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CASE SERIES
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Familial hypokalemic periodic paralysis: A case series and review


1 Flushing Hospital Medical Center, New York City, New York, USA
2 Nephrology Division, GMC, Secunderabad, India
3 Department of Medicine, GMC, Baramulla, Jammu and Kashmir, India
4 Pathology Division, GMC, Srinagar, Jammu and Kashmir, India

Date of Submission31-Jul-2020
Date of Decision25-Oct-2020
Date of Acceptance14-Dec-2020

Correspondence Address:
Farhat Abbas,
Pathology Division, GMC, Srinagar - 190 011, Jammu and Kashmir
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_417_20

  Abstract 


The periodic paralyses (PPs) are a group of rare neuromuscular disorders related to muscle ion channels, presenting with episodes of sudden muscle weakness. The majority of cases of PP are inherited, resulting from genetic mutations in the subunits of channel proteins of the sodium, potassium, or calcium channels or the SCL4A1 protein. We describe two siblings, a 15-year-old male and an 11-year-old male, presenting with complaints of weakness. Both patients had consumed a large carbohydrate-rich meal the previous night with a history of similar episodes of weakness suggesting a diagnosis of PP. Laboratory investigations were unremarkable except for hypokalemia in both patients, and they were started on potassium supplementation, which resulted in the resolution of symptoms. The elder sibling was started on acetazolamide for prophylaxis, but due to non-response, was put on spironolactone which he tolerated well. Genetic mutation analysis confirmed the diagnosis of familial hypokalemic periodic paralysis (FHPP) with a p.Arg672His mutation in the sodium channel, gene SCN4A (17q23.3) in both siblings. The diagnosis of PP is important to consider in patients with sudden recurring episodes of weakness or paralysis, especially in otherwise healthy adolescents/young adults. The treatment of FHPP is challenging, with cautious potassium supplementation for acute attacks. Workup for other causes should be performed, and genetic analysis is recommended to confirm the diagnosis.

Keywords: Familial, hypokalemia, periodic paralysis



How to cite this URL:
Shafi O, Latief M, Hassan Z, Abbas F, Farooq S. Familial hypokalemic periodic paralysis: A case series and review. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=319303




  Introduction Top


The periodic paralyses (PPs) are a group of rare neuromuscular disorders related to muscle ion channels, presenting with episodes of sudden muscle weakness. The symptoms are usually precipitated by fasting, heavy exercise, high-carbohydrate meals, stress, or certain medications. The majority of cases of PP are inherited, most commonly in an autosomal dominant pattern.[1] The paralyses have traditionally been classified as either hypokalemic or hyperkalemic, based on whether the attacks are associated with low or elevated serum potassium levels, respectively. The most common variety is that of hypokalemic periodic paralysis (HypoPP), with an estimated prevalence of around 1 in 100,000.[2] HypoPP was first described in the early 18th century and had been extensively studied by the second part of the 19th century. The first genetic mutation identified was reported in 1994.[1] Primary HypoPP can be familial with an autosomal dominant inheritance, where a milder phenotype is observed in females.[3],[4],[5],[6] A third of the cases are thought to arise as a result of de novo mutations.[7]


  Case Series Top


We describe two siblings presenting with episodic muscle weakness, with several family members having similar attacks of weakness.

Case 1

A 15-year-old adolescent male presented to the emergency department with complaints of weakness since early morning. He complained of weakness in all 4 extremities, rendering him incapable to get out of bed. He denied any history of diarrhea, trauma, or fever. There was no difficulty in breathing, palpitations, or change in voice. He had been at a wedding the previous night, where he consumed a large meal. His parents reported that he first experienced a brief self-resolving episode of weakness lasting a few hours at 2.5 years of age. The next episode occurred a year later, and subsequently, he has been having episodes of weakness at intervals of weeks to months. The frequency of attacks of weakness has increased to almost daily in the last couple of months. The weakness usually lasts for a few hours, although infrequently it would last an entire day. The usual trigger has been the consumption of large carbohydrate-rich meals. He denies the intake of alcoholic beverages or taking any medications. On examination, the teenager was hemodynamically stable. He was conscious and oriented. Neurological examination revealed decreased tone in all the limbs and the deep tendon reflexes could not be elicited. He was unable to perform any voluntary movements and only flickering was observed (power ⅕ in all four limbs). There were no signs of meningeal irritation, cranial nerve involvement, or cerebellar dysfunction. Examination of the cardiovascular and respiratory systems was unremarkable.

Case 2

The younger brother of case 1, 11-year-old, also presented with complaints of weakness since morning, making it difficult to complete his daily activities. There was no history of difficulty breathing or vomiting. He also had consumed a large meal the previous night. This was his second episode of weakness, almost 9 months after the first episode, which was brief, mild, and had resolved within an hour. Clinical examination including neurological examination was unremarkable except for power of ⅗ in both upper limbs and ⅘ in bilateral lower limbs.

Family history

Similar symptoms of episodic weakness were experienced by the mother and other family members on the maternal side, including one uncle, one aunt, and his maternal grandfather. There was also a history of similar illness in 2 other siblings of the affected grandfather. None of the family members had taken any treatment for the same. There was no history of similar complaints on the paternal side.

Management

Laboratory investigations for case 1 revealed hypokalemia (2.7 mEq/L), with other electrolytes in normal range [Table 1]. Electrocardiogram (EKG) showed changes of hypokalemia (flat T wave and ST-segment depression), with normal sinus rhythm. Supplemental potassium was given parenterally under close monitoring, following which the symptoms improved. Other investigations revealed a normal hemogram, kidney function tests, liver function tests, and creatine phosphokinase (CPK) level. The thyroid profile of the child was also normal. Electromyography (EMG) and nerve conduction studies performed after the resolution of the weakness were normal. Evaluation for Case 2 was unremarkable, except for mild hypokalemia (3.1 mEq/L) with a normal CPK, thyroid profile, and EKG [Table 1]. He showed a rapid resolution of symptoms with oral potassium supplementation. Based on the characteristic clinical pattern of trigger induced weakness associated with hypokalemia, with a strong family history a provisional diagnosis of familial HypoPP (FHPP) was made for both the siblings. Case 1 was started on tablet acetazolamide (250 mg twice daily) with oral potassium supplementation as prophylactic therapy along with advice regarding behavioral changes such as avoiding heavy carbohydrate-rich meals. He did not have any improvement in the episodes of weakness with acetazolamide and thus spironolactone (100 mg daily) was started which he tolerated well. At follow-up, he reported symptomatic improvement with a substantial decrease in the episodes of weakness. Case 2 was advised to avoid triggers through lifestyle changes with a plan to begin prophylactic medications if there is an increase in frequency of attacks or significant impairment in daily activities due to the weakness. Genetic mutation analysis showed that both siblings and the mother had a p.Arg672His mutation in the sodium channel, gene SCN4A (17q23.3), confirming the diagnosis of FHPP.
Table 1: Laboratory parameters at presentation

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  Discussion Top


The PPs are classified as primary or hereditary and secondary or acquired. The primary PPs are a result of genetic mutations in the subunits of channel proteins of the sodium, potassium, or calcium channels or the SCL4A1 protein, present in the skeletal muscle membrane. HypoPP, hyperkalemic PP (HyperPP), and Anderson–Tawil syndrome are the commonly recognized forms of primary PPs.[1],[8]

The most common genetic abnormality (60%–70% of cases) in HypoPP is noted in the dihydropyridine-sensitive calcium channel of the skeletal muscle, encoded by the CACNA1S gene.[1],[9] A mutation in SCN4A, a sodium channel, is seen in around 10%–20% of inherited cases, also classified as HypoPP-2 by some authors to differentiate it from the former, more common calcium channelopathy, HypoPP-1.[1],[7],[8] Recently, a novel mutation in a K channel subunit (KCNE3) has been identified in a cohort with HypoPP.[9] Other mutations have also been linked to the illness, in cases where none of the above defects are present.[7] The exact mechanism of weakness resulting from the calcium channel defects has not been delineated. The various mechanisms postulated include a decreased calcium current density with slower activation of the channels, abnormalities in excitation-contraction coupling, decreased ATP-sensitive potassium current, and a secondary calcium-sensitive channelopathy.[10],[11],[12] In contrast, the sodium channel defects produce an aberrant gating pore current, which results in altered depolarization responsible for the episodes of weakness.[13]

The episodes of weakness in HypoPP are sudden in onset, with rare involvement of bulbar, ocular, or respiratory muscles. The usual age of onset is in the later childhood or teenage years (range from 5 to 35 years), with a variable frequency of attacks (anywhere from days, weeks, to months).[7],[14] The typical duration of attacks is for several hours, although episodes can last from minutes to days in some cases. The usual triggers for the attacks are stress, rest after vigorous exercise, carbohydrate-rich meals, alcohol, and certain medications (steroids, beta-agonists, and insulin), although the episodes are known to occur spontaneously also.[7],[14] The patient has muscle weakness on clinical examination, associated with hypo- or areflexia at the time of an attack, with a normal neurological examination once the episode resolves. Many patients develop a myopathy (predominantly affecting the proximal muscles), which is often progressive, causing weakness independent of the attacks.[2],[15] Laboratory evaluation during an attack of weakness will commonly demonstrate hypokalemia, although the levels can also be normal in some cases. It is mandatory to rule out secondary causes of periodic paralysis, especially thyrotoxic PP, which is associated with profoundly low levels of serum potassium. Cardiac arrhythmias are rarely seen in HypoPP, although EKG may reveal changes of hypokalemia.[4] The diagnosis of FHPP is confirmed with genetic mutation analysis; however, no mutation is identified in around 15% of cases.[16] In such cases, provocative testing by administering a glucose load (and/or insulin), exercise, or corticotropin (adrenocorticotropic hormone) is performed under a controlled environment with careful monitoring.[17] Electromyography (EMG), if performed during an episode of weakness, reveals reduced amplitude of the compound muscle action potential (CMAP), along with decreased recruitment of motor units. In addition, EMG findings reported include increased polyphasic motor unit potentials, increased insertional activity, and reduced muscle fiber conduction velocity. In the interictal period, the "exercise test" is performed to increase the utility of EMG. The procedure involves recording CMAPs at rest after an electrical stimulus. The patient then performs 2–5 min of exercise, and CMAPs are recorded every 1–2 min subsequently.[18] A decrease in the evoked motor amplitude (by 40% or more) after 30 min of exercise is consistent with a diagnosis of PP, although it has been noted to have poor sensitivity for identifying HypoPP compared to Hyper PP.[18] Muscle biopsy is an invasive procedure, which reveals nonspecific vacuolar changes, seen in all forms of PPs and thus has limited diagnostic utility.[7] The acute management of attacks of weakness in FHPP consists of cautious potassium supplementation. The oral route is preferred, administered in incremental doses starting at 0.2–0.4 mEq/kg, and repeated at intervals of 15–30 min based on clinical, laboratory, and EKG response. In cases where oral ingestion is not possible or tolerated, intravenous administration of potassium chloride under close monitoring is warranted.[19] All patients should be educated about interventions that may help prevent attacks such as avoiding specific triggers, consuming low-carbohydrate diets, and the avoidance of vigorous exercise. Prophylactic medications help improve the quality of life and morbidity and mortality associated with FHPP and its complications.[20] Carbonic anhydrase inhibitors (CAIs) are effective in preventing or reducing the frequency of attacks in the majority of patients with PP. Although the mechanism of action is not exactly known, acetazolamide is thought to affect the potassium channels in skeletal muscles.[2],[7] Acetazolamide administration paradoxically decreases serum potassium; thus, supplemental potassium is often coprescribed in patients with HypoPP. Dichlorphenamide, a lesser known CAI, is approved by the US food and drug administration for HypoPP and is the only medication that demonstrated effectiveness in a randomized double-blind placebo-controlled trial.[21],[22] Those cases with mutations in the SCN4A gene are less likely to respond to acetazolamide compared to those with calcium channel mutations as per one review,[23] which is consistent with our patient (Case 1) having a poor response to acetazolamide. Potassium-sparing diuretics, such as spironolactone, triamterene, and eplerenone, have also been used as a preventive treatment in HypoPP.[15] Gynecomastia is a known side effect of spironolactone, while eplerenone has fewer hormonal interactions. Other medications that have been used in HypoPP include verapamil, topiramate, and pinacidil.[24],[25]

Furthermore, caution should be exercised in the use of inhalation anesthetics and succinylcholine in patients with HypoPP, given the potential association between malignant hyperthermia and hypokalemia.[20]


  Conclusion Top


The siblings had recurrent episodes of weakness with a history of similar attacks in other family members. The clinical features, hypokalemia, and pattern of inheritance were characteristic for FHPP, and the acute weakness resolved completely with potassium replacement in both cases. Although a rare disorder, the diagnosis of periodic paralysis is important to consider in patients with sudden recurring episodes of weakness or paralysis, especially in otherwise healthy adolescents/young adults. Workup for other causes should be performed, and genetic analysis is recommended to confirm the diagnosis.

The treatment of FHPP is challenging, given the paucity of clinical trials and is based mostly on anecdotal reports. There is a need to better understand the genetics of these disorders and its relationship to phenotype and various therapeutics.

Consent

Patients have consented for the publication of this case series.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Statland JM, Fontaine B, Hanna MG, Johnson NE, Kissel JT, Sansone VA, et al. Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve 2018;57:522-30.  Back to cited text no. 1
    
2.
Fontaine B. Periodic paralysis. Adv Gen 2008;63:3-23.  Back to cited text no. 2
    
3.
Fontaine B, Lapie P, Plassart E, Tabti N, Nicole S, Reboul J, et al. Periodic paralysis and voltage-gated ion channels. Kidney Int 1996;49:9-18.  Back to cited text no. 3
    
4.
Ober KP. Thyrotoxic periodic paralysis in the United States. Report of 7 cases and review of the literature. Medicine 1992;71:109-20.  Back to cited text no. 4
    
5.
Kung AW. Clinical review: Thyrotoxic periodic paralysis: A diagnostic challenge. J Clin Endocrinol Metab 2006;91:2490-5.  Back to cited text no. 5
    
6.
Ke Q, Luo B, Qi M, Du Y, Wu W. Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. Muscle Nerve 2013;47:41-5.  Back to cited text no. 6
    
7.
Venance SL, Cannon SC, Fialho D, Fontaine B, Hanna MG, Ptacek LJ, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain 2006;129:8-17.  Back to cited text no. 7
    
8.
Finsterer J. Primary periodic paralyses. Acta Neurol Scand 2008;117:145-58.  Back to cited text no. 8
    
9.
Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, et al. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 2009;72:1544-7.  Back to cited text no. 9
    
10.
Morrill JA, Brown RH Jr., Cannon SC. Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H. The Journal of neuroscience. Official J Soc Neurosci 1998;18:10320-34.  Back to cited text no. 10
    
11.
Tricarico D, Servidei S, Tonali P, Jurkat-Rott K, Camerino DC. Impairment of skeletal muscle adenosine triphosphate-sensitive K+channels in patients with hypokalemic periodic paralysis. J Clin Invest 1999;103:675-82.  Back to cited text no. 11
    
12.
Ruff RL. Insulin acts in hypokalemic periodic paralysis by reducing inward rectifier K+ current. Neurology 1999;53:1556-63.  Back to cited text no. 12
    
13.
Francis DG, Rybalchenko V, Struyk A, Cannon SC. Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia. Neurology 2011;76:1635-41.  Back to cited text no. 13
    
14.
Cannon SC. Channelopathies of skeletal muscle excitability. Compr Physiol 2015;5:761-90.  Back to cited text no. 14
    
15.
Weber F, Lehmann-Horn F. Hypokalemic Periodic Paralysis 2002 Apr 30. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1338/. [Last accessed on 2020 May 11; Last updated on 2018 Jul 26].  Back to cited text no. 15
    
16.
Sternberg D, Maisonobe T, Jurkat-Rott K, Nicole S, Launay E, Chauveau D, et al. Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A. Brain 2001;124:1091-9.  Back to cited text no. 16
    
17.
Cannon SC, George AL. Pathophysiology of myotonia and periodic paralysis. In: Asbury AK, McKhann GM, McDonald WI, Peter J. Goadsby, McArthur JC et al., editors. Diseases of the Nervous System. 3rd ed.. Cambridge: Cambridge University Press; 2002. p. 1183.  Back to cited text no. 17
    
18.
McManis PG, Lambert EH, Daube JR. The exercise test in periodic paralysis. Muscle Nerve 1986;9:704-10.  Back to cited text no. 18
    
19.
Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgrad Med J 1999;75:193-7.  Back to cited text no. 19
    
20.
Caciotti A, Morrone A, Domenici R, Donati MA, Zammarchi E. Severe prognosis in a large family with hypokalemic periodic paralysis. Muscle Nerve 2003;27:165-9.  Back to cited text no. 20
    
21.
Tawil R, McDermott MP, Brown R Jr., Shapiro BC, Ptacek LJ, McManis PG, et al. Randomized trials of dichlorphenamide in the periodic paralyses. Ann Neurol 2000;47:46-53.  Back to cited text no. 21
    
22.
U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Keveyis (Dichlorphenamide) NDA 011366/S-030 Approval Letter, August 07, 2015. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/011366Orig1s030ltr.pdf. [Last accessed on 2020 May 31].  Back to cited text no. 22
    
23.
Matthews E, Portaro S, Ke Q, Sud R, Haworth A, Davis MB, et al. Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype. Neurology 2011;77:1960-4.  Back to cited text no. 23
    
24.
Fiore DM, Strober JB. Treatment of hypokalemic periodic paralysis with topiramate. Muscle Nerve 2011;43:127-9.  Back to cited text no. 24
    
25.
Sansone V, Meola G, Links TP, Panzeri M, Rose MR. Treatment for periodic paralysis. Cochrane Database Syst Rev 2008;1:CD00504  Back to cited text no. 25
    



 
 
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