PracticeUpdate

Family With Myotonic Dystrophy 1 Shown to Carry Interruptions Exhibiting Milder, Atypical Phenotype MD1 interruptions may carry potential consequences for diseasemanagement A family with myotonic dystrophy 1 has been shown to carry interruptions showing a milder and atypical phenotype, according to a case report presented at ICNMD 2018. disease paternally. Participant 4 (P4) was the son of participant 3 and mother and son exhibited the same interruption pattern. The remaining sisters harbored a different interruption pattern. The male interrupted participant (P4, age 37 years) was com- pletely asymptomatic on clinical examination, despite the 108 CTG progenitor allele.

Emma A. Koehorst, MSc, of the Institute for Health Science Research Germans Trias i Pujol Research Center in Badalona, Spain, and colleagues described a family with myotonic dystrophy 1 that was shown to carry interruptions showing a milder and atypical phenotype.

The three sisters exhibited most typical features of myotonic dystrophy 1, but without predominant distal weakness. The most remarkable observation was that the three sisters’ symptoms began at a later age (>50 years). This classified them as suffering from late-onset myotonic dystrophy 1. Their symptoms largely resembled a classic/adult phenotype. Ms. Koehorst explained that in recent years, individuals with myotonic dystrophy 1 who carry variant repeat patterns in CTG expansion have been described. Phenotypical consequences of interrupted CTG expansion remain highly controversial. Variant repeat patterns have been associated with a com- plex co-segregated neurological phenotype, including an intermediate Charcot-Marie-Tooth neuropathy, deafness, and encephalopathy. A milder phenotype with later age of onset, absence of muscle atrophy, CNS involvement, or an atypical phenotypewith symptoms resemblingmyotonic dystrophy 2 has also been found. The number of described individualswithmyotonic dystrophy 1 who exhibit these interruptions is low (estimated prevalence 3% to 5%). Ms. Koehorst concluded that the presence of four interrupted cases was reported in a cohort of 50 individuals with myotonic dystrophy 1. Prevalence was 3.4 % in these families with myotonic dystrophy 1. The cohort exhibited inheritability of the interruption pattern, an exact replica in terms of maternal transmission. “We found classic symptoms in our interrupted patients,” Ms. Koehorst asserted, “including cardiac involvement and myoto- nia. Age of onset, however, was surprisingly late (>50 years of age), uncommon with these presenting symptoms. In addition, the male interrupted patient is still asymptomatic, despite his age of 37 years. Furthermore, our interrupted patients show a shift in muscle involvement to a more proximal rather than distal weakness, mostly observed in uninterrupted patients with myotonic dystrophy 1.” She continued, “The prevalence of 2.7% of interrupted cases in our cohort is similar to the previously observed prevalence of 3% to 5%. Our dataset is small, however, and we will continue to collect data and introduce new patients into our cohort to further analyze the effect these interruptions exert and their potential consequences for disease management.” The results contribute to observations of a milder and/or atypical clinical phenotype of variant repeat carrying in patients with myotonic dystrophy 1. Age of onset is later than expected and weakness is predominantly proximal. The latter resembles the phenotype of myotonic dystrophy 2. www.practiceupdate.com/c/70785

Ms. Emma A. Koehorst Ms. Koehorst explained to Elsevier’s PracticeUpdate , “Myotonic dystrophy 1 is a muscle dystrophy characterized by wide phenotypic variability. Myotonic dystrophy 1 can be explained only partly by underlying RNA toxicity, meaning that other disease modifiers influence the clinical phenotype.” She continued, “Until recently, it was thought that CTG expansion was an uninterrupted sequence. However, variant repeat expan- sions have been found such as CTC, CCG, CGG, and CAG. The effect that these interruptions exert on the clinical phenotype is controversial and data are scarce due to low prevalence of the interruptions. Speculations range from a milder phenotype to a complex co-segregated neurological phenotype. This con- troversy and lack of data led us to undertake this case study.” Ms. Koehorst and colleagues analyzed a cohort of 50 individuals with myotonic dystrophy 1 to find new individuals carrying inter- ruptions and to determine their clinical phenotypes. Blood DNA was obtained from participants and triplet-primed polymerase chain reaction at the 5’ and 3’ sites was performed. Acil digestion and sequencing was used to determine the pres- ence of these interruptions and type of interruption present (CCG, CTC, or GGC). Of the 50 individuals with myotonic dystrophy 1, four were found to harbor CCG interruptions in the 3’ end of CTG expansion. These individuals were found to belong to the same family, in which participants 1, 2, and 3 were sisters who inherited the including cardiac involvement and myotonia. Age of onset, however, was surprisingly late (>50 years of age), uncommon with these presenting symptoms. " " We found classic symptoms in our interrupted patients,

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