Familial Hypokalemic Periodic Paralysis in Blacks VICTOR A. CORBETT, M.D., and FRANK Q. NUTTALL, M.D., Ph.D., F.A.C.P., Saint Paul, Minnesota, and Minneapolis, Minnesota
Two cases of familial hypokalemic periodic paralysis in Negro brothers occurred, and—because this has been reported to be an unusual disease among blacks—the family pedigree was investigated. Histories were obtained on 79 family members in four generations. Twenty seven ( 3 4 % ) had symptoms of periodic paralysis or weakness. As far as we could determine, there were no Caucasian ancestors.
HYPOKALEMIC
PERIODIC
PARALYSIS
is a relatively
rare
disease characterized by episodic attacks of flaccid paralysis most commonly involving only the skeletal muscles of the extremities, and it tends to be familial. It has been reported most frequently in Caucasians. This disorder is considered to be extremely rare in Negroes. A review of the literature showed only two reports. One, an abstract, summarizes an electrophysiologic study on four members of a Negro family in which there were six members with symptoms ( 1 ) . The other is a single case reported as a letter to the editor ( 2 ) . We have recently seen two Negro brothers with documented hypokalemic periodic paralysis, and investigation of the family pedigree showed a very high prevalence of the disease. As far as we can determine, the seven previously reported Negro patients are not members of this pedigree. Case Reports PATIENT 1
A 24-year-old black man was admitted to the Minneapolis Veterans Administration Hospital on 28 August 1970 with a history of sudden onset of paralysis of his upper and lower extremities. The day before admission, he had engaged in unusually heavy manual labor and, after work had played a strenuous game of football. Also, before going to bed, he had eaten a large bowl of ice cream. At 0300 he awoke and found he was unable to move his arms or legs. Initially he was not particularly surprised or concerned because he had many relatives with a similar history. However, early in the afternoon of the same day, a maternal aunt, with whom he was living, became concerned because his symptoms had not cleared and decided to bring him to the emergency room. An examination by the emergency room physician showed • From the Endocrine-Metabolic Section, Veterans Administration Hospital, and the Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Annals of Internal Medicine 83:63-65, 1975
Downloaded from https://annals.org by Duke Medical Library user on 01/10/2019
flaccid paralysis of the upper and lower extremities, absent deep tendon reflexes, normal sensory findings, and intact cranial nerves. Despite the striking paralysis, he was not anxious. Vital signs were blood pressure, 125/75 mm Hg; pulse, 80; respirations, 16. The remainder of the examination showed unremarkable results. A serum potassium was 1.5 meq/litre; sodium, 138 meq/litre; chloride, 105 meq/ litre; and carbon dioxide combining power, 22 meq/litre. His chemistry profile was normal with the exception of a serum glutamic oxalacetic transaminase of 69 Karmen units/ml (normal, 10 to 4 0 ) . Protein-bound iodine was 8 . 5 ^ / 1 0 0 ml, and repeat was 4.3 fxg/\00 ml (normal, 4.0 to 8.0). Serum total thyroxine was 8.5 ^g/100 ml (normal, 6 to 12) and T 3 resin uptake, 27% (normal, 25% to 3 5 % ) . Thyroxine binding globulin was normal. Hemoglobin, leukocyte count, and urinalysis were within normal limits. An electrocardiogram showed first degree atrioventricular block, T wave depression, and a Q-T interval of 0.44. Two days after admission, while on a 120 meq Na and 60 meq K diet supplemented with 45 meq KC1, urinary excretion of Na and K was 435 meq/24 h and 113 meq/ 24 h, respectively. A total of 240 meq of potassium was given orally and intravenously in the first 24 hours after admission. He then was given a normal diet. Twenty-four hours after admission, he could move all extremities but had mild residual weakness that lasted another day. Serum potassium was 5.1 meq/litre. He was discharged on acetazolamide 250 mg twice daily. Subsequently he has had only one episode of mild weakness in July 1972, at which time his serum K was 2.5 meq/litre. He has been followed by the Metabolic Section of the Minneapolis Veterans Hospital and has been asymptomatic for the past 28 months. PATIENT 2
A 23-year-old black man (brother of Patient 1), was referred to the Minneapolis Veterans Hospital from Great Lakes Naval Hospital, where he had been diagnosed as having hypokalemic periodic paralysis. He gave a history of having been in good health until September 1970. At that time, 4 days after surgery for a giant cell tumor of the left great toe, he suddenly developed weakness of both lower extremities. The cause of paralysis was not determined, and he spontaneously recovered over the next 2 weeks without specific therapy. In December 1971, he again had sudden onset of weakness involving both upper and lower extremities. Neurologic examination at that 63
Figure 1 . Pedigree of family kindred with hypokalemic periodic paralysis.
time showed a flaccid paralysis with absent deep tendon reflexes and normal sensory findings. Again he was treated nonspecifically and had a spontaneous recovery. Both episodes occurred while he was stationed in the South Pacific. On 7 July 1972, after running one mile he again had sudden onset of paralysis of upper and lower extremities with normal sensory modalities. He was seen at the Military Hospital in Okinawa and found to have a serum potassium of 2.0 meq/litre. He was treated with intravenous KC1, and there was rapid improvement in symptoms. He was started on acetazolamide and then transferred to Great Lakes Naval Hospital for further work-up. At the Great Lakes Naval Hospital, physical examination showed no abnormalities. The following laboratory studies showed normal results: serum electrolytes, 24hour urinary electrolytes, serum calcium, phosphorus, fasting blood sugar, hemoglobin, leukocyte count, urinalysis, total serum thyroxine, and I131 uptake. An electromyogram was interpreted as being normal. Creatine phosphokinase was slightly elevated at 111 IU/litre (normal, less than 90 IU/litre). An attempt to induce paralysis with intravenous insulin was tried, with a fall in serum potassium occurring, but the patient failed to develop symptoms. He was discharged on spironolactone 25 mg four times daily, and since then he has been followed by the Metabolic Section at the Minneapolis Veterans Hospital. Spironolactone was withdrawn, and acetazolamide, 250 54
July 1975 • Annals of Internal Medicine • Volume 83 • Number 1
Downloaded from https://annals.org by Duke Medical Library user on 01/10/2019
mg twice daily, was started. He has been symptom-free since July 1972. Serum potassium has ranged from 3.4 meq/litre to 4.0 meq/litre. FAMILY KINDRED
The pedigree of the family is shown in Figure 1. To obtain information concerning the incidence of symptoms in the family, 9 members of the family other than the two index patients were contacted and interviewed. Histories could be obtained on 79 persons of four generations. Of these, 27 (34%) had a typical history of episodic weakness or paralysis. Of the 27 family members, 15 were men and 12 were women. Sixty percent of the men had complete paralysis, whereas this occurred in only 33% of the women. The remainder had episodic weakness. Because not all members of the family could be located, the actual number of persons with symptoms could be higher than indicated. It also should be pointed out that most members of the fourth generation are under the age of 20, therefore, it is expected that the incidence in this generation will increase. Because it was important to determine the racial background of the family, all members interviewed were specifically asked if they knew of any Caucasian member of the family. As far as we could determine, there were none in the four generations indicated; however, it was not possible to obtain information about prior generations. In an interview with three members of the second generation, it was determined that they had two paternal
uncles with periodic paralysis; however, their father and mother were apparently without symptoms. Incomplete penetrance would explain the lack of clinically apparent disease in the father. In Caucasians, incomplete penetrance also has been reported ( 3 ) . From the information available, it seems that 3 men in this kindred died during an attack. Despite this, it was evident that the family members had a rather casual attitude toward the disease. Most of those interviewed stated that they knew the symptoms would clear if they waited long enough. In addition to our two patients, only their mother, her brother, and his five children have seen a physician specifically about treatment; they were treated with elixir of KC1. Discussion
This disease is characterized by episodic attacks of flaccid paralysis or weakness of extremity muscles associated with hypokalemia, loss of excitability of the muscle by mechanical or electrical stimulation, and normal sensory findings. The frequency of attacks can vary from daily to yearly. The onset of attacks usually begins in the second decade and reaches a maximum frequency and intensity during the third decade. Thereafter, there usually is a decrease in frequency and severity of symptoms. However, as the patient becomes older there is often persistence of weakness between attacks (4, 5 ) . Intravenous potassium administration often dramatically decreases the duration of attacks. However, potassium does not prevent attacks or alleviate interattack weakness (4, 5). Although spironolactone has been used as treatment with varying degrees of success, acetazolamide is now considered to be the treatment of choice (4, 5 ) . It seems that this drug not only is the most effective in preventing attacks but also prevents interattack weakness ( 5 ) . The two patients presented here clearly fit the criteria for hypokalemic periodic paralysis. Interviews with other family members revealed episodes that were completely typical clinically, but these, of course, cannot be docu-
mented with absolute certainty because laboratory studies have not been done during attacks in any of these individuals. Familial hypokalemic periodic paralysis in Caucasians is inherited as an autosomal dominant trait with incomplete penetrance ( 3 ) . The data reported here in a Negro kindred also are compatible with an autosomal dominant trait, probably with incomplete penetrance. The prevalence among Caucasians has been reported to be 0.8 per 100 000 population. From the reports in the literature it would seem that the disease is virtually unknown among Negroes. There have been no case reports from Africa except for a single white South African family (6). However, the incidence of the disease in the Negro population must be reconsidered. With the 22 living members of the family reported in the present study plus the 7 previously reported family members, the incidence in blacks in the United States would be between 0.1 and 0.2 per 100 000. If other families have the same indifference to the disease reported here, the incidence may be even higher. ACKNOWLEDGMENTS: Received 7 October 1974; revision accepted 10 January 1975. • Requests for reprints should be addressed to Frank Q. Nuttall, M.D., Ph.D., Endocrine-Metabolic Section, Minneapolis Veterans Administration Hospital, 54th St. and 48th Ave. South, Minneapolis, MN 55417. References 1. GLYNN MF, TULSO PJ, OESTER YT: Studies in familial periodic
paralysis (abstract). Clin Res 10:226, 1962 2. FORMAN B: Hypokalemic periodic paralysis (letter). JAMA 216:146, 1971 3. PRATT R: Familial periodic paralysis, in The Genetics of Neurological Disorders. London, Oxford University Press, 1967, pp. 169-170 4. PEARSON CM, KALYANARAMAN K:
Periodic
paralysis, in
BURY JB, WYNGAARDEN JB, FREDRICKSON DS. New York, Mc-
Graw-Hill Book Co., 1972, pp. 1181-1207 5. GRIGGS RC, ENGEL WK, RESNICK JS: Acetazolamide treatment
of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness. Ann Intern Med 73:39-48, 1970 6. CUSINS PJ: Familial periodic paralysis (7 cases in a Durbon family). S Afr Med J 37:1181-1184, 1963
Corbettand Nuttall • Periodic Paralysis in Blacks
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The
Metabolic Basis of Inherited Diseases, 3rd ed., edited by STAN-
65
Two cases of familial hypokalemic periodic paralysis in Negro brothers occurred, and—because this has been reported to be an unusual disease among blacks—the family pedigree was investigated. Histories were obtained on 79 family members in four generations. Twenty seven ( 3 4 % ) had symptoms of periodic paralysis or weakness. As far as we could determine, there were no Caucasian ancestors.
HYPOKALEMIC
PERIODIC
PARALYSIS
is a relatively
rare
disease characterized by episodic attacks of flaccid paralysis most commonly involving only the skeletal muscles of the extremities, and it tends to be familial. It has been reported most frequently in Caucasians. This disorder is considered to be extremely rare in Negroes. A review of the literature showed only two reports. One, an abstract, summarizes an electrophysiologic study on four members of a Negro family in which there were six members with symptoms ( 1 ) . The other is a single case reported as a letter to the editor ( 2 ) . We have recently seen two Negro brothers with documented hypokalemic periodic paralysis, and investigation of the family pedigree showed a very high prevalence of the disease. As far as we can determine, the seven previously reported Negro patients are not members of this pedigree. Case Reports PATIENT 1
A 24-year-old black man was admitted to the Minneapolis Veterans Administration Hospital on 28 August 1970 with a history of sudden onset of paralysis of his upper and lower extremities. The day before admission, he had engaged in unusually heavy manual labor and, after work had played a strenuous game of football. Also, before going to bed, he had eaten a large bowl of ice cream. At 0300 he awoke and found he was unable to move his arms or legs. Initially he was not particularly surprised or concerned because he had many relatives with a similar history. However, early in the afternoon of the same day, a maternal aunt, with whom he was living, became concerned because his symptoms had not cleared and decided to bring him to the emergency room. An examination by the emergency room physician showed • From the Endocrine-Metabolic Section, Veterans Administration Hospital, and the Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Annals of Internal Medicine 83:63-65, 1975
Downloaded from https://annals.org by Duke Medical Library user on 01/10/2019
flaccid paralysis of the upper and lower extremities, absent deep tendon reflexes, normal sensory findings, and intact cranial nerves. Despite the striking paralysis, he was not anxious. Vital signs were blood pressure, 125/75 mm Hg; pulse, 80; respirations, 16. The remainder of the examination showed unremarkable results. A serum potassium was 1.5 meq/litre; sodium, 138 meq/litre; chloride, 105 meq/ litre; and carbon dioxide combining power, 22 meq/litre. His chemistry profile was normal with the exception of a serum glutamic oxalacetic transaminase of 69 Karmen units/ml (normal, 10 to 4 0 ) . Protein-bound iodine was 8 . 5 ^ / 1 0 0 ml, and repeat was 4.3 fxg/\00 ml (normal, 4.0 to 8.0). Serum total thyroxine was 8.5 ^g/100 ml (normal, 6 to 12) and T 3 resin uptake, 27% (normal, 25% to 3 5 % ) . Thyroxine binding globulin was normal. Hemoglobin, leukocyte count, and urinalysis were within normal limits. An electrocardiogram showed first degree atrioventricular block, T wave depression, and a Q-T interval of 0.44. Two days after admission, while on a 120 meq Na and 60 meq K diet supplemented with 45 meq KC1, urinary excretion of Na and K was 435 meq/24 h and 113 meq/ 24 h, respectively. A total of 240 meq of potassium was given orally and intravenously in the first 24 hours after admission. He then was given a normal diet. Twenty-four hours after admission, he could move all extremities but had mild residual weakness that lasted another day. Serum potassium was 5.1 meq/litre. He was discharged on acetazolamide 250 mg twice daily. Subsequently he has had only one episode of mild weakness in July 1972, at which time his serum K was 2.5 meq/litre. He has been followed by the Metabolic Section of the Minneapolis Veterans Hospital and has been asymptomatic for the past 28 months. PATIENT 2
A 23-year-old black man (brother of Patient 1), was referred to the Minneapolis Veterans Hospital from Great Lakes Naval Hospital, where he had been diagnosed as having hypokalemic periodic paralysis. He gave a history of having been in good health until September 1970. At that time, 4 days after surgery for a giant cell tumor of the left great toe, he suddenly developed weakness of both lower extremities. The cause of paralysis was not determined, and he spontaneously recovered over the next 2 weeks without specific therapy. In December 1971, he again had sudden onset of weakness involving both upper and lower extremities. Neurologic examination at that 63
Figure 1 . Pedigree of family kindred with hypokalemic periodic paralysis.
time showed a flaccid paralysis with absent deep tendon reflexes and normal sensory findings. Again he was treated nonspecifically and had a spontaneous recovery. Both episodes occurred while he was stationed in the South Pacific. On 7 July 1972, after running one mile he again had sudden onset of paralysis of upper and lower extremities with normal sensory modalities. He was seen at the Military Hospital in Okinawa and found to have a serum potassium of 2.0 meq/litre. He was treated with intravenous KC1, and there was rapid improvement in symptoms. He was started on acetazolamide and then transferred to Great Lakes Naval Hospital for further work-up. At the Great Lakes Naval Hospital, physical examination showed no abnormalities. The following laboratory studies showed normal results: serum electrolytes, 24hour urinary electrolytes, serum calcium, phosphorus, fasting blood sugar, hemoglobin, leukocyte count, urinalysis, total serum thyroxine, and I131 uptake. An electromyogram was interpreted as being normal. Creatine phosphokinase was slightly elevated at 111 IU/litre (normal, less than 90 IU/litre). An attempt to induce paralysis with intravenous insulin was tried, with a fall in serum potassium occurring, but the patient failed to develop symptoms. He was discharged on spironolactone 25 mg four times daily, and since then he has been followed by the Metabolic Section at the Minneapolis Veterans Hospital. Spironolactone was withdrawn, and acetazolamide, 250 54
July 1975 • Annals of Internal Medicine • Volume 83 • Number 1
Downloaded from https://annals.org by Duke Medical Library user on 01/10/2019
mg twice daily, was started. He has been symptom-free since July 1972. Serum potassium has ranged from 3.4 meq/litre to 4.0 meq/litre. FAMILY KINDRED
The pedigree of the family is shown in Figure 1. To obtain information concerning the incidence of symptoms in the family, 9 members of the family other than the two index patients were contacted and interviewed. Histories could be obtained on 79 persons of four generations. Of these, 27 (34%) had a typical history of episodic weakness or paralysis. Of the 27 family members, 15 were men and 12 were women. Sixty percent of the men had complete paralysis, whereas this occurred in only 33% of the women. The remainder had episodic weakness. Because not all members of the family could be located, the actual number of persons with symptoms could be higher than indicated. It also should be pointed out that most members of the fourth generation are under the age of 20, therefore, it is expected that the incidence in this generation will increase. Because it was important to determine the racial background of the family, all members interviewed were specifically asked if they knew of any Caucasian member of the family. As far as we could determine, there were none in the four generations indicated; however, it was not possible to obtain information about prior generations. In an interview with three members of the second generation, it was determined that they had two paternal
uncles with periodic paralysis; however, their father and mother were apparently without symptoms. Incomplete penetrance would explain the lack of clinically apparent disease in the father. In Caucasians, incomplete penetrance also has been reported ( 3 ) . From the information available, it seems that 3 men in this kindred died during an attack. Despite this, it was evident that the family members had a rather casual attitude toward the disease. Most of those interviewed stated that they knew the symptoms would clear if they waited long enough. In addition to our two patients, only their mother, her brother, and his five children have seen a physician specifically about treatment; they were treated with elixir of KC1. Discussion
This disease is characterized by episodic attacks of flaccid paralysis or weakness of extremity muscles associated with hypokalemia, loss of excitability of the muscle by mechanical or electrical stimulation, and normal sensory findings. The frequency of attacks can vary from daily to yearly. The onset of attacks usually begins in the second decade and reaches a maximum frequency and intensity during the third decade. Thereafter, there usually is a decrease in frequency and severity of symptoms. However, as the patient becomes older there is often persistence of weakness between attacks (4, 5 ) . Intravenous potassium administration often dramatically decreases the duration of attacks. However, potassium does not prevent attacks or alleviate interattack weakness (4, 5). Although spironolactone has been used as treatment with varying degrees of success, acetazolamide is now considered to be the treatment of choice (4, 5 ) . It seems that this drug not only is the most effective in preventing attacks but also prevents interattack weakness ( 5 ) . The two patients presented here clearly fit the criteria for hypokalemic periodic paralysis. Interviews with other family members revealed episodes that were completely typical clinically, but these, of course, cannot be docu-
mented with absolute certainty because laboratory studies have not been done during attacks in any of these individuals. Familial hypokalemic periodic paralysis in Caucasians is inherited as an autosomal dominant trait with incomplete penetrance ( 3 ) . The data reported here in a Negro kindred also are compatible with an autosomal dominant trait, probably with incomplete penetrance. The prevalence among Caucasians has been reported to be 0.8 per 100 000 population. From the reports in the literature it would seem that the disease is virtually unknown among Negroes. There have been no case reports from Africa except for a single white South African family (6). However, the incidence of the disease in the Negro population must be reconsidered. With the 22 living members of the family reported in the present study plus the 7 previously reported family members, the incidence in blacks in the United States would be between 0.1 and 0.2 per 100 000. If other families have the same indifference to the disease reported here, the incidence may be even higher. ACKNOWLEDGMENTS: Received 7 October 1974; revision accepted 10 January 1975. • Requests for reprints should be addressed to Frank Q. Nuttall, M.D., Ph.D., Endocrine-Metabolic Section, Minneapolis Veterans Administration Hospital, 54th St. and 48th Ave. South, Minneapolis, MN 55417. References 1. GLYNN MF, TULSO PJ, OESTER YT: Studies in familial periodic
paralysis (abstract). Clin Res 10:226, 1962 2. FORMAN B: Hypokalemic periodic paralysis (letter). JAMA 216:146, 1971 3. PRATT R: Familial periodic paralysis, in The Genetics of Neurological Disorders. London, Oxford University Press, 1967, pp. 169-170 4. PEARSON CM, KALYANARAMAN K:
Periodic
paralysis, in
BURY JB, WYNGAARDEN JB, FREDRICKSON DS. New York, Mc-
Graw-Hill Book Co., 1972, pp. 1181-1207 5. GRIGGS RC, ENGEL WK, RESNICK JS: Acetazolamide treatment
of hypokalemic periodic paralysis. Prevention of attacks and improvement of persistent weakness. Ann Intern Med 73:39-48, 1970 6. CUSINS PJ: Familial periodic paralysis (7 cases in a Durbon family). S Afr Med J 37:1181-1184, 1963
Corbettand Nuttall • Periodic Paralysis in Blacks
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The
Metabolic Basis of Inherited Diseases, 3rd ed., edited by STAN-
65
