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Nemaline myopathy: A tale of two cultures
Neuromuscular Disorders 19 (2009) 177–178
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Annotation
Nemaline myopathy: A tale of two cultures In 2004 Anderson and her colleagues reported an identical large 2502 bp deletion in the Nebulin gene, including exon 55 and parts of the adjacent introns, in five patients with nemaline myopathy from five Ashkenazi Jewish families [1]. In the current issue of the Journal, Lehtokari and colleagues [2] present a report coordinated through the ENMC consortium on nemaline myopathy, from the three major laboratories with an interest in nemaline myopathy of Carina Wallgren-Pettersson (Helsinki), Alan Beggs (Boston), and Nigel Laing (Perth). They revisited the DNA of their patients with nemaline myopathy, without a defined mutation in any of the currently-known 6 genes associated with nemaline myopathy and screened for the Ashkenazi Jewish deletion. In a total of 355 probands they found 14 with the identical deletion. Twelve were Ashkenazi Jewish families and included two already documented by Anderson. No great surprise. What was of more interest was that two of the families were not of known Ashkenazi Jewish origin. Unfortunately, there was no information on the roots of these two families. It is understandable that molecular geneticists may be mesmerised by genetic mutations, but there is often also an interesting clinical and historical component to many of these situations. Some 25 years ago I saw a four-month-old floppy infant with feeding difficulties and some delay in motor milestones. She had minimal facial weakness and mild ptosis, anti-gravity movement of the limbs and ability to sit unsupported. In view of the mild nature of the problem, I deferred a muscle biopsy for a couple of months in order to assess the course. The parents were non-consanguineous, orthodox, Ashkenazi Jews with no previous history of muscle disease. Shortly afterwards, the child went into respiratory failure on a transatlantic flight to New York and ended up in a New York hospital. After the respiratory problem settled, she was referred to a neuromuscular centre where an electromyogram (EMG) showed a denervation pattern and a diagnosis of spinal muscular atrophy was suggested, with a somewhat gloomy prognosis. On return to the UK, the parents were understandably somewhat distraught and thought it somewhat remiss of me for having given an inappropriately optimistic prognosis. EMGs in young infants can be misleading, and I was able to reassure them that a diagnosis of spinal muscular atrophy was incompatible with the clinical features and antigravity movement of the limbs, and it was more likely to be a mild congenital myopathy. A needle muscle biopsy established a diagnosis of nemaline myopathy. She subsequently made good progress, achieved independent ambulation but had recurrent respiratory problems and needed continuous nocturnal ventilation for her diaphragmatic weakness from about a year of age. In recent years, I started getting recurrent requests from the parents for urgent consultations. These were not related to any 0960-8966/$ - see front matter Ó 2009 Published by Elsevier B.V. doi:10.1016/j.nmd.2009.01.004
acute problems with the patient but connected with their arrangements for a shidduch (traditional Jewish matchmaking) for their eldest son. In checking back the detailed records of some of the potentially eligible Ashkenazi families, they found a common ancestor some 4 or 5 generations back between one parent in each family and were accordingly concerned about genetic implications. It was thus important for them to establish whether their son was a possible carrier of the gene for nemaline myopathy. DNA from the family had been studied by Dr. Wallgren-Pettersson’s laboratory in Finland and a presumptive linkage to the nebulin gene was established but an intensive search had not yet revealed a mutation in the very large gene. On the basis of the available linkage data, it seemed likely that the son was not a carrier. However, this was not sufficient for the family to be able to move forward with the matrimonial possibilities. On one of their subsequent visits to New York, they were advised to consult Dor Yeshorim, an organisation providing confidential carrier detection for single individuals of Ashkenazi Jewish origin in relation to some of the genetic conditions with a high frequency in Ashkenazi Jews. The organisation had been established in the 1980s by a Rabbi Joseph Ekstein, who lost four of his 10 children to Tay-Sachs disease, which had a high prevalence in this relatively inbred community. He was intent on doing something about it and the programme turned out to be extremely successful in almost eliminating Tay-Sachs disease from the orthodox Ashkenazi Jewish community. The organisation suggested they consult Dr. Berish Rubin, whose genetics laboratory had recently identified the gene for another condition prevalent in Ashkenazi Jews, familial dysautonomia, He was prepared to screen their DNA, as well as that of other Ashkenazi families with nemaline myopathy. This led to the discovery of a large deletion in their nemaline gene. Shortly after this revelation, I had another urgent telephone call from the family who wished to see me as soon as possible, with some special news! They were jubilant that a mutation had been found in their family and that their son was not a carrier, and extended an invitation to me to join them for the forthcoming wedding in Israel. The Ashkenazi Jews originally lived from medieval times in the Rhineland in the west of Germany, referred to in Hebrew as Ashkenaz. From the 11th century onwards they migrated east to countries such as Poland, Lithuania, Hungary and Russia, where they remained settled for several centuries. In modern times, there have been two major migrations of Ashkenazi Jews. Towards the end of the 19th century, there was a major migration from Lithuania and adjoining countries to escape the brutal pogroms of the Russians against the Jews in the villages and towns. Many of these families settled in England, the United States, Argentina, South Africa and elsewhere. Although integrating into the local communities they remained ethnically fairly insular with very little intermarriage
178
Editorial / Neuromuscular Disorders 19 (2009) 177–178
until the past 50 years or so. Since then there has been a considerable assimilation and intermarriage within these communities of the less orthodox members. In the 1930s, prior to the Second World War, Kindertransports were organised from Germany, Austria and other European countries overrun by the Germans in order to save the children, when their parents were arrested and sent to concentrations camps. Many of these children were adopted into non-Jewish families in Britain and other countries. In Belgium, Poland and other countries there was a particular programme of ‘‘hidden children” who were given over by their parents to Roman Catholic priests, on the understanding that they would be taken into hiding for their safety and given a completely new name and identity. Many of these children did not know their true identity or Jewish background till they were adult. It is not always easy to recognise cryptic Ashkenazi Jews and the individuals themselves may not be aware of it. For personal reasons others may not wish to divulge it. Well known examples include Karl Marx, who was an atheist, whose Jewish mother and father had converted to Christianity before he was born. The same would apply to the hidden children of the second world war. A well-known example was the former American Secretary of State, Madeleine Albright, whose Jewish Czech parents converted to Roman Catholicism just before the 2nd World War to escape persecution in the Holocaust. There was also the unusual case of the Catholic priest, Father Romuald Jakub Weksler-Waskinel, who was unaware of his background until his mother on her deathbed told him she was not his true mother but his Jewish mother had handed the baby to her to save his life when they were being transported to the death camps. In a recent programme on the British Broadcasting Corporation (BBC) television ‘‘Who do you think you are?” several well-known personalities were able to trace their roots and discover unexpected Jewish ancestry. Finally, there is another twist to the tale. In early 2008, I had a request from a paediatric colleague for an urgent consultation in connection with an infant born to an orthodox young Jewish couple, who was currently still in the neonatal intensive care unit of a London hospital, following major respiratory problems. She had feeding difficulties in the newborn period, followed by recurrent respiratory infections needing ventilator support. She was seen by a paediatric neurologist who did an EMG, which showed a denervation pattern and he suggested a diagnosis of possible spinal muscular atrophy (déjà vu of my original case). Once again the clinical history did not fit in with a diagnosis of infantile SMA, and I suggested that it was more likely to be a congenital myopathy such as nemaline myopathy, and in view of the Jewish orthodox background of the parents, one might even be able to identify a specific deletion in the nebulin gene. A muscle biopsy confirmed the diagnosis of nemaline myopathy. I subsequently met the young couple, who were non-consanguineous and had previously had a normal child. The father was training as a rabbi. The only spoke in the wheels was that they were not of Ashkenazi origin but Sephardi, on both sides of the family. The mother had been born in England but her parents were from Morocco and the father’s parents also came from Morocco. The Sephardi Jews were mainly from the Iberian Peninsula and lived in Spain and Portugal until the time of the Spanish Inquisition in the 15th century and their expulsion from both these countries.
Many families fled to the Ottoman Empire, or to Morocco and also to France, the Netherlands, Italy and other countries. Once again, they remained fairly insular within the local communities of which they formed part. From a genetic point of view, the Sephardic Jews did not have a high frequency of the same recessive disorders, such as Tay-Sachs disease, prevalent amongst the Ashkenazis. Of interest was that they tended to have other diseases, such as favism, with sensitivity to fava beans and haemolytic crises, which was common in Africans and communities around the Mediterranean. It brought back to me a recollection of visiting Dr. Chaim Sheba, director of the Tel Hashomer Hospital in Tel Aviv in the 1960s and meeting a visiting professor, Ernest Beutler, who had discovered the deficiency of the X-linked enzyme glucose-6-phosphate dehydrogenase in favism. Sheba had shown it to also have a high frequency in the Sephardic population. He was also able to use it as a marker to trace Sephardic migrations from various parts of the world to Israel. Incidentally Beutler also pioneered Reference Manager, the first computer based retrieval system for medical publications. He died recently in October 2008 at the age of 80. This young couple now posed an interesting question as to whether Sephardic Jews might possibly have the Ashkenazi mutation for nemaline myopathy, or whether it was more likely to be another separate genetic mutation. The answer came with the discovery in this family of a mutation in the small alpha-actin gene (ACTA 1). So the founder effect of the Ashkenazi lineage of the deletion in the nebulin gene remains firm. With the increasing assimilation in the current generations between different ethnic groups, this mutation will undoubtedly find a wider expression in the generations to come. Indeed, this form of nemaline myopathy may become more common in non-Ashkenazi families, as the screening programmes by organisations such as Dor Yeshorim, gradually curtail the disease in successive generations of orthodox Ashkenazis, as has already happened with Tay-Sachs disease. It will also be of interest to track this mutation in nemaline myopathies in other communities. In Israel for example there has been a large migration of Ashkenasi Jews, but there has been extensive intermarriage between Ashkenasi and Sephardi Jews in the present generation, with less tendency to recognise the traditional roots. So cryptic Ashkenazi genes my well crop up in unexpected places. Acknowledgements I am grateful to Thomas Voit, Haluk Topaloglu, Jean-Claude Kaplan, Alan Emery, Richard Edwards and Zohar Argov for helpful comments. References [1] Anderson SL, Ekstein J, Donnelly MC, et al. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 2004;115:185–90. [2] Lehtokari V-L, Greenleaf RS, Dechene ET, et al. The exon 55 deletion in the nebulin gene – One single founder mutation with world-wide occurrence. Neuromuscul Disord 2009;19:179–81.
Editor-in-Chief Victor Dubowitz
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Annotation
Nemaline myopathy: A tale of two cultures In 2004 Anderson and her colleagues reported an identical large 2502 bp deletion in the Nebulin gene, including exon 55 and parts of the adjacent introns, in five patients with nemaline myopathy from five Ashkenazi Jewish families [1]. In the current issue of the Journal, Lehtokari and colleagues [2] present a report coordinated through the ENMC consortium on nemaline myopathy, from the three major laboratories with an interest in nemaline myopathy of Carina Wallgren-Pettersson (Helsinki), Alan Beggs (Boston), and Nigel Laing (Perth). They revisited the DNA of their patients with nemaline myopathy, without a defined mutation in any of the currently-known 6 genes associated with nemaline myopathy and screened for the Ashkenazi Jewish deletion. In a total of 355 probands they found 14 with the identical deletion. Twelve were Ashkenazi Jewish families and included two already documented by Anderson. No great surprise. What was of more interest was that two of the families were not of known Ashkenazi Jewish origin. Unfortunately, there was no information on the roots of these two families. It is understandable that molecular geneticists may be mesmerised by genetic mutations, but there is often also an interesting clinical and historical component to many of these situations. Some 25 years ago I saw a four-month-old floppy infant with feeding difficulties and some delay in motor milestones. She had minimal facial weakness and mild ptosis, anti-gravity movement of the limbs and ability to sit unsupported. In view of the mild nature of the problem, I deferred a muscle biopsy for a couple of months in order to assess the course. The parents were non-consanguineous, orthodox, Ashkenazi Jews with no previous history of muscle disease. Shortly afterwards, the child went into respiratory failure on a transatlantic flight to New York and ended up in a New York hospital. After the respiratory problem settled, she was referred to a neuromuscular centre where an electromyogram (EMG) showed a denervation pattern and a diagnosis of spinal muscular atrophy was suggested, with a somewhat gloomy prognosis. On return to the UK, the parents were understandably somewhat distraught and thought it somewhat remiss of me for having given an inappropriately optimistic prognosis. EMGs in young infants can be misleading, and I was able to reassure them that a diagnosis of spinal muscular atrophy was incompatible with the clinical features and antigravity movement of the limbs, and it was more likely to be a mild congenital myopathy. A needle muscle biopsy established a diagnosis of nemaline myopathy. She subsequently made good progress, achieved independent ambulation but had recurrent respiratory problems and needed continuous nocturnal ventilation for her diaphragmatic weakness from about a year of age. In recent years, I started getting recurrent requests from the parents for urgent consultations. These were not related to any 0960-8966/$ - see front matter Ó 2009 Published by Elsevier B.V. doi:10.1016/j.nmd.2009.01.004
acute problems with the patient but connected with their arrangements for a shidduch (traditional Jewish matchmaking) for their eldest son. In checking back the detailed records of some of the potentially eligible Ashkenazi families, they found a common ancestor some 4 or 5 generations back between one parent in each family and were accordingly concerned about genetic implications. It was thus important for them to establish whether their son was a possible carrier of the gene for nemaline myopathy. DNA from the family had been studied by Dr. Wallgren-Pettersson’s laboratory in Finland and a presumptive linkage to the nebulin gene was established but an intensive search had not yet revealed a mutation in the very large gene. On the basis of the available linkage data, it seemed likely that the son was not a carrier. However, this was not sufficient for the family to be able to move forward with the matrimonial possibilities. On one of their subsequent visits to New York, they were advised to consult Dor Yeshorim, an organisation providing confidential carrier detection for single individuals of Ashkenazi Jewish origin in relation to some of the genetic conditions with a high frequency in Ashkenazi Jews. The organisation had been established in the 1980s by a Rabbi Joseph Ekstein, who lost four of his 10 children to Tay-Sachs disease, which had a high prevalence in this relatively inbred community. He was intent on doing something about it and the programme turned out to be extremely successful in almost eliminating Tay-Sachs disease from the orthodox Ashkenazi Jewish community. The organisation suggested they consult Dr. Berish Rubin, whose genetics laboratory had recently identified the gene for another condition prevalent in Ashkenazi Jews, familial dysautonomia, He was prepared to screen their DNA, as well as that of other Ashkenazi families with nemaline myopathy. This led to the discovery of a large deletion in their nemaline gene. Shortly after this revelation, I had another urgent telephone call from the family who wished to see me as soon as possible, with some special news! They were jubilant that a mutation had been found in their family and that their son was not a carrier, and extended an invitation to me to join them for the forthcoming wedding in Israel. The Ashkenazi Jews originally lived from medieval times in the Rhineland in the west of Germany, referred to in Hebrew as Ashkenaz. From the 11th century onwards they migrated east to countries such as Poland, Lithuania, Hungary and Russia, where they remained settled for several centuries. In modern times, there have been two major migrations of Ashkenazi Jews. Towards the end of the 19th century, there was a major migration from Lithuania and adjoining countries to escape the brutal pogroms of the Russians against the Jews in the villages and towns. Many of these families settled in England, the United States, Argentina, South Africa and elsewhere. Although integrating into the local communities they remained ethnically fairly insular with very little intermarriage
178
Editorial / Neuromuscular Disorders 19 (2009) 177–178
until the past 50 years or so. Since then there has been a considerable assimilation and intermarriage within these communities of the less orthodox members. In the 1930s, prior to the Second World War, Kindertransports were organised from Germany, Austria and other European countries overrun by the Germans in order to save the children, when their parents were arrested and sent to concentrations camps. Many of these children were adopted into non-Jewish families in Britain and other countries. In Belgium, Poland and other countries there was a particular programme of ‘‘hidden children” who were given over by their parents to Roman Catholic priests, on the understanding that they would be taken into hiding for their safety and given a completely new name and identity. Many of these children did not know their true identity or Jewish background till they were adult. It is not always easy to recognise cryptic Ashkenazi Jews and the individuals themselves may not be aware of it. For personal reasons others may not wish to divulge it. Well known examples include Karl Marx, who was an atheist, whose Jewish mother and father had converted to Christianity before he was born. The same would apply to the hidden children of the second world war. A well-known example was the former American Secretary of State, Madeleine Albright, whose Jewish Czech parents converted to Roman Catholicism just before the 2nd World War to escape persecution in the Holocaust. There was also the unusual case of the Catholic priest, Father Romuald Jakub Weksler-Waskinel, who was unaware of his background until his mother on her deathbed told him she was not his true mother but his Jewish mother had handed the baby to her to save his life when they were being transported to the death camps. In a recent programme on the British Broadcasting Corporation (BBC) television ‘‘Who do you think you are?” several well-known personalities were able to trace their roots and discover unexpected Jewish ancestry. Finally, there is another twist to the tale. In early 2008, I had a request from a paediatric colleague for an urgent consultation in connection with an infant born to an orthodox young Jewish couple, who was currently still in the neonatal intensive care unit of a London hospital, following major respiratory problems. She had feeding difficulties in the newborn period, followed by recurrent respiratory infections needing ventilator support. She was seen by a paediatric neurologist who did an EMG, which showed a denervation pattern and he suggested a diagnosis of possible spinal muscular atrophy (déjà vu of my original case). Once again the clinical history did not fit in with a diagnosis of infantile SMA, and I suggested that it was more likely to be a congenital myopathy such as nemaline myopathy, and in view of the Jewish orthodox background of the parents, one might even be able to identify a specific deletion in the nebulin gene. A muscle biopsy confirmed the diagnosis of nemaline myopathy. I subsequently met the young couple, who were non-consanguineous and had previously had a normal child. The father was training as a rabbi. The only spoke in the wheels was that they were not of Ashkenazi origin but Sephardi, on both sides of the family. The mother had been born in England but her parents were from Morocco and the father’s parents also came from Morocco. The Sephardi Jews were mainly from the Iberian Peninsula and lived in Spain and Portugal until the time of the Spanish Inquisition in the 15th century and their expulsion from both these countries.
Many families fled to the Ottoman Empire, or to Morocco and also to France, the Netherlands, Italy and other countries. Once again, they remained fairly insular within the local communities of which they formed part. From a genetic point of view, the Sephardic Jews did not have a high frequency of the same recessive disorders, such as Tay-Sachs disease, prevalent amongst the Ashkenazis. Of interest was that they tended to have other diseases, such as favism, with sensitivity to fava beans and haemolytic crises, which was common in Africans and communities around the Mediterranean. It brought back to me a recollection of visiting Dr. Chaim Sheba, director of the Tel Hashomer Hospital in Tel Aviv in the 1960s and meeting a visiting professor, Ernest Beutler, who had discovered the deficiency of the X-linked enzyme glucose-6-phosphate dehydrogenase in favism. Sheba had shown it to also have a high frequency in the Sephardic population. He was also able to use it as a marker to trace Sephardic migrations from various parts of the world to Israel. Incidentally Beutler also pioneered Reference Manager, the first computer based retrieval system for medical publications. He died recently in October 2008 at the age of 80. This young couple now posed an interesting question as to whether Sephardic Jews might possibly have the Ashkenazi mutation for nemaline myopathy, or whether it was more likely to be another separate genetic mutation. The answer came with the discovery in this family of a mutation in the small alpha-actin gene (ACTA 1). So the founder effect of the Ashkenazi lineage of the deletion in the nebulin gene remains firm. With the increasing assimilation in the current generations between different ethnic groups, this mutation will undoubtedly find a wider expression in the generations to come. Indeed, this form of nemaline myopathy may become more common in non-Ashkenazi families, as the screening programmes by organisations such as Dor Yeshorim, gradually curtail the disease in successive generations of orthodox Ashkenazis, as has already happened with Tay-Sachs disease. It will also be of interest to track this mutation in nemaline myopathies in other communities. In Israel for example there has been a large migration of Ashkenasi Jews, but there has been extensive intermarriage between Ashkenasi and Sephardi Jews in the present generation, with less tendency to recognise the traditional roots. So cryptic Ashkenazi genes my well crop up in unexpected places. Acknowledgements I am grateful to Thomas Voit, Haluk Topaloglu, Jean-Claude Kaplan, Alan Emery, Richard Edwards and Zohar Argov for helpful comments. References [1] Anderson SL, Ekstein J, Donnelly MC, et al. Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene. Hum Genet 2004;115:185–90. [2] Lehtokari V-L, Greenleaf RS, Dechene ET, et al. The exon 55 deletion in the nebulin gene – One single founder mutation with world-wide occurrence. Neuromuscul Disord 2009;19:179–81.
Editor-in-Chief Victor Dubowitz