BACKGROUND AND PURPOSE: Hyperkalemic periodic paralysis (hyperKPP) is a muscle sodium-ion channelopathy characterized by recurrent paralytic attacks. A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability. However, little is known about the pathology of hyperKPP-induced fixed weakness, including the pattern of muscle involvement. The aim of this study was to characterize the patterns of muscle involvement in hyperKPP by whole-body magnetic resonance imaging (MRI). METHODS: We performed whole-body muscle MRI in seven hyperKPP patients carrying the T704M mutation in the SCN4A skeletal sodium-channel gene. Muscle fat infiltration, suggestive of chronic progressive myopathy, was analyzed qualitatively using a grading system and was quantified by the two-point Dixon technique. RESULTS: Whole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals. Muscle involvement followed a selective pattern, primarily affecting the posterior compartment of the lower leg and anterior thigh muscles. The muscle fat fraction increased with patient age in the anterior thigh (r=0.669, p=0.009), in the deep posterior compartment of the lower leg (r=0.617, p=0.019), and in the superficial posterior compartment of the lower leg (r=0.777, p=0.001). CONCLUSIONS: Our whole-body muscle MRI findings provide evidence for chronic progressive myopathy in hyperKPP patients. The reported data suggest that a selective pattern of muscle involvement-affecting the posterior compartment of the lower leg and the anterior thigh-is characteristic of chronic progressive myopathy in hyperKPP.
Channelopathies ; Humans ; Leg ; Magnetic Resonance Imaging* ; Muscles ; Muscular Atrophy ; Muscular Diseases* ; Paralysis, Hyperkalemic Periodic* ; Pathology ; Thigh

In cases of hyperkalemia with preserved renal function, the differential diagnoses that should be considered are drug-related disorders, primary tubular disease, and hormonal diseases including primary adrenal insufficiency. Addison's disease represents a rare disorder characterized by primary adrenal failure, general weakness, poor appetite, nausea, dizziness, and hyperpigmentation. It may also cause fatal adrenal crisis, involving hypotension, loss of consciousness, hyperkalemia, or hyperkalemic periodic paralysis under stressful conditions. We describe herein the case of a 54-year-old Korean male who developed Addison's disease, due to adrenal tuberculosis, in addition to painless thyroiditis, which led to hyperkalemic periodic paralysis.
Addison Disease* ; Appetite ; Diagnosis, Differential ; Dizziness ; Humans ; Hyperkalemia ; Hyperpigmentation ; Hyperthyroidism ; Hypotension ; Male ; Middle Aged ; Nausea ; Paralysis, Hyperkalemic Periodic* ; Thyroid Gland* ; Thyroiditis* ; Tuberculosis ; Unconsciousness

Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype.
Acetazolamide ; Adolescent ; Channelopathies ; Humans ; Hydrochlorothiazide ; Hyperkalemia ; Muscle, Skeletal ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Parents ; Phenotype ; Sodium ; Sodium Channels

Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype.
Acetazolamide ; Adolescent ; Channelopathies ; Humans ; Hydrochlorothiazide ; Hyperkalemia ; Muscle, Skeletal ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Parents ; Phenotype ; Sodium ; Sodium Channels

Hyperkalemic periodic paralysis is characterized by episodic flaccid paralysis of the skeletal muscles due to an increase in serum potassium concentrations. Primary hyperkalemic periodic paralysis is caused by point mutations in SCN4A, encoding a voltage-gated skeletal muscle sodium channel. However, hyperkalemia-related diseases, such as renal failure, adrenal insufficiency, hypoaldosteronism, and chronic diuretic use, can induce secondary hyperkalemic periodic paralysis. Diagnosis of this disease is based on clinical features, nerve conduction studies, and a DNA sequence analysis. In cases of diagnostic uncertainty, a provocation test can be used to ensure the correct diagnosis. Here, we report a case of secondary hyperkalemic periodic paralysis with hyperkalemia that was induced by diabetic nephropathy, and review the relevant literature.
Adrenal Insufficiency ; Diabetic Nephropathies ; Dietary Sucrose ; Hyperkalemia ; Hypoaldosteronism ; Muscle, Skeletal ; Neural Conduction ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Point Mutation ; Potassium ; Renal Insufficiency ; Sequence Analysis, DNA ; Sodium Channels ; Uncertainty

BACKGROUND: Hyperkalemic periodic paralysis (HYPP) is characterized by episodic flaccid paralysis of skeletal muscles that is exacerbated by the consumption of potassium-containing foods, fasting, or rest following exercise. HYPP is largely diagnosed based on clinical features and electrodiagnostic findings. METHODS: Seven patients from three families were assessed by interviews and clinical examinations. Standardized protocols comprising short and long exercise tests were applied to 15 unaffected control subjects and the 7 patients with familial HYPP. RESULTS: Exercise of short duration induced an immediate increase in the amplitude of the compound motor action potential (CMAP) in the patients, and this was significantly larger and lasted longer than that observed in controls within 50 seconds (p<0.05). A long exercise test induced a large increase in the CMAP amplitude in patients immediately after exercise completion, which decreased to normal values with 1 minute. In contrast, controls showed a decreased CMAP amplitude immediately after exercise, which subsequently also returned to the normal value. Precipitants of attacks were vigorous exercise and hunger in all patients, and cold and potassium-rich foods in five patients. All patients experienced clinical myotonia at the eyelids or lips. CONCLUSIONS: We conclude that exercise tests may be helpful in confirming abnormal excitability of muscle membranes in patients with HYPP. We have described the clinical and electromyographic characteristics in familial HYPP with the Met1592Val mutation in the SCN4A gene.
Action Potentials ; Cold Temperature ; Electromyography ; Exercise Test ; Eyelids ; Fast Foods ; Humans ; Hunger ; Lip ; Membranes ; Muscle, Skeletal ; Muscles ; Myotonia ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Reference Values

BACKGROUND AND PURPOSE: Mutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects. METHODS: Six unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients' DNA. We also analyzed the patients' clinical history, physical findings, laboratory tests, and responses to treatment. RESULTS: We identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation. CONCLUSIONS: Clinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.
Channelopathies ; Diagnosis, Differential ; DNA ; Humans ; Hypokalemic Periodic Paralysis ; Muscle, Skeletal ; Mutation, Missense ; Myasthenic Syndromes, Congenital ; Myotonia ; Myotonia Congenita ; Myotonic Disorders ; Paralyses, Familial Periodic ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Sequence Analysis ; Sodium ; Sodium Channels

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

Hyperkalemic periodic paralysis and paramyotona congenita share common clinical manifestations, such as autosomal dominant diseases with missense mutations at a gene encoding alpha-subunit of skeletal muscle voltage sensitive sodium channel (SCN4A). Exercise and cold provocation tests are physiological phenomena of clinical characteristics of these diseases. The authors experienced a case with hyperkalemic periodic paralysis and performed these tests comparing them with a patient with hypokalemic periodic paralysis and a normal person. Significant decremental changes of CMAPs were found by both tests in the case with hyperkalemic periodic paralysis, compared with those in a case of hypokalemic periodic paralysis or normal control. In conclusion, we suggest that exercise and cold provocation tests may be useful for the differential diagnosis between hyperkalemic periodic paralysis and hypokalemic periodic paralysis.
Diagnosis, Differential ; Electrodiagnosis ; Genes, vif ; Humans ; Hypokalemic Periodic Paralysis ; Muscle, Skeletal ; Mutation, Missense ; Paralysis ; Paralysis, Hyperkalemic Periodic* ; Physiological Phenomena ; Sodium Channels

We report clinical characteristics of seven members in a family with hyper kalemic periodic paralysis (HYPP). Duration of periodic paralysis were noted for 3 to 7 days in adult patients, but for 20 to 45 minutes in children with the disease. The paralysis were usually appeared after severe exercise, pregnancy, heavy watermelon intake, and exposure to cold. Adult patients experienced paramyotonic phenomenon, when they exposed to cold. The paralysis were relieved after continuous movement, when they felt a weakness in extremities after exercise. Appearance and aggravation of symptoms were correlated with increased potassium levels in the blood on provocation tests for HYPP. The potassium levels increased within the upper limit of normal range except one patient. The increased potassium levels fell to previous level, when the paralysis was improved. The number of onset and duration of symptoms were decreased after medication with acetazolamide 250 mg a day.
Acetazolamide ; Adult ; Child ; Citrullus ; Extremities ; Humans ; Paralysis ; Paralysis, Hyperkalemic Periodic* ; Potassium ; Pregnancy ; Reference Values