Hum. Genet. 48, 113--116 (1979)
© by Springer-Verlag 1979
Periodic Hypokalemic Paralysis Transmitted by an Unaffected Male With Negative Family History: A Delayed Mutation? H. H. Ropersl*and H. B. Szliwowski 2 ~Institute for Human Genetics, University of Freiburg, Albertstr. 11, D-7800 Freiburg, Federal Republic of Germany 2Institut Edith Cavell-Marie Depage, Brussels, Belgium
Summary. A pedigree is described that includes three cases of periodic hypokalemic paralysis. Apparently, the disease has arisen by de novo mutation in a father of two affected daughters, who, however, is not affected himself. This is unexpected, since in males the disorder is generally inherited as a fully dominant trait. Therefore we propose that these findings result from an early somatic or a half-chromatid mutation.
Introduction Periodic hypokalemic paralysis is a well-described, though rather rare, genetic disorder, whose basic defect is unknown (Pearson and Kalyanaraman, 1972). Clinically it is characterized by episodes of hypokalemia and muscular weakness, usually beginning during the night. The duration of the attacks is variable; mostly they last 6--24 h and affect mainly the trunk and limbs. The respiratory and pharyngeal muscles are usually spared (McArdle, 1964). Typically, the disease becomes manifest at or around puberty; with advancing age the frequency and severity of attacks tend to decrease. The disorder is inherited as an autosomal dominant trait, but frequently men are affected more severely than women. It is probable that this fact accounts for the marked androtropy observed by many authors; the estimated male preponderance ranges from 2:1 to about 12:1 (for review, see Becker, 1964). Therefore, seemingly unaffected mothers carrying the gene may have several affected children, as frequently observed. In contrast, male carriers always seem to be affected, though rare exceptions cannot be excluded (see pedigree of Sagild and Helweg-Larsen, 1955). The great majority of cases are familial, but sporadic cases have often been reported (reviewed by Conn and Streeten, 1960); these are probably due to new mutations. * To whom offprint requests should be sent
0340-6717/79/0048/0113/$01.00
114
H.H. Ropers and H. B. Szliwowski
I n t h e p e d i g r e e p r e s e n t e d h e r e , a h e a l t h y s o n o f u n a f f e c t e d p a r e n t s has a p p a r e n t l y t r a n s m i t t e d t h e t r a i t to t w o o f his t h r e e d a u g h t e r s .
Family
History
The pedigree of this family is illustrated in Figure I, and reveals three affected individuals. All are descendants of an unaffected healthy male (III4), who is now 67 years old and has never had any clinical sign of the disorder. Upon physical examination (Dr. Borde, Oberkirch) he was healthy except for chronic bronchitis, which he claims to have acquired during World War II. His serum potassium was in the normal range. In his youth, IIh was a regular member of a football team. From 1931 to 1932 and in 1939 he served in the Yugoslavian army, and thereafter he had to join the German army as an infantryman. He has been married twice; his first wife (III3) was of Yugoslavian extraction and was clinically unaffected. He has two daughters of this marriage, one of whom (1V4) developed symptoms of periodic hypokalemic paralysis at the age of 12. Later she married and had two children herself. Her first child, a boy (V2), is clinically affected. The second child, a girl, is now 12 years old and not affected so far. After his first wife had died during World War II, I114 married again. His second wife (III5), now 58 years old and healthy, was born in Latvia. Their only daughter, IV6, suffers from periodic hypokalemic paralysis, like her half-sister IV4. The family history of 1114 is unremarkable. Two of his three brothers are alive and healthy (1112 died in childhood), and both parents, all aunts and uncles, and the maternal grandparents are quite free of periodic paralysis. In the three affected family members the clinical symptoms were very similar. In all of them the disorder became manifest between the ages of 11 and 12, with muscular weakness, a feeling of heaviness in the limbs, and paralytic attacks. The attacks regularly began during the night, so that the patients were unable to get out of bed in the morning. During puberty, patient IV6 was repeatedly bedridden for periods of 2--3 days. In both female patients, IV4 and IV6, the severity of clinical signs decreased significantly after puberty; 1V6 is now 21 and only mildly affected. Her (infrequent) attacks can be successfully treated by oral administration of potassium. Between attacks, her serum potassium is in the low-normal range. Physical examination including an X-ray of the thorax revealed right side elevation of the diaphragm and hyporeflexia.
1
5
6
v__ Fig. 1. Pedigree of the family. The data concerning generation I and II were collected by 1114and have been confirmed in every detail by his wife III5, his daughter IV6, and one of his first cousins (not shown in the pedigree). All patients and their healthy sibs, and also III4 and IIIs, were seen by the authors. 1112, III3, IVl, and all family members of generations I and II are deceased
Periodic Hypokalemic Paralysis
115
Otherwise, the status was unremarkable (Freiburg University Medical Clinic). In the male patient, now 15 years old, the onset of clinical symptoms was marked by a sensation of heaviness in the limbs, paresthesia, and tetraplegia accompanied by areflexia. During attacks, his serum potassium ranged between 1.5 and 3.4mEq/1.
Pedigree Analysis and Discussion In this family, the clinical picture and course, laboratory findings (in V2), and response to potassium treatment prove beyond any reasonable doubt that all three affected family members suffer from periodic hypokalemic paralysis. In agreement with an autosomally dominant mode of inheritance, patient V2 has inherited the disease from his mother, IV4, who is also affected. The origin and mode of transmission of the defective gene are not clear, however, for the two patients in generation IV, IV4, and IV6. They are half-sisters born to the two different unrelated wives of their father, III4; neither the two wives nor the father has ever had any sign of the disease. The father's history (which was verified by a first cousin living in Federal Germany) rules out the possibility that he was clinically affected in his younger years. The respective mothers' (III3 and IIIs) histories are less well documented; moreover, the fact that affected women may be asymptomatic raises the possibility that both women may carry, by chance, the same genetic defect. However, this must be considered very unlikely, because the frequency of asymptomatic female carriers in the population presumably does not exceed that of affected males, i.e., it will be 1:50000 or less. The observation that both daughters, IV4 and IV6, are fully affected also argues against this construction. An alternative possibility, i.e., that the disorders in both affected females are the result of independent de novo mutations, is even more unlikely and can be discarded. Therefore, it is far more plausible to assume that the healthy father, III4, has transmitted the defective gene to two of his three daughters. This pattern of inheritance would be expected if he were an asymptomatic carrier. For two reasons, however, we doubt whether it is justifiable to regard him as a true carrier of the trait. First of all, the father never had any clinical sign of periodic hypokalemic paralysis, which is remarkable in the light of the observation that in general more than 95% of male carriers are clinically affected (deduced from HelwegLarsen and Hauge's data, as cited by Becker, 1964). Regular transmission in males is demonstrated by several large pedigrees (for review, see Becker, 1964). Even the few published examples of apparently healthy male carriers may rather exemplify incomplete ascertainment of symptoms in these individuals. Secondly, III4 does not seem to have inherited the gene from his parents. Both were healthy, and so were his brothers III1 and III6 and their offspring and all sibs of generations I and II (III2 died of an infection during childhood). This strongly supports the assumption that the gene defect causing periodic paralysis has arisen from a de novo mutation. This, however, should lead to clinical symptoms in III4, which have not been observed. Therefore, disregarding the unappealing and unlikely possibility that III4 is a true nonsymptomatic carrier, this healthy male may carry a so-called delayed mutation (Auerbach and Kilbey, 1971).
116
H.H. Ropers and H. B. Szliwowski
Several different biological models have been p r o p o s e d to explain the delayed-mutation p h e n o m e n o n , as discussed previously (Wolff et al., 1978). Of these, the possible existence in m a n of half-chromatid mutations (i.e., mutations arising during meiosis after the last r o u n d o f D N A replication and affecting only one D N A strand o f a chromatid) has been o f considerable theoretical interest (Gartler and Francke, 1975; Cantu, 1975; Lenz, 1975). Half-chromatid mutations ( H C M ) result in mosaicism of somatic and germinal tissues. Somatic mosaicism is only detectable if the mutation is expressed at the cellular level and, apart f r o m H C M , also results f r o m early somatic mutation. In the case of X-linked disorders, the existence o f germinal mosaicism is occasionally revealed by pedigree analysis, as recently demonstrated by W o l f f et al. (1978). In our present kindred, neither germinal n o r somatic mosaicism can be proven with certainty, because periodic hypokalemic paralysis is an autosomally d o m i n a n t trait that is, not detectable at the cellular level at present. Nevertheless, the clinical and genetic data seem to justify the following conclusions: 1. In III4, at least some (and possibly all) o f the diploid germ cells carry a copy o f the defective gene; therefore, up to 50% o f the haploid gametes transmit the mutation; 2. The defective gene is expressed only in some o f the relevant somatic cells (or defective somatic cells m a y be completely lacking), thus explaining why III4 is clinically unaffected; 3. These findings could result equally well from an early somatic m u t a t i o n or an H C M in one of the parental gametes.
References Auerbach, C., Kilbey, B. J.: Mutation in eukaryotes. Ann. Rev. Genet. 5, 163--218 (1971) Becker, P. E.: Myopathien. In: Humangenetik, ein kurzes Handbuch in 5 B~inden, Vol. III/1. P. E. Becker, ed., pp. 495--501. Stuttgart: Thieme 1964 Cantu, J. M.: Heterogenic monozygosity: evidence for transmission on halfchromatid mutations in humans? Am. J. Hum. Genet. 28, 190--191 (1976) Conn, J. W., Streeten, D. H. P.: Periodic paralysis. In: The metabolic basis of inherited disease, 1st ed. Stanbury, Wyngaarden, Fredrickson, eds., pp. 867--918. New York: McGraw-Hill 1960 Helweg-Larsen, H. F., Hauge, M., Sagild, U.: Hereditary transient muscular paralysis in Denmark. Genetic aspects of familial periodic paralysis and familial periodic adynamia. Acta genet. (Basel) 5, 263--281 (1955) Lenz, W.: Half chromatid mutations may explain incontinentia pigmenti in males. Am. J. Hum. Genet. 27, 690--691 (1975) McArdle, B.: Metabolic and endocrine myopathies. In: Disorders of voluntary muscles, J. Walton, ed., pp. 607--638. London: Churchill 1964 Pearson, C. M., Kalyanaraman, K.: The periodic paralyses. In: The metabolic basis of inherited disease, 3rd ed. Stanbury, Wyngaarden, Fredrickson, eds., pp. 1181--1203. New York: McGraw-Hill 1972 Sagild, U., Helweg-Larsen, H. F.: Det kliniske billede ved arvelige transitoriske muskellammelser; periodisk adynami og periodisk paralyse. Nord. med. 53, 981--995 (1955) Wolff, G., Hameister, H., Ropers, H. H.: X-linked mental retardation: transmission of the trait by an unaffected male. Am. J. Med. Genet. 2,217--224 (1978) Received December 5, 1978
© by Springer-Verlag 1979
Periodic Hypokalemic Paralysis Transmitted by an Unaffected Male With Negative Family History: A Delayed Mutation? H. H. Ropersl*and H. B. Szliwowski 2 ~Institute for Human Genetics, University of Freiburg, Albertstr. 11, D-7800 Freiburg, Federal Republic of Germany 2Institut Edith Cavell-Marie Depage, Brussels, Belgium
Summary. A pedigree is described that includes three cases of periodic hypokalemic paralysis. Apparently, the disease has arisen by de novo mutation in a father of two affected daughters, who, however, is not affected himself. This is unexpected, since in males the disorder is generally inherited as a fully dominant trait. Therefore we propose that these findings result from an early somatic or a half-chromatid mutation.
Introduction Periodic hypokalemic paralysis is a well-described, though rather rare, genetic disorder, whose basic defect is unknown (Pearson and Kalyanaraman, 1972). Clinically it is characterized by episodes of hypokalemia and muscular weakness, usually beginning during the night. The duration of the attacks is variable; mostly they last 6--24 h and affect mainly the trunk and limbs. The respiratory and pharyngeal muscles are usually spared (McArdle, 1964). Typically, the disease becomes manifest at or around puberty; with advancing age the frequency and severity of attacks tend to decrease. The disorder is inherited as an autosomal dominant trait, but frequently men are affected more severely than women. It is probable that this fact accounts for the marked androtropy observed by many authors; the estimated male preponderance ranges from 2:1 to about 12:1 (for review, see Becker, 1964). Therefore, seemingly unaffected mothers carrying the gene may have several affected children, as frequently observed. In contrast, male carriers always seem to be affected, though rare exceptions cannot be excluded (see pedigree of Sagild and Helweg-Larsen, 1955). The great majority of cases are familial, but sporadic cases have often been reported (reviewed by Conn and Streeten, 1960); these are probably due to new mutations. * To whom offprint requests should be sent
0340-6717/79/0048/0113/$01.00
114
H.H. Ropers and H. B. Szliwowski
I n t h e p e d i g r e e p r e s e n t e d h e r e , a h e a l t h y s o n o f u n a f f e c t e d p a r e n t s has a p p a r e n t l y t r a n s m i t t e d t h e t r a i t to t w o o f his t h r e e d a u g h t e r s .
Family
History
The pedigree of this family is illustrated in Figure I, and reveals three affected individuals. All are descendants of an unaffected healthy male (III4), who is now 67 years old and has never had any clinical sign of the disorder. Upon physical examination (Dr. Borde, Oberkirch) he was healthy except for chronic bronchitis, which he claims to have acquired during World War II. His serum potassium was in the normal range. In his youth, IIh was a regular member of a football team. From 1931 to 1932 and in 1939 he served in the Yugoslavian army, and thereafter he had to join the German army as an infantryman. He has been married twice; his first wife (III3) was of Yugoslavian extraction and was clinically unaffected. He has two daughters of this marriage, one of whom (1V4) developed symptoms of periodic hypokalemic paralysis at the age of 12. Later she married and had two children herself. Her first child, a boy (V2), is clinically affected. The second child, a girl, is now 12 years old and not affected so far. After his first wife had died during World War II, I114 married again. His second wife (III5), now 58 years old and healthy, was born in Latvia. Their only daughter, IV6, suffers from periodic hypokalemic paralysis, like her half-sister IV4. The family history of 1114 is unremarkable. Two of his three brothers are alive and healthy (1112 died in childhood), and both parents, all aunts and uncles, and the maternal grandparents are quite free of periodic paralysis. In the three affected family members the clinical symptoms were very similar. In all of them the disorder became manifest between the ages of 11 and 12, with muscular weakness, a feeling of heaviness in the limbs, and paralytic attacks. The attacks regularly began during the night, so that the patients were unable to get out of bed in the morning. During puberty, patient IV6 was repeatedly bedridden for periods of 2--3 days. In both female patients, IV4 and IV6, the severity of clinical signs decreased significantly after puberty; 1V6 is now 21 and only mildly affected. Her (infrequent) attacks can be successfully treated by oral administration of potassium. Between attacks, her serum potassium is in the low-normal range. Physical examination including an X-ray of the thorax revealed right side elevation of the diaphragm and hyporeflexia.
1
5
6
v__ Fig. 1. Pedigree of the family. The data concerning generation I and II were collected by 1114and have been confirmed in every detail by his wife III5, his daughter IV6, and one of his first cousins (not shown in the pedigree). All patients and their healthy sibs, and also III4 and IIIs, were seen by the authors. 1112, III3, IVl, and all family members of generations I and II are deceased
Periodic Hypokalemic Paralysis
115
Otherwise, the status was unremarkable (Freiburg University Medical Clinic). In the male patient, now 15 years old, the onset of clinical symptoms was marked by a sensation of heaviness in the limbs, paresthesia, and tetraplegia accompanied by areflexia. During attacks, his serum potassium ranged between 1.5 and 3.4mEq/1.
Pedigree Analysis and Discussion In this family, the clinical picture and course, laboratory findings (in V2), and response to potassium treatment prove beyond any reasonable doubt that all three affected family members suffer from periodic hypokalemic paralysis. In agreement with an autosomally dominant mode of inheritance, patient V2 has inherited the disease from his mother, IV4, who is also affected. The origin and mode of transmission of the defective gene are not clear, however, for the two patients in generation IV, IV4, and IV6. They are half-sisters born to the two different unrelated wives of their father, III4; neither the two wives nor the father has ever had any sign of the disease. The father's history (which was verified by a first cousin living in Federal Germany) rules out the possibility that he was clinically affected in his younger years. The respective mothers' (III3 and IIIs) histories are less well documented; moreover, the fact that affected women may be asymptomatic raises the possibility that both women may carry, by chance, the same genetic defect. However, this must be considered very unlikely, because the frequency of asymptomatic female carriers in the population presumably does not exceed that of affected males, i.e., it will be 1:50000 or less. The observation that both daughters, IV4 and IV6, are fully affected also argues against this construction. An alternative possibility, i.e., that the disorders in both affected females are the result of independent de novo mutations, is even more unlikely and can be discarded. Therefore, it is far more plausible to assume that the healthy father, III4, has transmitted the defective gene to two of his three daughters. This pattern of inheritance would be expected if he were an asymptomatic carrier. For two reasons, however, we doubt whether it is justifiable to regard him as a true carrier of the trait. First of all, the father never had any clinical sign of periodic hypokalemic paralysis, which is remarkable in the light of the observation that in general more than 95% of male carriers are clinically affected (deduced from HelwegLarsen and Hauge's data, as cited by Becker, 1964). Regular transmission in males is demonstrated by several large pedigrees (for review, see Becker, 1964). Even the few published examples of apparently healthy male carriers may rather exemplify incomplete ascertainment of symptoms in these individuals. Secondly, III4 does not seem to have inherited the gene from his parents. Both were healthy, and so were his brothers III1 and III6 and their offspring and all sibs of generations I and II (III2 died of an infection during childhood). This strongly supports the assumption that the gene defect causing periodic paralysis has arisen from a de novo mutation. This, however, should lead to clinical symptoms in III4, which have not been observed. Therefore, disregarding the unappealing and unlikely possibility that III4 is a true nonsymptomatic carrier, this healthy male may carry a so-called delayed mutation (Auerbach and Kilbey, 1971).
116
H.H. Ropers and H. B. Szliwowski
Several different biological models have been p r o p o s e d to explain the delayed-mutation p h e n o m e n o n , as discussed previously (Wolff et al., 1978). Of these, the possible existence in m a n of half-chromatid mutations (i.e., mutations arising during meiosis after the last r o u n d o f D N A replication and affecting only one D N A strand o f a chromatid) has been o f considerable theoretical interest (Gartler and Francke, 1975; Cantu, 1975; Lenz, 1975). Half-chromatid mutations ( H C M ) result in mosaicism of somatic and germinal tissues. Somatic mosaicism is only detectable if the mutation is expressed at the cellular level and, apart f r o m H C M , also results f r o m early somatic mutation. In the case of X-linked disorders, the existence o f germinal mosaicism is occasionally revealed by pedigree analysis, as recently demonstrated by W o l f f et al. (1978). In our present kindred, neither germinal n o r somatic mosaicism can be proven with certainty, because periodic hypokalemic paralysis is an autosomally d o m i n a n t trait that is, not detectable at the cellular level at present. Nevertheless, the clinical and genetic data seem to justify the following conclusions: 1. In III4, at least some (and possibly all) o f the diploid germ cells carry a copy o f the defective gene; therefore, up to 50% o f the haploid gametes transmit the mutation; 2. The defective gene is expressed only in some o f the relevant somatic cells (or defective somatic cells m a y be completely lacking), thus explaining why III4 is clinically unaffected; 3. These findings could result equally well from an early somatic m u t a t i o n or an H C M in one of the parental gametes.
References Auerbach, C., Kilbey, B. J.: Mutation in eukaryotes. Ann. Rev. Genet. 5, 163--218 (1971) Becker, P. E.: Myopathien. In: Humangenetik, ein kurzes Handbuch in 5 B~inden, Vol. III/1. P. E. Becker, ed., pp. 495--501. Stuttgart: Thieme 1964 Cantu, J. M.: Heterogenic monozygosity: evidence for transmission on halfchromatid mutations in humans? Am. J. Hum. Genet. 28, 190--191 (1976) Conn, J. W., Streeten, D. H. P.: Periodic paralysis. In: The metabolic basis of inherited disease, 1st ed. Stanbury, Wyngaarden, Fredrickson, eds., pp. 867--918. New York: McGraw-Hill 1960 Helweg-Larsen, H. F., Hauge, M., Sagild, U.: Hereditary transient muscular paralysis in Denmark. Genetic aspects of familial periodic paralysis and familial periodic adynamia. Acta genet. (Basel) 5, 263--281 (1955) Lenz, W.: Half chromatid mutations may explain incontinentia pigmenti in males. Am. J. Hum. Genet. 27, 690--691 (1975) McArdle, B.: Metabolic and endocrine myopathies. In: Disorders of voluntary muscles, J. Walton, ed., pp. 607--638. London: Churchill 1964 Pearson, C. M., Kalyanaraman, K.: The periodic paralyses. In: The metabolic basis of inherited disease, 3rd ed. Stanbury, Wyngaarden, Fredrickson, eds., pp. 1181--1203. New York: McGraw-Hill 1972 Sagild, U., Helweg-Larsen, H. F.: Det kliniske billede ved arvelige transitoriske muskellammelser; periodisk adynami og periodisk paralyse. Nord. med. 53, 981--995 (1955) Wolff, G., Hameister, H., Ropers, H. H.: X-linked mental retardation: transmission of the trait by an unaffected male. Am. J. Med. Genet. 2,217--224 (1978) Received December 5, 1978
