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▼ Description
The 2 dominantly inherited, clinically similar types of episodic flaccid generalized weakness, HOKPP and HYPP, are distinguished by the changes in serum potassium levels during paralytic attacks. An important clinical difference between the 2 entities is represented by the triggers of attacks of weakness, e.g., HYPP can be provoked by oral potassium administration, whereas this is a remedy for HOKPP. Concurrence of myotonia is found in HYPP but usually not in HOKPP patients (Jurkat-Rott et al., 2000).

Jurkatt-Rott and Lehmann-Horn (2007) provided a review of the clinical features, pathogenesis, and therapeutic options for HYPP.

▼ Clinical Features
Gamstorp (1956, 1963) first described hyperkalemic periodic paralysis, which she called 'adynamia episodica hereditaria.' Attacks were characterized by muscle weakness, i.e., adynamia, rather than by complete paralysis, and occurred with no recognizable periodicity. Myotonia was sometimes coexistent. Samaha (1965) reported an affected family in which myotonia was also present. Van'T Hoff (1962) reported a family in which 9 persons in 4 generations were affected with myotonic periodic paralysis. All suffered from periodic attacks of weakness which could be induced by administering potassium and alleviated by administering calcium. Both between and during attacks, affected persons had myotonic lid lag (ocular muscle myotonia) lasting 15-20 seconds after elevation of the eyes. Saunders et al. (1968) reported familial myotonic periodic paralysis with muscle wasting.

Gould et al. (1985) reported an 11-year-old boy with hyperkalemic periodic paralysis and bidirectional cardiac dysrhythmia (BVT). The mother also showed BVT, as well as the short stature, microcephaly, and clinodactyly shown by the son. The mother, but not the son, had lingual myotonia, which has been thought by Lisak et al. (1972) and by Layzer et al. (1967) to be the minimal expression of this disorder. Sudden death with this cardiac complication has been reported (Lisak et al., 1972).

Lehmann-Horn et al. (1987) recognized 3 types of adynamia episodica: (1) a form in combination with clinical or electromyographic myotonia (Carson and Pearson, 1964; van'T Hoff, 1962; Krull et al., 1966; van der Meulen et al., 1961); (2) a form without any signs of myotonia (Bradley, 1969); and (3) a form in combination with paramyotonia, which is presumably the same as paramyotonia of von Eulenburg (paramyotonia congenita).

Bradley et al. (1990) suggested that progressive myopathy may be as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder. They studied 4 families with the hyperkalemic form in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy was consistent with a myopathy.

Brancati et al. (2003) reported an Italian kindred with 9 individuals affected with a severe form of HYPP and mild features of paramyotonia congenita. Onset of paralytic episodes was in the first 6 to 12 months in all patients. The episodes were frequent, 2 to 3 times per week, lasting 10 minutes to 2 hours, and were usually accompanied by muscle stiffness, usually of the lower limbs. During adolescence, episodes were precipitated by rest after exercise, cold, alcohol intake, and fasting. The frequency and severity of attacks worsened over the years, occurring daily and spontaneously. Five of 6 patients had normal serum potassium during attacks. Diffuse interictal weakness, primarily in the proximal muscles, occurred around the fourth to fifth decade.

Gay et al. (2008) described a female infant with severe fatal neonatal nondystrophic myotonia who presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness, leading to severe hypoxia and loss of consciousness; she died at 20 months of age following a bronchopulmonary infection.

Normokalemic Potassium-Sensitive Periodic Paralysis

Vicart et al. (2004) reported 4 unrelated families with 'normokalemic potassium-sensitive periodic paralysis' caused by mutation in the SCN4A gene (603967.0022-603967.0024). In 1 family with at least 5 affected members, age at onset of paralytic attacks ranged from 14 months to 3 years. During childhood and adolescence, the attacks were characterized by generalized weakness; as adults, the attacks were usually restricted to the lower limbs. Most patients reported muscle stiffness, cramping, and pain after the attacks. Two family members had severe attacks after general anesthesia. Repeated serum potassium levels during attacks were normal in 3 patients. Four additional patients from 3 unrelated families had a later age at onset (15 to 23 years) and milder disease course. Myotonia was not a feature in any of the patients, except in 1 patient with lid lag, and most patients responded to acetazolamide treatment. Two unrelated patients demonstrated paralysis after potassium challenge in a controlled situation. Vicart et al. (2004) stated that a diagnosis of hyperkalemic periodic paralysis was suggested by the reports of muscle stiffness and cramping as well as EMG findings; however, the finding of normal serum potassium levels during attacks in 5 patients suggested that normokalemic periodic paralysis may be a variable expression of HYPP.

Clinical Variability

Abbott et al. (2001) reported a male proband with a atypical HYPP who was negative for mutations in the SCN4A gene. He presented at 22 months of age with episodic weakness of the extremities. Most episodes came on during sleep and were brief (12 hours), although they occasionally lasted for days. Serum potassium levels during attacks were normal. High carbohydrate meals helped resolve attacks and treatment with a carbonic anhydrase inhibitor prevented attacks. The age at onset, frequent nature of attacks, and improvement with carbohydrate loading were all consistent with HYPP; however, provocative testing with potassium had not been performed. Frequent attacks upon awakening and absence of myotonia were considered atypical for this diagnosis.

▼ Biochemical Features
In intact muscle fibers from a patient with periodic paralysis with myotonia, Lehmann-Horn et al. (1987) found evidence for a noninactivating tetrodotoxin-sensitive sodium channel. In a solution of elevated potassium, the patient muscle depolarized, became inexcitable, and was paralyzed.

▼ Mapping
In a large family with hyperkalemic periodic paralysis with myotonia, Fontaine et al. (1990) found tight linkage to the human growth hormone gene (GH1; 139250) on chromosome 17 and to the adult muscle sodium channel alpha-subunit gene (SCN4A) which they had mapped to chromosome 17. Analysis using both the channel probe and the closely linked GH1 yielded a multipoint lod score of 7.02 at theta = 0.00. Ptacek et al. (1991) confirmed the linkage in a second large affected family, the first with this disorder to be well characterized (Tyler et al., 1951).

Fontaine et al. (1990) referred to a report by G. Couzot in 1887 (cited by Burama and Schipperheyn, 1979) of a periodic paralysis pedigree with cosegregating short stature, raising the possibility of a linked GH1 mutation in that family. They stated that recombination between the sodium channel gene and hypokalemic periodic paralysis had been found in at least 1 instance. In 6 European families with HYPP, Koch et al. (1991) demonstrated no recombinants between the disease and both SCN4A and GH1 (maximum lod = 7.14 at theta = 0.00).

Ptacek et al. (1991) found close linkage of paramyotonia congenita (PMC) to SCN4A (lod score = 4.4 at theta = 0.0), leading them to suggest that PMC and HYPP are allelic disorders. Using dinucleotide repeat polymorphisms, McClatchey et al. (1992) showed linkage of both HYPP and PMC to the SCN4A gene.

Genetic Heterogeneity

Abbott et al. (2001) reported a male proband with a atypical HYPP who was negative for mutations in the SCN4A gene. In this patient and in his mildly affected father, 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.

▼ Molecular Genetics
In 3 of 7 unrelated patients with HYPP, Ptacek et al. (1991) identified the same mutation in the SCN4A gene (T704M; 603967.0001). In a severe form of HYPP with features of PMC, Brancati et al. (2003) identified the T704M mutation, demonstrating the wide phenotypic variability of the disorder.

In 9 of 12 families with HYPP, Feero et al. (1993) identified mutations in the SCN4A gene: 3 families with M1592V (603967.0002), and 6 with T704M (603967.0001). No mutation was identified in 3 affected families, and in 1 of these 3 families the disease was not linked to the SCN4A gene, suggesting the existence of a clinically similar but genetically distinct form of hyperkalemic periodic paralysis.

Hisama (2005) described a 7-generation family in which multiple members were affected with a complicated neurologic phenotype including variable features of neuropathy, myotonia, and periodic paralysis. The same family had been described in the medical literature since 1934. The proband had late-onset demyelinating Charcot-Marie-Tooth disease (CMT1B; 118200), muscle cramping, and myotonia. His sister had hyperkalemic periodic paralysis, and his father had severe childhood-onset CMT and periodic paralysis. Multiple other relatives had similar features of 1 or both disorders. Molecular analysis identified a missense mutation in the MPZ gene (159440) in the proband and a missense mutation in the SCN4A gene (603967.0001) in the sister; the father was deceased. One other family member tested had the MPZ mutation, and 4 other family members had the SCN4A mutation. Hisama (2005) commented on the unusual occurrence of 2 genetically unlinked neurologic disorders in this family and emphasized the diagnostic difficulties.

In a female infant with severe fatal neonatal nondystrophic myotonia and overlapping features of PMC and HYPP, Gay et al. (2008) identified a heterozygous mutation (N1297K; 603967.0027) in the SCN4A gene.

▼ Genotype/Phenotype Correlations
Miller et al. (2004) identified mutations in the SCN4A gene in 30 of 47 (64%) kindreds with HYPP; 10 kindreds had the T704M (603967.0001) mutation and 10 had the M1592V (603967.0002) mutation. The average age at onset in patients with mutations was 2 years, compared to 14 years in those without mutations. Clinical myotonia occurred in 74% of patients with mutations and 55% of patients without mutations. Muscle biopsy showed vacuolar myopathy in 67% of patients with mutations. Patients with the T704M mutation had onset before age 1 year, had increased frequency of attacks compared to others, and had a 50% chance of favorable response to acetazolamide. In a diagnostic flow chart for the periodic paralyses, Miller et al. (2004) indicated that HYPP shows early onset and is characterized by frequent attacks lasting less than 24 hours with increased serum potassium levels.

▼ Nomenclature
Lehmann-Horn et al. (1993) suggested the term 'sodium channel disease' to encompass the different allelic syndromes caused by SCN4A mutations.

▼ Animal Model
In Quarter horses, Rudolph et al. (1992) found tight linkage of hyperkalemic periodic paralysis to the SCN4A gene, indicating that it is an authentic model of the human disease. Rudolph et al. (1992) identified a phe-to-leu mutation in transmembrane domain IVS-3 of the SCN4A gene as the cause of the horse disease. The experience reflects the adverse effect of purposeful breeding in thoroughbreds; only 4 stallions were said to be responsible for 30% of the gene pool. Quarter horses, the most popular equine breed in the United States, were originally bred in the 1600s to run the one-quarter mile. Pronounced muscularity was a desirable trait and frequently mentioned in the descriptions of the breed. It has been suggested that the spontaneous electrical activity detected by electromyography in HYPP-afflicted horses may lead to the muscular hypertrophy characteristic of this line. HYPP in horses as in humans shows dominant inheritance, potassium induction of attacks, elevated serum potassium during attacks, and membrane potential abnormalities in isolated muscle cells.

Hayward et al. (2008) introduced a missense substitution corresponding to the human M1592V mutation into the mouse Scn4a gene and found that few homozygous mutant (m/m) mice survived and those that did showed fixed limb weakness, muscle atrophy, and abnormal muscle morphology. Heterozygous (+/m) mice showed only a mild myopathy at 4 months of age, but myopathic changes developed with age and included electrical myotonia, fiber type switching to a more oxidative type, size variation, and internalized nuclei, and +/m muscle developed less tetanic force and exhibited slower relaxation compared with muscle from wildtype controls. Rapid and sustained weakness of isolated mutant muscle was induced when the extracellular K+ concentration was increased to that observed in exercising human muscle interstitium, and weakness was exacerbated by lowering extracellular Ca(2+) and by partial inhibition of the Na+/K+ pump. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, particularly in the presence of high extracellular K+. Hayward et al. (2008) concluded that this myotonia is consistent with persistent Na+ influx through the noninactivating mutant Na+ channel that mildly depolarizes the membrane and thereby increases excitability.

Tags: 17q23.3