To the best of our knowledge, this is the largest study in Japan to assess mothers and children who were both diagnosed with DM1. Similar studies of this scale are rare, even outside of Japan. In this study, no significant correlation was found between the number of CTG repeats in mothers and their children, and the presence of a high number of repeats did not lead to an early diagnosis of CDM. However, age at symptom onset and age at diagnosis were significantly higher in mothers of children in the non-CDM group. Therefore, study findings revealed important information regarding pregnancy, childbirth, neonatal management of women with DM1, and the suitability of prenatal diagnosis in pregnant women with DM1, despite the limited number of study participants.
DM1 severity is commonly correlated with the number of CTG repeats present in the DMPK gene 16. CDM is considered an early-onset and severe form of DM1 1,2,16. However, no significant increase in the CTG repeat number was observed among children with CDM relative to that observed in those without CDM. The lack of difference between children with and without CDM may have been due to the small number of children without CDM included in the study. Further, the two individuals without CDM were determined to have relatively severe DM1 because they presented DM1 symptoms during childhood, which may have affected the results. In fact, the children in this study had a CTG repeat number of ≥ 1,000. The absence of clear diagnostic criteria for CDM may also have influenced findings 13.
The proportion of children with CDM versus DM1 in this study was greater than those reported previously 10–12. We believe that this difference may be due to the factors such as serious cases of DM1 are easier to diagnose than milder cases, the absence of paternally inherited cases in this study, and the absence of established diagnostic criteria for CDM.
An investigation of characteristics of mothers revealed no significant correlation between CTG repeat number and age at diagnosis, which indicated that elevated repeat numbers did not result in an earlier diagnosis. This may be because the timing of DM1 diagnosis was influenced not only by the severity of symptoms but also by how individuals perceived the disease. The significantly younger age at diagnosis among mothers whose children had CDM was probably influenced by the diagnosis of the child, which in turn prompted physicians to establish a diagnosis for the mother. In cases of DM1, patients with mild symptoms tended to have delayed diagnoses 17. Particularly in women, DM1 is often associated with infertility, abnormalities during pregnancy, miscarriage, and premature delivery 13,17−21, hence, obstetricians and gynecologists must be aware that obstetric consultations may potentially lead to a DM1 diagnosis.
Japanese cases of polyhydramnios during pregnancy or threatened preterm labor that led to a diagnosis of DM1 have been reported 20,22. However, the results of our study revealed that it is difficult to predict whether fetuses would present with CDM in cases without polyhydramnios despite being diagnosed with DM1 based on the expanding CTG repeat number. However, our study did reveal that a young maternal age at symptom onset may be a risk factor for the occurrence of CDM. Therefore, a reduction in CDM risk may be possible to predict when the pregnant mother has not yet developed DM1 symptoms.
Barbé et al. suggested that high levels of methylation upstream and downstream of the CTG repeat were better correlated with CDM onset than the CTG repeat number itself 23. We anticipate that the development of testing strategies other than CTG repeat number will be necessary for identifying predictors of DM1 severity in children 24,25. In our study, CTG repeat numbers were higher in all children than their corresponding mothers, and symptoms were more severe in children than in mothers. However, no children died during infancy, and life expectancy was better than that expected based on previous reports 1,2,6,13,18. The small number of cases and large time gaps between births in our study prevented a detailed statistical analysis of long-term prognoses among pediatric participants. In addition, clinical features during early infancy and thereafter varied greatly between individual cases regardless of CDM diagnosis. Therefore, we cannot assert that there is no hope of long-term survival for children diagnosed with CDM, as has been indicated in prior reports. Our study has several limitations, including its single-center retrospective design and disproportional participant composition (primarily patients with CDM). Additional multicenter studies with larger cohorts are needed.
The tendency of patients with mild symptoms to be overlooked, rather than diagnosed with DM1, may have affected the findings of this study. In particular, this study may have included patients with relatively severe disease, which may have affected our statistical analysis. Therefore, some of the results of this study, especially the proportion of infants with CDM, may not be valid for all DM1 groups. However, even among cases of severe DM1, no children died during infancy. This result indicates that high repeat numbers do not guarantee early mortality.
The findings of our study suggest that even when the CTG repeat number of the fetus is determined by prenatal genetic testing, extreme care must be taken when using this information to determine the future of the pregnancy. Multiple articles have already reported difficulties associated with prenatal genetic testing for DM1 26, and our study supports the findings of prior authors. Affected mothers and families should be provided accurate information derived from the latest available evidence and given broad support, not only from obstetricians but also from clinical genetic specialists including genetic counselors, pediatricians, and neurologists to make informed independent decisions.