected male had 2 daughters, each by a different wife, with this disorder. One of the affected daughters had an affected son. Buruma et al. (1985) reported a large family with HOKPP with 28 affected patients in 4 generations. All patients investigated showed permanent muscle weakness.
Ma et al. (1986) reported the unusual occurrence of high frequency of periodic paralysis among Chinese patients with primary hyperaldosteronism and resultant hypokalemia due to adrenal cortical adenoma. Among 50 consecutive patients with an adenoma, 42% presented with periodic paralysis. Other features included palpitations (30%) and syncope (12%). Those with paralysis had significantly lower mean serum potassium and significantly higher aldosterone levels than those without paralysis. Ma et al. (1986) also noted that hypokalemic paralysis can occur in Orientals with barium poisoning, and as a side-effect of gossypol, a fertility regulating agent used in China.
Raskin et al. (1981) and Pun et al. (1989) observed periodic paralysis with Sjogren syndrome (270150), which can be complicated by distal renal tubular acidosis and hypokalemia.
Boerman et al. (1995) reported a large Dutch family in which 55 members had HOKPP inherited in an autosomal dominant pattern. Nineteen patients had typical episodic attacks of paralysis, whereas 14 had muscle weakness without attacks. Reduced muscle fiber conduction velocity was present. Age of onset ranged from 9 to 19 years of age.
In a review of 71 patients from 56 kindreds with HOKPP, Miller et al. (2004) found that 64% of kindreds had mutations in either the CACNA1S or SCN4A genes. The arg1239-to-his (R1239H; 114208.0001) and arg528-to-his (R528H; 114208.0003) mutations of the CACNA1S gene were the most common mutations, each found in 42% of kindreds. Five kindreds had SCN4A mutations. No mutations were identified in 20 kindreds. HOKPP patients with mutations had a significantly earlier age at disease onset (10 years) compared to those without mutations (22 years); however, 2 patients with mutations presented at ages 23 and 26 years, respectively. Among those with mutations, the disease was most severe during the teenage years, and 72% of patients had residual muscle weakness. Muscle biopsies showed vacuolar changes in 80% of patients with CACNA1S mutations; these changes were not seen in any patients without mutations. Treatment with acetazolamide was beneficial in 85% of those with mutations and 100% of those without mutations. In a diagnostic flow chart for the periodic paralyses, Miller et al. (2004) indicated that HOKPP shows onset in childhood to adolescence and is characterized by infrequent but severe attacks, often lasting up to 24 hours, and decreased serum potassium. Myotonia is not a feature.
Chabrier et al. (2008) reported a Turkish boy, born of consanguineous parents, with very early onset of HOKPP at 1 year of age. He showed hypotonia and respiratory insufficiency at birth, which the authors postulated may have been related to the disorder. Although oral potassium supplementation was initiated, he was still symptomatic and showed chronic global muscle weakness at age 6 years.
Clinical Variability
Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes. He had onset of episodic paralytic weakness at the age of 14 years. Episodes were characterized by weakness primarily affecting the lower extremities and lasting hours to days, and were usually precipitated by strenuous exercise followed by rest or after prolonged sitting. Carbohydrate ingestion did not precipitate attacks, alcohol intake appeared to facilitate recovery from an attack, and potassium had no effect. He was classified as having hypokalemic periodic paralysis because of the typical age of onset, paralytic attacks that most often occurred after exercise, a low potassium level during a spontaneous attack, and the ability to precipitate an attack with insulin and glucose on 1 occasion. Atypical for this diagnosis was that a second provocative test was negative and that attacks usually occurred while awake.
In a large family with HOKPP, Buruma et al. (1985) excluded close linkage with 25 genetic marker systems. By studying linkage with polymorphic markers associated with the candidate loci in a single multigenerational pedigree, Casley et al. (1992) excluded all 3 as the site of the mutation in HOKPP: the adult skeletal muscle sodium channel (SCN4A; 603967), the T-cell receptor beta locus (TCRB; see 186930), and the HRAS locus (190020). Fontaine et al. (1991) likewise excluded linkage to the SCN4A gene, and concluded that the hyperkalemic and hypokalemic forms of periodic paralysis are determined by mutations at different loci.
In a genomewide search in 3 affected European families of different geographic origins, Fontaine et al. (1994) localized the HOKPP gene to chromosome 1q31-q32. They also demonstrated that the CACNL1A3 gene maps to the same region, sharing a 5-cM interval with the HOKPP locus. Moreover, CACNL1A3 was found to cosegregate with hypokalemic periodic paralysis without recombinants in the 2 informative families. This gene encodes a dihydropyridine (DHP) receptor which functions as a voltage-gated calcium channel and is also critical for excitation-contraction coupling in a voltage-sensitive and calcium-independent manner.
Genetic Heterogeneity
Genetic heterogeneity of HOKPP was demonstrated by Plassart et al. (1994), who found that the disorder in a large family of French origin was not genetically linked to 1q32.
Abbott et al. (2001) reported a male proband with atypical HOKPP who was negative for mutations in the SCN4A and CACNA1S genes. In this patient and in his 2 similarly affected family members, Abbott et al. (2001) identified a substitution in the KCNE3 gene (R83H; 604433.0001). However, studies by Sternberg et al. (2003) and Jurkat-Rott and Lehmann-Horn (2004) concluded that the R83H variant does not play a causative role in periodic paralysis and that it is a polymorphism. For further discussion, see 604433.0001.
In 11 of 33 probands with HOKPP, Ptacek et al. (1994) identified mutations in the CACNL1A3 gene (114208.0001; 114208.0002) that occurred at 1 of 2 adjacent nucleotides within the same codon. This was the first human disease to be related to DHP receptor mutations. In a large Dutch family with HOKPP, Boerman et al. (1995) identified a mutation in the CACNL1A3 gene (114208.0003).
Davies et al. (2001) found that 11 of 36 families with HOKPP harbored mutations in the CACNA1S gene (114208.0001 and 114208.0003), whereas only 1 family had a mutation in the SCN4A gene (603967.0020), suggesting that SCN4A mutations are an uncommon cause of HOKPP in the U.K. Among 58 independent index cases of HOKPP, Sternberg et al. (2001) found that 40 were linked to the CACNA1S gene and 5 to the SCN4A gene, all of which were in the same codon (see, e.g., 603967.0016). Thirteen families remained without known mutations, indicating genetic heterogeneity.
Chabrier et al. (2008) identified a de novo mutation in the CACNA1S gene (114208.0008) in a Turkish boy with very early onset of HOKPP.
Matthews et al. (2009) identified mutations in the CACNA1S or SCN4A gene in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations, including 3 novel mutations, affected arginine residues in the S4 voltage sensing region in 1 of the transmembrane domains of each gene. The most common mutations affected residues arg528 (25 cases) and arg1239 (39 cases) in CACNA1S (see, e.g., R1239H; 114208.0001 and R528H; 114208.0003). The most common mutations in SCN4A affected residues arg672 (see, e.g., 603967.0016) and arg1132. The findings supported the hypothesis that loss of positive charge in S4 voltage sensors is important to the pathogenesis of this disorder. (Sokolov et al., 2007).
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