Neuromusc. Disord., Vol. 2, No. 2, pp. 85-86, 1992 Printed in Great Britain
0960-8966/92 $5.00 + 0.00 Pergamon Press Ltd
LESSON FOR THE MONTH GENETIC COUNSELLING
The young couple were referred to my muscle clinic this week for genetic counselling. They had recently lost their first-born son at 11 days with myotubular myopathy. The family history was negative on both sides and there had not been any miscarriages or neonatal deaths. During pregnancy the mother had expressed concern from an early stage at the poor foetal movements. There was no associated polyhydramnios. The baby was born at 36 weeks gestation by elective Caesarean section for persistent breech presentation. He weighed 2500 g. He was floppy and immobile. Although he initially breathed spontaneously, he became ventilator-dependent after 24 h. As he was considered too ill to transport to a regional centre an open biopsy was taken from the quadriceps and sent for pathological diagnosis. The parents were informed on day 10 that he had myotubular myopathy. He died the following day. Beyond the fact that the condition was genetic, no further details were discussed with them. I explained to them the X-linked inheritance of the severe congenital form of myotubular myopathy, its involvement o f males only, with females carrying the gene and usually being symptom-free, and discussed the possible options of prenatal diagnosis with selective termination of affected male foetuses on the basis of chorionic villus sampling early in pregnancy. There were, however, two problems. We were unsure if blood had been stored from the affected infant for D N A analysis as a reference for assessment of any future pregnancy and also that although the locus for the gene in the region of Xq28 was well established, the gene itself had not yet been isolated and characterized, so that any linkage studies dependent on adjacent probes still carried a small residual risk of a false negative result. The mother was not at all keen on any termination and also had some concern about the residual 50% risk of a female being a carrier of the gene and asked about the possibility of in vitro fertilization with a donor ovum and her
husband's semen. After further discussion about the logistics of this approach she eventually came round to the option of selective fertilization of a female ovum of her own with her husband's semen, accepting that the residual risk of carrying the mutant gene might be much easier to deal with in the next generation, given the possibility of further advances in the characterization of the gene and the sensitivity of accurate diagnosis in the future. I then stressed again that all our discussions in relation to genetic counselling were dependent on the accuracy of the index diagnosis and that I would need to verify this with direct assessment of the muscle biopsy. I also pointed out that there were a number of disorders that could present in the newborn period with the floppy infant syndrome, and one common disorder that might have a very similar presentation to myotubular myopathy, together with the associated respiratory failure, was congenital myotonic dystrophy and if I had been dealing clinically with the infant I would routinely have asked the mother two questions, and under the circumstances thought it appropriate to do so anyway. Firstly, could she close her eyes tightly? She was unable to screw her eyes up tightly and could not bury her eyelashes. Secondly, could she clench her fist tightly, hold it for a few seconds, and then open it rapidly? There was an obvious stiffness and delay in the opening of her hand. She commented that she had been aware of this stiffness for some time, particularly when typing. The presence of myotonia was confirmed by electromyography. I now had to explain that I was unable to agree with the original diagnosis and that I thought the infant had congenital myotonic dystrophy and that she also had the gene. I also had to explain the dominant inheritance with involvement of both sexes and there were now a number of additional key questions I needed to ask about the family. Did she think her parents or any other members of her family had any muscle weakness or stiffness? She was not aware of it. Did anyone have cataracts? Both her parents had cataracts. 85
86
Lesson for the month.
Her father's had come on fairly late in life, but her mother's had been unusually early (according to the ophthalmologist), in her early 50s. I then explained the importance of trying to diagnose other members of the family, who might be very mildly affected and possibly unaware of any problem, not only from a genetic point of view but also because they were unusually abnormally sensitive to anaesthetics and might be at particular risk if the anaesthetist were not alerted to this. She commented that it was interesting that I should have raised the question of anaesthesia as her mother always reacted badly to anaesthetics and took a long time to come round afterwards and several days to fully get over the effects. In the context of closure of the eyes, she mentioned that, according to her husband, she tended to sleep with her eyes partially open, and that her grandfather, on her mother's side, also apparently did. I discussed with them the recent advances in the molecular genetics of myotonic dystrophy, and that it was now possible to confirm a diagnosis in an individual on the basis of the DNA studies, and that this also provided the basis for accurate parental diagnosis. The only practical option at present seemed to be selective termination of an affected foetus, and conversely retention of an unaffected one. The genetic aspects would need a lot of further sensitive discussion, explanation and clarification. For the moment the main difficulty for the mother, who was just coming to terms with the problem of being a carrier of a lethal gene, having now to come to terms with a different
situation with a different genetic scenario and with actually being affected by the gene herself. She spontaneously verbalized this herself and asked about her own prognosis, to which I gave a guardedly optimistic response that the mothers of infants with the severe congenital form often have a relatively mild clinical involvement, as in her case, and may remain relatively stable over a prolonged period. Comments
(1) Molecular genetic analysis and the corresponding genetic counselling are futile if the index diagnosis is wrong; (2) the possibility of congenital myotonic dystrophy should be considered in any floppy newborn infant, particularly with associated facial weakness, respiratory failure or swallowing difficulty. The diagnosis is confirmed by examining the mother rather than investigating the infant, who will not show evidence of myotonia and whose biopsy will not be diagnostic [1]; (3) the histological features in some cases of congenital myotonic dystrophy may be similar to those of myotubular myopathy [2]. V. DUBOWlTZ
Editor-in-Chief REFERENCES 1. 2.
Dubowitz V. Muscle Disorders in Childhood. London: W B Saunders, 1978: 139. Dubowitz V. A Colour Atlas o f Muscle Disorders in Childhood. London/Chicago: Wolfe Medical Publications/Year Book Publishers, 1989: 99, 106.
0960-8966/92 $5.00 + 0.00 Pergamon Press Ltd
LESSON FOR THE MONTH GENETIC COUNSELLING
The young couple were referred to my muscle clinic this week for genetic counselling. They had recently lost their first-born son at 11 days with myotubular myopathy. The family history was negative on both sides and there had not been any miscarriages or neonatal deaths. During pregnancy the mother had expressed concern from an early stage at the poor foetal movements. There was no associated polyhydramnios. The baby was born at 36 weeks gestation by elective Caesarean section for persistent breech presentation. He weighed 2500 g. He was floppy and immobile. Although he initially breathed spontaneously, he became ventilator-dependent after 24 h. As he was considered too ill to transport to a regional centre an open biopsy was taken from the quadriceps and sent for pathological diagnosis. The parents were informed on day 10 that he had myotubular myopathy. He died the following day. Beyond the fact that the condition was genetic, no further details were discussed with them. I explained to them the X-linked inheritance of the severe congenital form of myotubular myopathy, its involvement o f males only, with females carrying the gene and usually being symptom-free, and discussed the possible options of prenatal diagnosis with selective termination of affected male foetuses on the basis of chorionic villus sampling early in pregnancy. There were, however, two problems. We were unsure if blood had been stored from the affected infant for D N A analysis as a reference for assessment of any future pregnancy and also that although the locus for the gene in the region of Xq28 was well established, the gene itself had not yet been isolated and characterized, so that any linkage studies dependent on adjacent probes still carried a small residual risk of a false negative result. The mother was not at all keen on any termination and also had some concern about the residual 50% risk of a female being a carrier of the gene and asked about the possibility of in vitro fertilization with a donor ovum and her
husband's semen. After further discussion about the logistics of this approach she eventually came round to the option of selective fertilization of a female ovum of her own with her husband's semen, accepting that the residual risk of carrying the mutant gene might be much easier to deal with in the next generation, given the possibility of further advances in the characterization of the gene and the sensitivity of accurate diagnosis in the future. I then stressed again that all our discussions in relation to genetic counselling were dependent on the accuracy of the index diagnosis and that I would need to verify this with direct assessment of the muscle biopsy. I also pointed out that there were a number of disorders that could present in the newborn period with the floppy infant syndrome, and one common disorder that might have a very similar presentation to myotubular myopathy, together with the associated respiratory failure, was congenital myotonic dystrophy and if I had been dealing clinically with the infant I would routinely have asked the mother two questions, and under the circumstances thought it appropriate to do so anyway. Firstly, could she close her eyes tightly? She was unable to screw her eyes up tightly and could not bury her eyelashes. Secondly, could she clench her fist tightly, hold it for a few seconds, and then open it rapidly? There was an obvious stiffness and delay in the opening of her hand. She commented that she had been aware of this stiffness for some time, particularly when typing. The presence of myotonia was confirmed by electromyography. I now had to explain that I was unable to agree with the original diagnosis and that I thought the infant had congenital myotonic dystrophy and that she also had the gene. I also had to explain the dominant inheritance with involvement of both sexes and there were now a number of additional key questions I needed to ask about the family. Did she think her parents or any other members of her family had any muscle weakness or stiffness? She was not aware of it. Did anyone have cataracts? Both her parents had cataracts. 85
86
Lesson for the month.
Her father's had come on fairly late in life, but her mother's had been unusually early (according to the ophthalmologist), in her early 50s. I then explained the importance of trying to diagnose other members of the family, who might be very mildly affected and possibly unaware of any problem, not only from a genetic point of view but also because they were unusually abnormally sensitive to anaesthetics and might be at particular risk if the anaesthetist were not alerted to this. She commented that it was interesting that I should have raised the question of anaesthesia as her mother always reacted badly to anaesthetics and took a long time to come round afterwards and several days to fully get over the effects. In the context of closure of the eyes, she mentioned that, according to her husband, she tended to sleep with her eyes partially open, and that her grandfather, on her mother's side, also apparently did. I discussed with them the recent advances in the molecular genetics of myotonic dystrophy, and that it was now possible to confirm a diagnosis in an individual on the basis of the DNA studies, and that this also provided the basis for accurate parental diagnosis. The only practical option at present seemed to be selective termination of an affected foetus, and conversely retention of an unaffected one. The genetic aspects would need a lot of further sensitive discussion, explanation and clarification. For the moment the main difficulty for the mother, who was just coming to terms with the problem of being a carrier of a lethal gene, having now to come to terms with a different
situation with a different genetic scenario and with actually being affected by the gene herself. She spontaneously verbalized this herself and asked about her own prognosis, to which I gave a guardedly optimistic response that the mothers of infants with the severe congenital form often have a relatively mild clinical involvement, as in her case, and may remain relatively stable over a prolonged period. Comments
(1) Molecular genetic analysis and the corresponding genetic counselling are futile if the index diagnosis is wrong; (2) the possibility of congenital myotonic dystrophy should be considered in any floppy newborn infant, particularly with associated facial weakness, respiratory failure or swallowing difficulty. The diagnosis is confirmed by examining the mother rather than investigating the infant, who will not show evidence of myotonia and whose biopsy will not be diagnostic [1]; (3) the histological features in some cases of congenital myotonic dystrophy may be similar to those of myotubular myopathy [2]. V. DUBOWlTZ
Editor-in-Chief REFERENCES 1. 2.
Dubowitz V. Muscle Disorders in Childhood. London: W B Saunders, 1978: 139. Dubowitz V. A Colour Atlas o f Muscle Disorders in Childhood. London/Chicago: Wolfe Medical Publications/Year Book Publishers, 1989: 99, 106.
