Eur. Neurol. 11: 296-299 (1978)
Monozygous Twins Discordant for Amyotrophic Lateral Sclerosis M. Jokelainen, J. Palo and J. Lokki Departments of Neurology and Genetics, University of Helsinki, Helsinki
Key Words. Twins • Monozygosity • Amyotrophic lateral sclerosis • Motor neuron disease
Introduction
Amyotrophic lateral sclerosis (ALS) is a pro gressive disease of the central nervous system with unknown etiology. Metabolic disturbances and toxic agents have been suspected but viral etiology has recently gained wider support (6—8). Recently Estrin (2) suggested the pos sibility of sublethal intrauterine injury to ante rior horn cells as the causative or basically predisposing factor in the development of ALS. This concept was founded on the discovery of a pair of dizygotic twins developing typical ALS later in their lives. We now report monozygotic twins discordant for ALS, a combination that has not been reported previously in the litera ture.
Case Reports The twins were born in a rural community. The mother died 4 months later and the twins were placed
separately into 2 families. Both foster-mothers were sisters of the deceased mother. The normal twin’s foster-mother promptly weaned her own son and started to breast-feed the new child. The twins were later taken home again, where they lived together with the father from age 4 to 16, when the affected sister moved to Helsinki, the normal sister also came 2 years later. Both started to work at the same garment fac tory as seamstresses. They lived together from age 18 to 23, when the affected twin got married. The normal twin also married but she had no children. None of the relatives was known to have ALS or any other disease resembling it. The twins were not aware of any contacts with other ALS patients. The affected sister was bitten by a poisonous Finnish snake, viper (Vipera berus), at the age of 12. The normal sister had 2 bone fractures (right wrist and right elbow), and the affected sister had more infec tious diseases. Both twins had struma in their teens. The normal twin was treated with drugs but the affect ed one was operated. The left thyroid lobe was re moved; it was nodose, non-toxic, and degenerated. First evidence of ALS in the affected twin was noted in 1974, when she experienced slowly increasing weakness in her lower extremities at the age o f 66. Her symptoms proceeded steadily and by the time she was
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
Abstract. A pair of identical female twins were discordant for amyotrophic lateral sclerosis. The affected twin was not breast-fed; was bitten by a poisonous snake, and was operated on for struma. She had more infections than her sister but no fractures. Her plasma insulin response to glucose loading was also higher. The twins lived separated in their early childhood.
297
Monozygous Twins and ALS
seen for the first time in April 1975, she had lost weight, had moderate dysphagia and slight dysarthria. Her tongue was atrophic on both sides and showed also some fibrillations. Abundant fasciculations were observed in her thighs which were atrophic, especially on the extensor side. The tendon reflexes were present and the plantar responses were extensor. Wide-spread fasciculations and fibrillations were found in the EMG both in the upper and lower extremities while the MCV of the right ulnar and deep peroneal nerve was normal. By November 1975 the muscular weakness had spread to the upper extremities, dysarthria was un changed but dysphagia had become much worse. The patient was taken to the hospital on February 5, 1976, and she died 2 days later. In microscopic examination of the autopsy samples a clear-cut degeneration of lower motor neurons could be demonstrated through out the spinal cord and medulla oblongata. Mild degeneration of myelinated axons of peripheral nerves, as well as signs of neurogenic atrophy of the skeletal muscles were also observed, but morphologic signs of pyramidal tract lesions could not be seen. No evidence of ALS was found in a detailed medi cal history of the normal sister. The EMG from the right deltoid and anterior tibial muscle were normal in January 1976 and so was the MCV of the right deep peroneal nerve. The MCV of the right median nerve was somewhat slower titan normal, 49 m/sec. The right opponens pollicis muscle also displayed some fibrillations and fasciculations. These findings did not suggest the presence of a wider lesion of motor neu rons but rather a slight affection of the right median nerve. The EMG was repeated in April 1976. The findings in the right hand were normal this time and no fibrillations or fasciculations were noted. The MCV of the right median nerve was the same as earlier, 49 m/sec. She was still healthy in January 1978.
The confirmation of monozygosity of the twins was achieved by comparing their physical characteristics and by analyzing their special blood groups and HLA antigens. 11 poly morphic genetic loci were studied for calculat ing the probability of monozygosity (9). The outer physical characteristics, the form of face, eyes, nose, mouth and ear lobes were equal. The twins were concordant for all genetic mark ers tested in the study, and the probability of monozygosity was calculated as 0.9981 (table 1). A large number of other laboratory examina tions were carried out on both twins, but no significant findings were observed in most of the tests. The results of 2- and 3-hour peroral
Table II. The results of an oral glucose tolerance test with simultaneous plasma insulin determinations
Time, h
0 0.5 1 2 3
Blood glucose mMj\
Plasma insulin rnU/1
affected
healthy
affected healthy
4.6 9.3 8.1 6.7 -
4.5 6.4 6.9 6.1 4.8
9.0 82.8 100.6 57.3 -
6.7 42.3 41.5 23.4 9.1
The weight of the affected twin was 54 kg and that of the healthy twin was 72 kg.
Table I. Marker phenotypes studied for zygosity determination
Twins
f
Histocompatibility loci
Red cell antigens
ABO MNS P,
rhesus
O
CCDee
MsNs +
K
Le a
Le b
Fy a
Fy b
Jk a
U1 a
HLA-A
HLA-B
-
+
+
+
—
-
3,28
7, w40
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
Sex
Jokelainen/Palo/Lokki
298
Discussion
Because of the high probability figures the twins can be considered as monozygous. The fact that they were discordant for ALS strongly suggests that the disease is not truly hereditary. The possibility of intrauterine injury postulated by Estrin (2) seems also to be excluded; en vironmental factors may be more likely causes responsible for the development of ALS. Considering the development of later im munity it should be observed that the affected twin was not breast-fed. This difference is interesting because the composition of early diet is suspected as having some etiologic role, for example, in the development of multiple sclerosis (see 1). The twins lived separated from the age of 4 months to 4 years, 16 to 18 years, and after 23 years of age. While the risk of contracting multiple sclerosis appears to be present in early childhood no such tendency has thus far been found for ALS (5). The fact that the twins lived separated for a part of their early childhood and proved to be discordant for ALS may sup port the significance of early events also in the etiology of ALS although the twins spent even longer periods of time separated from each other later in life. The snake bite may be relevant to the devel opment of ALS because various toxins, most notably cholera toxin, can bind to the cell surface, particularly to gangliosides (3). On the other hand, there are reports indicating that at
least cobra venom may be useful in the treat ment of ALS. One should also consider the possibility that a virus or viroid was transmitted to the affected sister by the snake bite or some other route. It was reported earlier that during oral glu cose tolerance test the plasma insulin response was exaggerated and prolonged in ALS cases with more advanced neuronal lesions of the cervical and lumbar segments (4). The present results agree with these findings and suggest an increase of tissue resistance to glucose and in sulin. Further studies are in progress to deter mine the number of insulin receptors and to investigate various autoimmune phenomena in ALS.
Acknowledgements We thank Dr. R. Fogelholm for co-operation and the Paulo Foundation for financial support.
References 1 Clausen, J.; Fog, T., and Hansen, I.B.: Myelin con stituents in multiple sclerosis. Studies of phospho lipid, glycolipid and fatty acid patterns in normal and multiple sclerosis brains; in Leibowitz, Progress in multiple sclerosis research and treatment (Academic Press, New York 1972). 2 Estrin, W.J.: Amyotrophic lateral sclerosis in dizygotic twins. Neurology, Minneap. 27.' 692-694 (1977). 3 Fishman, P.H. and Brady, R.O.: Biosynthesis and function of gangliosides. Science 194: 906-915 (1976). 4 Gustafson, A. and Stortebecker, P.: Vascular and metabolic studies of amyotrophic lateral sclerosis. II. Lipid and carbohydrate metabolism. Neurology, Minneap. 22: 528-536 (1972). 5 Jokelainen, M.: The epidemiology of amyotrophic lateral sclerosis in Finland. A study based on the death certificates of 421 patients. J. neurol. Sci. 29: 55-63 (1976).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
glucose tolerance tests with simultaneous plas ma insulin determinations were also within normal limits in both twins. However, the plas ma insulin response appeared much higher in the affected twin in spite of her lower weight and higher blood glucose values (table II).
299
Monozygous Twins and ALS
multiple sclerosis. Identification of viral antigens by immunofluorescence. Lancet i: 1119-1123 (1977). 9 Smith, M.S. and Penrose, L.S.: Monozygotic and dizygotic twin diagnosis. Ann. hum. Gen. 19: 273-289 (1955).
Received: March 16, 1978 Accepted: March 17,1978 Jorma Palo, MD, Department of Neurology, University of Helsinki, 00290 Helsinki 29 (Finland)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
6 Norris, F.H., jr.; Aguilar, M.J.; Colton, R.P.; Oldstone, M.B.A., and Cremer, N.E.: Tubular particles in a case of recurrent lymphocytic meningitis fol lowed by amyotrophic lateral sclerosis. J. Neuro path. exp. Neurol. 34: 133-147 (1975). 7 Oshiro, L.S.; Cremer, N.E.; Norris, F.H., jr., and Lennette, E.H.: Virus-like particles in muscle from a patient with amyotrophic lateral sclerosis. Neu rology, Minneap. 26: 57-60 (1976). 8 Pertschuk, L.P.; Cook, A.W.; Gupta, J.K.; Broome, J.D.; Vuletin, J.C.; Kim, D.S.; Brigati, D.J.; Rainford, E.A., and Nidsgorski, F.: Jejunal immunopathology in amyotrophic lateral sclerosis and
Monozygous Twins Discordant for Amyotrophic Lateral Sclerosis M. Jokelainen, J. Palo and J. Lokki Departments of Neurology and Genetics, University of Helsinki, Helsinki
Key Words. Twins • Monozygosity • Amyotrophic lateral sclerosis • Motor neuron disease
Introduction
Amyotrophic lateral sclerosis (ALS) is a pro gressive disease of the central nervous system with unknown etiology. Metabolic disturbances and toxic agents have been suspected but viral etiology has recently gained wider support (6—8). Recently Estrin (2) suggested the pos sibility of sublethal intrauterine injury to ante rior horn cells as the causative or basically predisposing factor in the development of ALS. This concept was founded on the discovery of a pair of dizygotic twins developing typical ALS later in their lives. We now report monozygotic twins discordant for ALS, a combination that has not been reported previously in the litera ture.
Case Reports The twins were born in a rural community. The mother died 4 months later and the twins were placed
separately into 2 families. Both foster-mothers were sisters of the deceased mother. The normal twin’s foster-mother promptly weaned her own son and started to breast-feed the new child. The twins were later taken home again, where they lived together with the father from age 4 to 16, when the affected sister moved to Helsinki, the normal sister also came 2 years later. Both started to work at the same garment fac tory as seamstresses. They lived together from age 18 to 23, when the affected twin got married. The normal twin also married but she had no children. None of the relatives was known to have ALS or any other disease resembling it. The twins were not aware of any contacts with other ALS patients. The affected sister was bitten by a poisonous Finnish snake, viper (Vipera berus), at the age of 12. The normal sister had 2 bone fractures (right wrist and right elbow), and the affected sister had more infec tious diseases. Both twins had struma in their teens. The normal twin was treated with drugs but the affect ed one was operated. The left thyroid lobe was re moved; it was nodose, non-toxic, and degenerated. First evidence of ALS in the affected twin was noted in 1974, when she experienced slowly increasing weakness in her lower extremities at the age o f 66. Her symptoms proceeded steadily and by the time she was
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
Abstract. A pair of identical female twins were discordant for amyotrophic lateral sclerosis. The affected twin was not breast-fed; was bitten by a poisonous snake, and was operated on for struma. She had more infections than her sister but no fractures. Her plasma insulin response to glucose loading was also higher. The twins lived separated in their early childhood.
297
Monozygous Twins and ALS
seen for the first time in April 1975, she had lost weight, had moderate dysphagia and slight dysarthria. Her tongue was atrophic on both sides and showed also some fibrillations. Abundant fasciculations were observed in her thighs which were atrophic, especially on the extensor side. The tendon reflexes were present and the plantar responses were extensor. Wide-spread fasciculations and fibrillations were found in the EMG both in the upper and lower extremities while the MCV of the right ulnar and deep peroneal nerve was normal. By November 1975 the muscular weakness had spread to the upper extremities, dysarthria was un changed but dysphagia had become much worse. The patient was taken to the hospital on February 5, 1976, and she died 2 days later. In microscopic examination of the autopsy samples a clear-cut degeneration of lower motor neurons could be demonstrated through out the spinal cord and medulla oblongata. Mild degeneration of myelinated axons of peripheral nerves, as well as signs of neurogenic atrophy of the skeletal muscles were also observed, but morphologic signs of pyramidal tract lesions could not be seen. No evidence of ALS was found in a detailed medi cal history of the normal sister. The EMG from the right deltoid and anterior tibial muscle were normal in January 1976 and so was the MCV of the right deep peroneal nerve. The MCV of the right median nerve was somewhat slower titan normal, 49 m/sec. The right opponens pollicis muscle also displayed some fibrillations and fasciculations. These findings did not suggest the presence of a wider lesion of motor neu rons but rather a slight affection of the right median nerve. The EMG was repeated in April 1976. The findings in the right hand were normal this time and no fibrillations or fasciculations were noted. The MCV of the right median nerve was the same as earlier, 49 m/sec. She was still healthy in January 1978.
The confirmation of monozygosity of the twins was achieved by comparing their physical characteristics and by analyzing their special blood groups and HLA antigens. 11 poly morphic genetic loci were studied for calculat ing the probability of monozygosity (9). The outer physical characteristics, the form of face, eyes, nose, mouth and ear lobes were equal. The twins were concordant for all genetic mark ers tested in the study, and the probability of monozygosity was calculated as 0.9981 (table 1). A large number of other laboratory examina tions were carried out on both twins, but no significant findings were observed in most of the tests. The results of 2- and 3-hour peroral
Table II. The results of an oral glucose tolerance test with simultaneous plasma insulin determinations
Time, h
0 0.5 1 2 3
Blood glucose mMj\
Plasma insulin rnU/1
affected
healthy
affected healthy
4.6 9.3 8.1 6.7 -
4.5 6.4 6.9 6.1 4.8
9.0 82.8 100.6 57.3 -
6.7 42.3 41.5 23.4 9.1
The weight of the affected twin was 54 kg and that of the healthy twin was 72 kg.
Table I. Marker phenotypes studied for zygosity determination
Twins
f
Histocompatibility loci
Red cell antigens
ABO MNS P,
rhesus
O
CCDee
MsNs +
K
Le a
Le b
Fy a
Fy b
Jk a
U1 a
HLA-A
HLA-B
-
+
+
+
—
-
3,28
7, w40
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
Sex
Jokelainen/Palo/Lokki
298
Discussion
Because of the high probability figures the twins can be considered as monozygous. The fact that they were discordant for ALS strongly suggests that the disease is not truly hereditary. The possibility of intrauterine injury postulated by Estrin (2) seems also to be excluded; en vironmental factors may be more likely causes responsible for the development of ALS. Considering the development of later im munity it should be observed that the affected twin was not breast-fed. This difference is interesting because the composition of early diet is suspected as having some etiologic role, for example, in the development of multiple sclerosis (see 1). The twins lived separated from the age of 4 months to 4 years, 16 to 18 years, and after 23 years of age. While the risk of contracting multiple sclerosis appears to be present in early childhood no such tendency has thus far been found for ALS (5). The fact that the twins lived separated for a part of their early childhood and proved to be discordant for ALS may sup port the significance of early events also in the etiology of ALS although the twins spent even longer periods of time separated from each other later in life. The snake bite may be relevant to the devel opment of ALS because various toxins, most notably cholera toxin, can bind to the cell surface, particularly to gangliosides (3). On the other hand, there are reports indicating that at
least cobra venom may be useful in the treat ment of ALS. One should also consider the possibility that a virus or viroid was transmitted to the affected sister by the snake bite or some other route. It was reported earlier that during oral glu cose tolerance test the plasma insulin response was exaggerated and prolonged in ALS cases with more advanced neuronal lesions of the cervical and lumbar segments (4). The present results agree with these findings and suggest an increase of tissue resistance to glucose and in sulin. Further studies are in progress to deter mine the number of insulin receptors and to investigate various autoimmune phenomena in ALS.
Acknowledgements We thank Dr. R. Fogelholm for co-operation and the Paulo Foundation for financial support.
References 1 Clausen, J.; Fog, T., and Hansen, I.B.: Myelin con stituents in multiple sclerosis. Studies of phospho lipid, glycolipid and fatty acid patterns in normal and multiple sclerosis brains; in Leibowitz, Progress in multiple sclerosis research and treatment (Academic Press, New York 1972). 2 Estrin, W.J.: Amyotrophic lateral sclerosis in dizygotic twins. Neurology, Minneap. 27.' 692-694 (1977). 3 Fishman, P.H. and Brady, R.O.: Biosynthesis and function of gangliosides. Science 194: 906-915 (1976). 4 Gustafson, A. and Stortebecker, P.: Vascular and metabolic studies of amyotrophic lateral sclerosis. II. Lipid and carbohydrate metabolism. Neurology, Minneap. 22: 528-536 (1972). 5 Jokelainen, M.: The epidemiology of amyotrophic lateral sclerosis in Finland. A study based on the death certificates of 421 patients. J. neurol. Sci. 29: 55-63 (1976).
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
glucose tolerance tests with simultaneous plas ma insulin determinations were also within normal limits in both twins. However, the plas ma insulin response appeared much higher in the affected twin in spite of her lower weight and higher blood glucose values (table II).
299
Monozygous Twins and ALS
multiple sclerosis. Identification of viral antigens by immunofluorescence. Lancet i: 1119-1123 (1977). 9 Smith, M.S. and Penrose, L.S.: Monozygotic and dizygotic twin diagnosis. Ann. hum. Gen. 19: 273-289 (1955).
Received: March 16, 1978 Accepted: March 17,1978 Jorma Palo, MD, Department of Neurology, University of Helsinki, 00290 Helsinki 29 (Finland)
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 6/25/2018 7:29:52 AM
6 Norris, F.H., jr.; Aguilar, M.J.; Colton, R.P.; Oldstone, M.B.A., and Cremer, N.E.: Tubular particles in a case of recurrent lymphocytic meningitis fol lowed by amyotrophic lateral sclerosis. J. Neuro path. exp. Neurol. 34: 133-147 (1975). 7 Oshiro, L.S.; Cremer, N.E.; Norris, F.H., jr., and Lennette, E.H.: Virus-like particles in muscle from a patient with amyotrophic lateral sclerosis. Neu rology, Minneap. 26: 57-60 (1976). 8 Pertschuk, L.P.; Cook, A.W.; Gupta, J.K.; Broome, J.D.; Vuletin, J.C.; Kim, D.S.; Brigati, D.J.; Rainford, E.A., and Nidsgorski, F.: Jejunal immunopathology in amyotrophic lateral sclerosis and
