Parent-of-Origin Effect on the Age at Symptom Onset in Myotonic Dystrophy Type 2

Background and ObjectivesThe existence of clinical anticipation, congenital form, and parent-of-origin effect in myotonic dystrophy type 2 (DM2) remains uncertain. Here, we aimed at investigating whether there is a parent-of-origin effect on the age at the first DM2-related clinical manifestation.MethodsWe identified patients with genetically confirmed DM2 with known parental inheritance from (1) the electronic medical records of our institutions and (2) a systematic review of the literature following the PRISMA 2020 guidelines and recorded their age at and type of first disease-related symptom. We also interrogated the Myotonic Dystrophy Foundation Family Registry (MDFFR) for patients with DM2 who completed a survey including questions about parental inheritance and age at the first medical problem which they related to their DM2 diagnosis.ResultsA total of 26 patients with DM2 from 18 families were identified at our institutions as having maternal (n = 14) or paternal (n = 12) inheritance of the disease, whereas our systematic review of the literature rendered a total of 61 patients with DM2 from 41 families reported by 24 eligible articles as having maternal (n = 40) or paternal (n = 21) inheritance of the disease. Both cohorts were combined for downstream analyses. Up to 61% and 58% of patients had muscle-related symptoms as the first disease manifestation in maternally and paternally inherited DM2 subgroups, respectively. Four patients developed hypotonia at birth and/or delayed motor milestones early in life, and 7 had nonmuscular presentations (2 had cardiac events within the second decade of life and 5 had cataracts), all of them with maternal inheritance. A maternal inheritance was associated with an earlier (within the first 3 decades of life) age at symptom onset relative to a paternal inheritance in this combined cohort, and this association was independent of the patient's sex (OR [95% CI] = 4.245 [1.429–13.820],p= 0.0117). However, this association was not observed in the MDFFR DM2 cohort (n = 127), possibly because age at onset was self-reported, and the information about the type of first symptom or medical problem that patients related to DM2 was lacking.DiscussionA maternal inheritance may increase the risk of an early DM2 onset and of cataracts and cardiovascular events as first DM2 manifestations.