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Original Articles Anticipation Resulting in Elimination of the Myotonic J7 Med Genet 1994;31:595-601 595 Original articles J Med Genet: first published as 10.1136/jmg.31.8.595 on 1 August 1994. Downloaded from Anticipation resulting in elimination of the myotonic dystrophy gene: a follow up study of one extended family C E M de Die-Smulders, C J Howeler, J F Mirandolle, H G Brunner, V Hovers, H Bruggenwirth, H J M Smeets, J P M Geraedts Abstract muscular manifestations, it is characterised by We have re-examined an extended myo- multiple systemic effects including cataract, tonic dystrophy (DM) family, previously mental retardation, cardiac involvement, and described in 1955, in order to study the testicular atrophy. Extreme variability is one of long term effects of anticipation in DM the hallmarks of the disease; clinical studies and in particular the implications for have led to the recognition of four disease types families affected by this disease. This fol- on the basis of age at onset and core symptoms: low up study provides data on 35 gene late onset (mild) type, adult onset (classical) carriers and 46 asymptomatic at risk type, childhood, and congenital type.'"3 family members in five generations. Anticipation, increasing severity and earlier Clinical anticipation, defined as the cas- age at onset in successive generations, has been cade ofmild, adult, childhood, or congen- observed in DM since the beginning of this ital disease in subsequent generations, century, but remained unexplained and contro- appeared to be a relentless process, oc- versial until recently."- With the discovery of curring in all affected branches of the an unstable CTG trinucleotide repeat in the 3' family. The cascade was found to proceed untranslated region of a protein kinase gene on asynchronously in the different branches, chromosome 19q, a biological explanation for mainly because of an unequal number of this phenomenon has emerged.>'4 The repeat generations with mild disease. The tran- length correlates with the severity of clinical sition from the mild to the adult type was symptoms and increases with transmission to associated with transmission through a subsequent generations.3 7 1516 However, most of http://jmg.bmj.com/ male parent. Stable transmission of the the dynamics of the unstable CTG trinucleo- asymptomatic/mild phenotype showed a tide repeat are not yet fully understood. female transmission bias. The exact implications of anticipation for We further examined the extent and DM families are still Department of unclear. As a rule the Clinical Genetics, causes of gene loss in this pedigree. Gene anticipation cascade proceeds and the pheno- University Hospital loss in the patient group was complete, type changes from mild type to adult type to Maastricht, PO Box owing to infertility of the male patients childhood/congenital type in subsequent gen- on September 26, 2021 by guest. Protected copyright. 1475, 6201 BL with Maastricht, The adult onset disease and the fact that erations. However, it is not known which events Netherlands mentally retarded patients did not pro- precede the cascade, which factors trigger C E M de Die-Smulders create. Out of the 46 at risk subjects in the the start of the cascade, and what happens after V Hovers two youngest generations, only one was the J P M Geraedts childhood/congenital onset generation. found to have a full mutation. This is the Fleischer4 argued that the disease would Department of only subject who may transmit the gene become extinct in families because of gene loss Neurology, University to the sixth Hospital Maastricht, generation. No protomu- in severely affected patients owing to celibacy, The Netherlands tation carriers were found in the fourth childless marriages, mental retardation, and C J Howeler and fifth generations. Therefore it is high infant mortality. Follow up studies to highly probable that the DM gene will be Department of determine whether the disease indeed disap- Neurology, de Wever eliminated from this pedigree within one pears from a given family have not been per- Hospital, Heerlen, generation. The high population fre- formed. We had the opportunity to re-examine The Netherlands quency of DM can at present not be a J F Mirandolle large DM family, the first three generations of explained by the contribution of asymp- which were described by de Jong"7 in 1955, and Department of tomatic cases in the younger generations so we could gain data on five generations. The Human Genetics, of known families, but is probably caused aim was to University Hospital study the consequences of anticipa- Nijmegen, The by the events in the ancestral genera- tion over more generations than can be studied Netherlands tions. in transverse studies. The inter- and intrage- H G Brunner nerational phenotypic variation was studied by H Briiggenwirth (J Med Genet H J M Smeets 1994;31:595-601) combining clinical and DNA data. The repro- ductive fitness of male and female patients was Correspondence to Dr de Die-Smulders. compared. To examine whether progressive Received 21 March 1994 Myotonic dystrophy (DM) is an autosomal severity leads to the extinction of the disease Accepted for publication dominant disorder with myotonia and muscular from a given pedigree, descendants of the third 18 April 1994 weakness as diagnostic features. Apart from the and fourth symptomatic generations were 596 de Die-Smulders, Howeler, Mirandolle, Brunner, Hovers, Bruggenwirth, Smeets, Geraedts studied, and the extent and causes of gene loss disease status of the intermediate family mem- in the youngest generations were evaluated. ber(s) was unknown. One at risk subject (V.20) was included in the group of gene carriers after DNA examination showed that she had inher- J Med Genet: first published as 10.1136/jmg.31.8.595 on 1 August 1994. Downloaded from Methods ited the expanded CTG repeat from her affec- FAMILY ted father. Eighteen out of the 36 gene carriers In 1955 de Jong'7 described an extended DM were no longer alive at the time of the study. family with three symptomatic generations (pedigree G). He gave detailed information on 50 family members, 16 of whom were desig- EXAMINATIONS nated as affected. Neurological examination and Careful histories from the patients or their slit lamp examination by an ophthalmologist family members or both were obtained to docu- were used as diagnostic methods. Electromyo- ment the age of onset and current clinical graphy was not available then. We carefully symptoms. When available, clinical records reviewed his data and only subjects showing were reviewed. Muscular weakness or myotonia definite signs of DM were classified as affected. or both, myotonic cataract, neonatal symptoms, We added data on the descendants of III.12, or mental retardation defined the onset of dis- who were examined by de Jong in 1958 (figure). ease. Neurological examination was performed II.2 and her descendants are not included in using a standardised form. Ophthalmological this follow up study, because she was not ex- assessments were carried out using a portable amined by de Jong. III.8, III.9, and III.10 and slit lamp. EMG examination was only per- their children were found to be normal in 1955. formed when the examination took place in They live abroad and were excluded from the hospital. present study. The living members of genera- tions IV and V were re-examined and so we were able to obtain data on five generations. CLINICAL CLASSIFICATION This follow up study was started with the To compare the disease types within and patients and at risk family members already between generations four clinical categories known to the Departments of Clinical Genetics were used, adapted from the classification of and Neurology of the University Hospital Harley et aP: mild, adult, childhood, and con- Maastricht and the Department of Neurology genital types. We added a category of additional of the De Wever Hospital in Heerlen, the later symptoms, because several of the present Netherlands. They were asked to approach patients have had symptomatic DM for over 40 their relatives. Most family members were years (table 1). Conclusions regarding the dis- visited and examined in their own homes, ease type were made on the basis of the results which turned out to have a significant advan- of our recent examination in combination with tage in terms of cooperation in the study. the data from medical records and de Jong's The total study comprises data on 81 family descriptions. members: initially there were 35 symptomatic http://jmg.bmj.com/ patients or obligate gene carriers (including de Jong's patients) and 46 at risk subjects. The at DNA ANALYSIS risk group comprised asymptomatic first degree Chromosomal DNA was isolated from peri- relatives of DM patients. Second and third pheral blood cells from 16 patients and 39 at degree relatives were defined as at risk if the risk subjects. Molecular analyses were 1 on September 26, 2021 by guest. Protected copyright. 11 III IV V 323 2.5 0.9 LI 0 Normal on clinical/DNA examination El ( Asymptomatic gene carrier !l O Mild type [] Adult type In Childhood type ** Congenital type E9 Not examined Pedigree of the family. The numbers beneath the symbol denote the size (kb) of CTG repeat expansion by Southern blot analysis. Anticipation resulting in elimination of the myotonic dystrophy gene 597 Table 1 Disease types in DM related to age at onset and core symptoms Disease Age at Initial symptoms Additional later symptoms type onset (y) J Med Genet: first published as 10.1136/jmg.31.8.595 on 1 August 1994. Downloaded from Mild > 50 Cataract or
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