Atypical presentation of hypokalemic periodic paralysis: A case report

Hypokalemic periodic paralysis (hypoPP) is a rare, autosomal dominant, genetic disorder associated with pathogenic variants in coding for skeletal muscle calcium and sodium channels (e.g., CACNA1S and SCN4A, respectively).1 Patients experience attacks of focal or global muscle weakness associated with concomitant hypokalemia.1, 2 Attack onset usually occurs between ages 5 and 35 y.1 Permanent weakness often develops in adulthood and progresses slowly.1, 2 A de novo non-synonymous, heterozygous, pathogenic variant in exon 21 of CACNA1S was previously identified in two patients with younger ages of onset and more severe clinical presentations than typically observed in patients with hypoPP.3, 4 We report the progression of disease and treatment course for one of these patients—a 15-y-old female. Since she started walking at age 12 mo, her gait was abnormal, with right foot inversion and frequent toe-walking. She also had fine motor difficulties and mild speech delays. At age 12 mo, she had a transient episode of unsteady gait during a viral upper respiratory infection. She recovered without intervention but subsequently was noted to have ankle contractures, scoliosis, and recurrent episodes characterized by difficulty walking, frequent falls, and inability to stand up from the floor. These episodes were triggered by illness, large carbohydrate meals, cold temperatures, prolonged sitting, or poor sleep quality. Episodes occurred two to three times per week, on average, and lasted from ~30 min to ~4 h. When she was ~18 mo of age, her mother recorded an episode of unsteady gait (Video S1), and the patient subsequently underwent serum creatine kinase testing, thyroid studies, basic cerebrospinal fluid studies, brain and full spine magnetic resonance imaging (MRI), electroencephalogram, serial electrocardiograms, and echocardiogram, all of which were normal. Her serum potassium level was normal when asymptomatic but low (e.g., 2.5 mEq/L) during attacks. Nerve conduction studies showed decreased compound muscle action potential amplitudes in the arms and legs, normal sensory responses, and normal electromyography. Chromosomal microarray, karyotype, and targeted gene testing for periodic paralysis were unrevealing. Differential diagnosis included paroxysmal dyskinesia (but treatment with carbamazepine worsened the episodes), paroxysmal dystonia (but L-dopa did not provide improvement), and hypoPP (but acetazolamide worsened episode frequency and severity). After trio whole-exome sequencing showed a de novo pathogenic variant in exon 21 of the CACNA1S gene (c.2691G > T; p.R897S),3 she was diagnosed with hypoPP at 3 y of age. After her diagnosis, she continued to have attacks ranging from mild weakness to full paralysis. Severe episodes typically lasted less than 1 h, but milder episodes could last for several days. She has had two to three emergency department visits annually due to prolonged attacks associated with dysphagia and occasionally respiratory insufficiency. Also, she has experienced progressive global weakness and severe muscle atrophy of the lower extremities, resulting in loss of ambulation at age 11 y. Since early childhood, most attacks have affected the lower extremities predominantly. She has received potassium supplements, which helped to decrease attack frequency and halt acute attacks. Treatment with acetazolamide 250 mg/d was associated with increased frequency and severity of attacks; a switch to eplerenone 25 mg/d provided a slight improvement in attack frequency. When she was 12 y old, the patient started dichlorphenamide (DCP) 50 mg twice daily. Other medications include potassium chloride supplementation 1.5 mEq/kg/d (in three divided doses) and potassium bicarbonate 20 mEq as needed for acute management of episodic weakness. This treatment regimen has improved her overall strength and decreased the frequency and severity of attacks compared with prior therapies. No severe episodes of weakness have been reported for more than 3 y. An MRI of both upper extremities performed 2 y after DCP was initiated found no intramuscular edema and no evidence of muscle atrophy. Although patients with hypoPP may develop progressive myopathy, permanent weakness does not usually develop until middle adulthood and increases with age.2, 5, 6 This patient had a severe clinical course with loss of ambulation at age 11 y, joint contractures, and complications leading to frequent hospitalizations. The efficacy of DCP for hypoPP attacks has been demonstrated in randomized controlled trials1; however, reducing the frequency of episodic attacks in patients with hypoPP may not prevent the development of permanent weakness.7 The inconsistent response to two drugs of the same class was surprising. This case suggests that poor response to one carbonic anhydrase inhibitor does not preclude an empiric trial with another drug in this class. Diana Castro: Conceptualization; writing – original draft; writing – review and editing. Alicia Henriquez: Conceptualization; writing – original draft; writing – review and editing. Editorial assistance was provided under the direction of the authors by Synchrony Medical Communications, LLC, West Chester, PA, USA, and funded by Strongbridge Biopharma (now Xeris Biopharma). At the time of this report, the authors' affiliation was The University of Texas Southwestern, Children's Health, Dallas, Texas, USA. None of the authors have any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Data sharing not applicable - no new data generated Video S1. Episode of unsteady gait, recorded when the patient was ~18 months of age. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.