Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement

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.

A Case of Addison's Disease Accompanied by Painless Thyroiditis and Hyperkalemic Periodic Paralysis / 대한내과학회지

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.

Management of a patient with hyperkalemic periodic paralysis requiring coronary artery bypass grafts.

Hyperkalemic periodic paralysis (HPP) is an autosomal-dominant inherited muscle disease characterized by episodes of flaccid weakness and intermittent myotonia. There are no previous reports in the literature about anesthesia for cardiac surgery with cardiopulmonary bypass in this disorder. We describe perioperative anesthetic management for on-pump coronary artery bypass grafting in a 75-year-old man with a history of hyperkalemic periodic paralysis. This case report outlines our management strategy and the issues encountered during the perioperative period.

Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A / 소아과

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.

Familial hyperkalemic periodic paralysis caused by a de novo mutation in the sodium channel gene SCN4A / 소아과

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.

A Case of Hyperkalemic Periodic Paralysis Induced by Diabetic Nephropathy / 대한내과학회지

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.

Electrodiagnostic Findings and Clinical Characteristics of Familial Hyperkalemic Periodic Paralysis With a SCN4A Met1592Val Mutation

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.

Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy

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.

Paralisia periódica hipocalêmica na síndrome de Sjögren / Hypokalemic periodic paralysis in Sjõgren's syndrome

Na síndrome de Sjõgren, o acometimento subclínico dos túbulos renais pode afetar uma parcela significativa de pacientes. A maioria apresenta acidose tubular renal distal (tipo 1), que pode se constituir na primeira manifestação da doença auto-imune e contribuir para sua maior duração e gravidade. A depleção de potássio, resultante da acidose tubular renal distal, pode ser extremamente grave e colocar em risco a vida do paciente se não diagnosticada e tratada. A paralisia periódica hipocalêmica foi observada em quase 40 por cento dos pacientes com síndrome de Sjõgren e acidose tubular renal distal. Descrevemos, a seguir, o caso de uma paciente com diagnóstico de síndrome de Sjõgren, estabelecido há quatro anos, que apresentou amortecimento e fraqueza em membros inferiores com dificuldade respiratória. Houve agravamento dos sintomas e necessidade de internamento em Unidade de Terapia Intensiva. A admissão, verificou-se potássio sérico de 2 mEq/L. Com o diagnóstico de paralisia hipocalêmica, procedeu-se ao tratamento imediato com reposição parenteral de KCl 19,1 por cento e oxigênio suplementar (máscara). Não houve necessidade de ventilação mecânica. A paciente recebeu alta com potássio sérico corrigido para 3,4 mEq/L.

Subclinical renal tubular dysfunction in Sjõgren's syndrome can affect a significant number of patients, the majority presenting with distal renal tubular acidosis (type 1). Such findings may be the first symptom of the auto-immune disease, and can contribute for a prolonged disease duration and severity. Potassium depletion resulting from distal renal tubular acidosis can be extremely severe, and can jeopardise patient's life, if its diagnosis and treatment are delayed. Hypocalemic periodic paralysis was observed in almost 40 percent of patients who suffer from Sjõgren's syndrome and distal renal tubular acidosis. The case that follows describes a patient who was diagnosed with Sjõgren's syndrome four years ago. Three days before being admitted to hospital, the patient complained that her lower limbs were numb and weak, and that breathing was difficult. Symptoms intensified, the patient was broght to the Intensive Care Unit, where the serum potassium was 2 mEq/L at admittance. Hypocalemic paralysis was diagnosed, and the patient was immediately treated with IV KCl 19.1 percent and supplementary oxygen by mask. Mechanical ventilation was not required. The patient was discharged with serum potassium corrected to 3.4 mEq/L.

Genetics of Channelopathy: Familial Periodic Paralysis

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.

Electrophysiological Changes by Exercise and Cold Provocation Test in a Patient with Hyperkalemic Periodic Paralysis

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.

Spectrum of inherited myotonias and periodic paralyses

To study the spectrum of inherited myotonias and periodic paralyses in Saudi Arabia. Forty nine patients with electromyography confirmed mytonotic disorders and periodic paralysis were seen at King Khalid University Hospital between January 1985 and January 1998. Data was analyzed and available patients reassessed in order to document fully the various clinical features and ascertain the diagnosis and mode of inheritance. There are 11 patients with Thomsen's disease; 21 patients with Becker's disease, most of them had an early onset of 2-3 years; 12 patients with myotonic dystrophy; and 5 Filipino patients with periodic paralyses, 3 of them with associated thyrotoxicosis. The spectrum of these disorders is similar to that described in western reports, apart from 2 main differences. First, is the clear predominance of Beckeri's disease [45%] which has a lower age of onset. This is probably the result of the high local consanguinity rate. Secondly is the absence of periodic paralysis in Saudis, while some patient had associated thyrotoxicosis, which is well recognized in Far East populations. These disorders are poorly studied in Saudi Arabia deserve further epidemiological and genetic assessment

Spectrum of inherited myotonias and periodic paralyses

To study the spectrum of inherited myotonias and periodic paralyses in Saudi Arabia. Forty nine patients with electromyography confirmed myotonic disorders and periodic paralysis were seen at King Khalid University Hospital between January 1985 and January 1998. Data was analyzed and available patients reassessed in order to document fully the various clinical features and ascertain the diagnosis and mode of inheritance. There are 11 patients with Thomsen's disease; 21 patients with Becker's disease, most of them had an early onset of 2-3 years; 12 patients with myotonic dystrophy; and 5 Filipino patients with periodic paralyses, 3 of them with associated thyrotoxicosis. The spectrum of these disorders is similar to that described in western reports, apart from 2 main differences. First, is the clear predominance of Becker's disease [45%] which has a lower age of onset. This is probably the result of the high local consanguinity rate. Secondly is the absence of periodic paralysis in Saudis, while some patients had associated thyrotoxicosis, which is well recognized in Far East populations. These disorders are poorly studied in Saudi Arabia and deserve further epidemiological and genetic assessment

A family with hyperkalemic periodic paralysis

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.

A Case of Adynamia Episodica Hereditaria

This is a case report of 32 year-old man with adynamia episodica hereditaria. Adynamia episodica hereditaria is a rare disorder characterized by episodic atacks of muscle weakness occuring in association with an increased serum concentration of potassium. The disorder is usually inherited as autosomal dominant trait and myotonia can be seen in much of the cases. And it is uncertain whether adynamia episodica hereditaria and paramyotonia congenita are variable manifestations of the same disease or not. We now reporta case of adynamia episodica hereditaria with myotonia with the special reference to pathophysiology of paralysis and myotonic symptom.

A Case of Adynamia Episodica Hereditaria

Four members of a family suffering from frequent attacks of flaccid paralysis with asymptomatic myotonia were evaluated. There was an autosomal dominant pattern of inheritance and their earliest symptoms were noticed between 1-3 years of age. The plasma potassium level rised during the attack and an EMG demonstrated myotonic discharge. Treatment with acetazolamide was beneficial. These findings were consistent with adynamia episodica hereditaria. The clinical features and pathogenesis were also described.