A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype

Abstract

Carriage of interruptions in CTG repeats of the myotonic dystrophy protein kinase gene has been associated with a broad spectrum of myotonic dystrophy type 1 (DM1) phenotypes, mostly mild. However, the data available on interrupted DM1 patients and their phenotype are scarce. We studied 49 Spanish DM1 patients, whose clinical phenotype was evaluated in depth. Blood DNA was obtained and analyzed through triplet-primed polymerase chain reaction (PCR), long PCR-Southern blot, small pool PCR, AciI digestion, and sequencing. Five patients of our registry (10%), belonging to the same family, carried CCG interruptions at the 3′-end of the CTG expansion. Some of them presented atypical traits such as very late onset of symptoms ( > 50 years) and a severe axial and proximal weakness requiring walking assistance. They also showed classic DM1 symptoms including cardiac and respiratory dysfunction, which were severe in some of them. Sizes and interrupted allele patterns were determined, *Alfonsina Ballester-Lopez and Emma Koehorst contributed equally to this work. and we found a contraction and an expansion in two intergenerational transmissions.Our study contributes to the observation that DM1 patients carrying interruptions present with atypical clinical features that can make DM1 diagnosis difficult, with a later than expected age of onset and a previously unreported aging-related severe disease manifestation. K E Y W O R D S atypical symptoms, interruptions, late onset, myotonic dystrophy type 1, severe phenotype, Steinert disease, variant repeats SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Ballester-Lopez A, Koehorst E, Almendrote M, et al. A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype. Human Mutation. 2020;41:420-431.

Stable Longitudinal Methylation Levels at the CpG Sites Flanking the CTG Repeat of DMPK in Patients with Myotonic Dystrophy Type 1

“…Supporting this, a correlation between methylation levels and age of onset has been reported previously [4,19]. Repeat interruptions have been linked to both higher downstream methylation levels [4,20] and later disease onset [16,17], and it is thus likely that this effect would have to be accounted for if an association between methylation levels and age of onset is to be made. The results of our longitudinal methylation study indicated that the methylation levels do not change with age, which contradicts the idea that age is a modifier of DMPK methylation levels.…”

“…Research over the last decade has shown that the variability in clinical phenotype and age of onset can be correlated to sequence interruptions in the CTG repeat [13,[16][17][18], as well as DNA methylation of the area surrounding the CTG repeat [19,20]. The hypermethylation of the DM1 locus was, at first, thought to only be present in patients with congenital onset DM1 (CDM1) [21]; however, studies have shown hypermethylation to also be present in patients with non-congenital DM1 [4,19,22] and particularly in patients with repeat interruptions [4,20].…”

“…Barbè et al [19] reported the hypermethylation of both upstream and downstream CpG sites, mainly in patients with maternal inheritance of the disease allele and only in patients with more than 600 CTG repeats, while Legarè et al [20] observed variability in the methylation of downstream, but not upstream, CpG sites. While repeat interruptions have been associated with later onset [16,17], lower levels of somatic instability [17,18], and a milder phenotype [18], the association of methylation with clinical features has been more unclear. Hypermethylation has been correlated with earlier disease onset [4,19], muscular and respiratory features [20], and longer CTG repeats [4,19,20] but also with lower levels of somatic instability [20].…”

An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics

“…Similarly, a DM1 family was found to have ‘CCG’ interruptions within the ‘CTG’ STR expansion in DMPK resulting in atypical traits such as severe axial and proximal weakness and late onset of symptoms [ 9 ].…”

High Throughput Screening for Expanded CTG repeats in Myotonic Dystrophy Type 1 Using Melt Curve Analysis

“…With traditional TP-PCR careful examination of the electropherograms from published reports of DM1 cases with interrupted CTG repeats show that the TP-PCR reaction does not fail, but proceeds with interruptions to the typical sawtooth pattern seen from uninterrupted CTG repeats. 11, 29, 31, 32 Indeed, TP-PCR has been used in search of interrupted repeats. 33 As we have shown by melt curve reconstruction, since our application of MCA uses the full spectrum of TP-PCR products, it is robust at detecting differences in the relative proportion of fragment lengths.…”