Familial periodic paralysis (FPP) is inherited as a dominant trait, and the intermittent failure to maintain the skeletal muscle resting potential is due to mutations in the genes coding for the voltage-gated ion channels. Because several variants of FPP have been delineated on the bases of clinical features, the expectation was that these variants might be due to involvement of different classes of ion channels. The reality of the situation has proven to be more complicated. Mutation-induced defects in the same channel may give rise to diverse phenotypes (phenotypic heterogeneity) and, conversely, mutation in different channel genes may produce a common phenotype (genetic heterogeneity). Regardless of which type of ion channel is defective, the final common pathway is the depolarization-induced loss of muscle excitability; gain-of-function defect in voltage-gated Na channel may cause myotonia, periodic paralysis or both, clinical features of hyperkalemic periodic paralysis and paramyotonia congenita, and loss-of-function defects in voltage-gated Na and Ca channel and K channel may be responsible for periodic paralysis, cardiac arrhythmia or both in hypokalemic periodic paralysis or Andersen's syndrome, respectively. This review focuses on the clinical features, molecular genetic defects, and pathophysiologic mechanisms that underlie FPP.
Arrhythmias, Cardiac ; Channelopathies* ; Clinical Coding ; Genetics* ; Hypokalemic Periodic Paralysis ; Ion Channels ; Membrane Potentials ; Molecular Biology ; Muscle, Skeletal ; Myotonia ; Myotonic Disorders ; Paralyses, Familial Periodic* ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Phenotype

Familial hypokalemic periodic paralysis (HOPP) is a rare autosomal-dominant disease characterized by reversible attacks of muscle weakness occurring with episodic hypokalemia. Mutations in the skeletal muscle calcium (CACNA1S) and sodium channel (SCN4A) genes have been reported to be responsible for familial HOPP. Fifty-one HOPP patients from 20 Korean families were studied to determine the relative frequency of the known mutations and to specify the clinical features associated with the identified mutations. DNA analysis identified known mutations in 12 families: 9 (75%) were linked to the CACNA1S gene and 3 (25%) to the SCN4A gene. The Arg528His mutation in the CACNA1S gene was found to be predominant in these 12 families. Additionally, we have detected one novel silent exonic mutation (1950C>T) in the SCN4A gene. As for a SCN4A Arg669His mutation, incomplete penetrance in a woman was observed. Characteristic clinical features were observed both in patients with and without mutations. This study presents comprehensive data on the genotype and phenotype of Korean families with HOPP.
Adolescent ; Adult ; Calcium Channels/*genetics ; Child ; Child, Preschool ; Genotype ; Humans ; Hypokalemic Periodic Paralysis/*genetics ; Infant ; *Mutation ; Phenotype ; Sodium Channels/*genetics

Adult ; Female ; Humans ; Hypokalemic Periodic Paralysis ; genetics ; Infant, Newborn ; Male ; NAV1.4 Voltage-Gated Sodium Channel ; genetics ; Pedigree ; Potassium Channels, Voltage-Gated ; genetics ; Young Adult

OBJECTIVEMutation screening was performed to a Chinese family with hypokalaemic periodic paraiysis(HOKPP) for locating the corresponding mutations of gene and for specifying the clinical features associated with mutations.

METHODSThe cilnical features of patients from HOKPP family were summurized. Techniques of target exon PCR and direct sequencing were used to screen the mutation in CACNA1S and SCN4A genes in all numbers of the family.

RESULTSTwo patients of the family showed the typical features of HOKPP: the age of disease onset is during the childhood, acetazolamide is effective to patients treated. A heterozygous point mutation 3716 (G>A) causing R1239H was found in exon 30 of CACNA1S gene of the patients, but not found in normal members of the family.

CONCLUSIONThe mutant R1239H in CACNA1S gene exists in Chinese patients with familial hypokalaemic periodic paralysis.

Adolescent ; Adult ; Base Sequence ; Calcium Channels ; genetics ; China ; DNA Mutational Analysis ; Family Health ; Female ; Humans ; Hypokalemic Periodic Paralysis ; genetics ; Male ; Mutation ; Pedigree ; Polymerase Chain Reaction

Ataxia ; genetics ; physiopathology ; Calcium Channels ; genetics ; physiology ; Epilepsy ; genetics ; physiopathology ; Genetic Diseases, Inborn ; genetics ; physiopathology ; Humans ; Hypokalemic Periodic Paralysis ; genetics ; physiopathology ; Malignant Hyperthermia ; genetics ; physiopathology ; Migraine with Aura ; genetics ; physiopathology ; Myopathy, Central Core ; genetics ; physiopathology ; Ryanodine ; metabolism ; Spinocerebellar Ataxias ; genetics ; physiopathology

The present research was aimed to investigate the relationships between the single nueleotide polymorphisms (SNPs) of CACNA1S gene 11 exon and thyrotoxic hypokalemic periodic paralysis (THPP)in the people of Han Nationality in Sichuan China. 100 male subjects were divided into four groups in this study, i.e., 22 patients with THPP, 23 patients with hypokalemic periodic paralysis (HPP), 33 patients with thyrotoxicosis but without hypokalemic periodic paralysis (NTHPP), and 22 healthy (control group) subjects. The sequences of the CACNA1S gene exon 11 polymorphisms, for the four groups respectively, were analysed by the SNPs method with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA direct sequencing. A meta-analysis of three additional studies was also performed. Three SNPs of exon 11 of the CACNA1S gene (C1491T, T1551C, C1564T) were present in all the four groups. The polymorphisms C1491T and T1551C were present in both homozygotes and heterozygotes, while the C1564T polymorphism was present only in heterozygotes. The genotype frequencies of variants at C1491T and T1551C were not significantly associated with TPP (dominant model: P=0.530 and P=0.568; allele frequency model: P=0.563 and P=0.568). A Meta-analysis yielded combined odds ratio (OR) for TPP of 2. 12 (95% CI: 0.80-5.60) at C1491T, 2.90 (95% CI: 0.71-11.78) at T1551C, and 1.61 (95% CI: 0.36-7.26) at C1564T with the dominant model. These results suggested that three SNPs of CACNA1S gene exon 11 definitely could exist but could not be associated with TPP people of Han Nationality in Sichuan.
Adult ; Base Sequence ; Calcium Channels ; genetics ; China ; ethnology ; Chromosomes, Human, Pair 11 ; genetics ; Exons ; Humans ; Hypokalemic Periodic Paralysis ; etiology ; genetics ; Male ; Molecular Sequence Data ; Polymorphism, Single Nucleotide ; Thyrotoxicosis ; complications ; genetics

Hypokalemic periodic paralysis (HOPP) is a rare disease characterized by reversible attacks of muscle weakness accompanied by episodic hypokalemia. Recent molecular work has revealed that the majority of familial HOPP is due to mutations in a skeletal muscle voltage-dependent calcium-channel: the dihydropyridine receptor. We report a 13-yr old boy with HOPP from a family in which 6 members are affected in three generations. Genetic examination identified a nucleotide 3705 C to G mutation in exon 30 of the calcium channel gene, CACNA1S. This mutation predicts a codon change from arginine to glycine at the amino acid position #1239 (R1239G). Among the three known mutations of the CACNA1S gene, the R1239G mutation was rarely reported. This boy and the other family members who did not respond to acetazolamide, showed a marked improvement of the paralytic symptoms after spironolactone treatment.
Acetazolamide/pharmacology ; Adolescent ; Arginine/chemistry ; Calcium Channels/chemistry/*genetics ; Codon ; Exons ; Family Health ; Female ; Glycine/chemistry ; Humans ; Hypokalemia/metabolism ; Hypokalemic Periodic Paralysis/*diagnosis/*genetics ; Korea ; Male ; Muscle, Skeletal/metabolism ; Mutation ; Pedigree ; Protein Structure, Tertiary ; Sequence Analysis, DNA ; Spironolactone/pharmacology

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.
Ataxia ; Bartter Syndrome ; Brugada Syndrome ; Cardiovascular System ; Channelopathies* ; Diabetes Insipidus, Nephrogenic ; Diabetes Mellitus ; Endocrine System ; Epilepsy, Generalized ; Genetics ; Hypoglycemia ; Hypokalemic Periodic Paralysis ; Immune System ; Ion Channels ; Isaacs Syndrome ; Long QT Syndrome ; Membranes ; Migraine with Aura ; Myasthenia Gravis ; Nervous System ; Neuromyelitis Optica ; Organelles ; Polycystic Kidney Diseases ; Respiratory System ; Seizures, Febrile