Life Expectancy and Causes of Death in Patients with Myotonic Dystrophy Type 2.

Background: Myotonic Dystrophy type 2 (DM2) is a dominantly inherited multisystem disease caused by a CCTG repeat expansion in intron 1 of the CNBP gene. Although in the last two decades over 1500 patients with DM2 have been diagnosed worldwide, our clinical impression of a reduced life expectancy in DM2 has not been investigated previously. Objective: The aim of this observational study was to determine the life expectancy and the causes of death in patients with genetically confirmed DM2. Methods: We identified the data of all deceased patients with DM2 in the Dutch neuromuscular database between 2000 and 2023. Ages and causes of death and the patients' clinical features during lifetime were determined. Age of death in DM2 was compared to the general population by using life tables with prognostic cohort life expectancy (CLE) and period life expectancy (PLE) data of the Dutch electronic database of statistics (CBS StatLine). Results: Twenty-six deceased patients were identified in the Dutch DM2 cohort (n = 125). Median age of death in DM2 (70.9 years) was significantly lower compared to sex- and age-matched CLE (78.1 years) and PLE (82.1 years) in the Netherlands. Main causes of death were cardiac diseases (31%) and pneumonia (27%). Seven patients (27%) had a malignancy at the time of death. Conclusion: These results provide new insights into the phenotype of DM2. Life expectancy in patients with DM2 is reduced, possibly attributable to multiple causes including increased risk of cardiac disease, pneumonia, and malignancies. The occurrence of a significantly reduced life expectancy has implications for clinical practice and may form a basis for advanced care planning, including end-of-life care, to optimize quality of life for patients with DM2 and their family. Research in larger cohorts should be done to confirm these findings and to ascertain more about the natural course in DM2.

Poor sleep quality and fatigue but no excessive daytime sleepiness in myotonic dystrophy type 2.

BACKGROUND: In myotonic dystrophy type 1 (DM1), sleep disorders are common, with excessive daytime sleepiness (EDS) as a predominant feature. In myotonic dystrophy type 2 (DM2), the presence of sleep disturbances is unknown. OBJECTIVE: To investigate the frequency of EDS, poor sleep quality and fatigue in DM2. METHODS: 29 genetically proven DM2 patients were surveyed using the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index (PSQI) and Checklist Individual Strength. The results were compared with 29 adult onset DM1 patients and 65 population controls, both matched for age and sex. RESULTS: Only 6.9% of DM2 patients had EDS compared with 44.8% of DM1 patients and 6.2% of population controls (DM2-DM1: p=0.001; DM2-controls: p=0.51). Sleep quality was poor (PSQI >5) in both DM2 and DM1 groups, and differed significantly from population controls (DM2 6.5+/-3.0; DM1 6.2+/-3.7; controls 4.3+/-3.0; DM2-controls: p=0.002). Poor sleep quality was not explained by depression or other comorbidity but was mainly due to sleep disturbances as a result of nocturnal pain. Comparable with the DM1 group, DM2 patients experienced severe fatigue (DM2 38.7+/-13.1; DM1 42.9+/-8.5; controls 21.1+/-11.1; DM2-controls: p<0.001). Results were not confounded by abnormal thyroid function or medication use. CONCLUSION: These results provide new insight into the phenotype of DM2 and have consequences for clinical treatment. In addition, the absence of EDS in DM2 is a new discriminative feature with adult onset DM1.

High incidence of falls in patients with myotonic dystrophy type 1 and 2: A prospective study.

We aimed to examine the incidence as well as the circumstances and the consequences of falling in adult patients with myotonic dystrophy type 1 and 2 (DM1/DM2). We performed a prospective cohort study in 209 subjects, of which 102 had DM1, 42 had DM2 and 65 healthy controls. An assessment of their falls was carried out during 100 consecutive days. In addition, falls during the previous year were reported. The primary outcome measure was the number of self-reported falls per participant during these 100 days. The secondary outcome measures included self-reported causes, circumstances and consequences of the falls. Mean (SD) falls per participant in 100 days was seven- to eightfold higher in patients with DM1 (0.74 (0.14)) and DM2 (0.62 (0.20)) compared to the controls (0.09 (0.04); p < 0.001)). Sixteen percent of DM1 and 17% of DM2 patients fell at least twice. Two-thirds of the falls occurred inside. Fifty percent of falls resulted in an injury, including a head trauma in four patients. Compared to non-fallers, those patients who fell were older (DM1/DM2), had a lower DM1-Activ score (DM1), had more muscle weakness (DM1), and reported less confidence in balance (DM1). This study demonstrates a high incidence and clinical relevance of falling in patients with DM1 and DM2. Fall prevention strategies in both DM1 and DM2 should focus on adaptations of the home environment and the patient's interaction in this environment.

Gastrointestinal involvement is frequent in Myotonic Dystrophy type 2.

The phenotype of DM2 shows similarities as well as differences to that of Myotonic Dystrophy type 1 (DM1). Gastrointestinal dysfunction is common in DM1 and 25% of the patients consider this to be the most disabling consequence of the disease. Little is known about gastrointestinal involvement in Myotonic Dystrophy type 2 (DM2). The aim of the study was to explore the occurrence and characteristics of gastrointestinal symptoms in patients with DM2. This was compared to symptoms in adult-onset DM1 patients, and to age- and sex-matched healthy controls. Twenty-nine genetically proven DM2 patients filled out two standardized questionnaires about gastrointestinal symptoms; most important outcome measures were answers to questions about dysphagia, abdominal pain, and constipation. The results were compared to those of 29 adult-onset DM1 patients, and to 87 age- and sex-matched healthy controls. Radiological measurement of colon transit time was investigated in 18 DM2 patients. Dysphagia for liquids (38%) and solid food (41%), abdominal pain (62%), and constipation (62%) were all significantly more common among DM2 patients than among healthy controls, and comparable to their occurrence in DM1. Colon transit time was increased in 24% of the DM2 patients. Our results show that gastrointestinal symptoms are highly prevalent in DM2 patients. Gastrointestinal dysfunction may be attributed to any part of the gastrointestinal tract. The results provide new insight into the clinical picture of DM2.

Qualitative and Quantitative Aspects of Pain in Patients With Myotonic Dystrophy Type 2.

Pain is a common but often ignored symptom in patients with myotonic dystrophy type 2 (DM2). In this explorative study, we assessed qualitative and quantitative aspects of pain in DM2 using 4 questionnaires and quantitative sensory testing. A disease control group (fibromyalgia [FMS]) as well as healthy controls were used to compare the results, because pain in DM2 shows many clinical similarities to pain in FMS. Thirty-four patients with genetically confirmed DM2 (71% female, mean age 54 years), 28 patients with FMS, and 33 healthy controls were included, age- as well as sex-matched. Pain prevalence was 65% in DM2, 100% in FMS (P < .001), and 15% in healthy controls (P < .001). The mean of the pressure pain thresholds was lower in DM2 than in healthy controls (P = .016), with the largest differences in the rectus femoris, trapezius, and thenar muscles. Mechanical and electric pain thresholds were significantly higher in DM2 than in FMS, and no differences were found in electric pain thresholds between DM2 and healthy controls. These results confirm that pain is a frequent and important symptom in patients with DM2, affecting quality of life. Peripheral mechanisms of pain seem to play a role in DM2. The widespreadness of the hyperalgesia suggests central sensitization, but this finding was not supported by the other results. This study opens new avenues for further research and eventually novel treatment strategies, in DM2 as well as in other muscular disorders. PERSPECTIVE: This article presents qualitative as well as quantitative aspects of pain in patients with DM2. Pain is a frequent and important symptom in patients with DM2, affecting quality of life. We found mechanical hyperalgesia, indicative of a peripheral mechanism of pain. The widespreadness of hyperalgesia may suggest central sensitization, but this finding was not supported by other results and needs further exploration.

Hearing impairment in patients with myotonic dystrophy type 2.

OBJECTIVE: To systematically assess auditory characteristics of a large cohort of patients with genetically confirmed myotonic dystrophy type 2 (DM2). METHODS: Patients with DM2 were included prospectively in an international cross-sectional study. A structured interview about hearing symptoms was held. Thereafter, standardized otologic examination, pure tone audiometry (PTA; 0.25, 0.5, 1, 2, 4, and 8 kHz), speech audiometry, tympanometry, acoustic middle ear muscle reflexes, and brainstem auditory evoked potentials (BAEP) were performed. The ISO 7029 standard was used to compare the PTA results with established hearing thresholds of the general population according to sex and age. RESULTS: Thirty-one Dutch and 25 French patients with DM2 (61% female) were included with a mean age of 57 years (range 31-78). The median hearing threshold of the DM2 cohort was higher for all measured frequencies, compared to the 50th percentile of normal (p < 0.001). Hearing impairment was mild in 39%, moderate in 21%, and severe in 2% of patients with DM2. The absence of an air-bone gap with PTA, concordant results of speech audiometry with PTA, and normal findings of BAEP suggest that the sensorineural hearing impairment is located in the cochlea. A significant correlation was found between hearing impairment and age, even when corrected for presbycusis. CONCLUSIONS: Cochlear sensorineural hearing impairment is a frequent symptom in patients with DM2, suggesting an early presbycusis. Therefore, we recommend informing about hearing impairment and readily performing audiometry when hearing impairment is suspected in order to propose early hearing rehabilitation with hearing aids when indicated.

High disease impact of myotonic dystrophy type 2 on physical and mental functioning.

The aim of the study was to investigate health status in patients with myotonic dystrophy type 2 (DM2) and determine its relationship to pain and fatigue. Data on health status (SF-36), pain (MPQ) and fatigue (CIS-fatigue) were collected for the Dutch DM2 population (n = 32). Results were compared with those of sex- and age-matched adult-onset myotonic dystrophy type 1 (DM1) patients. In addition, we compared the obtained scores on health status of the DM2 group with normative data of the Dutch general population (n = 1742). Compared to DM1, the SF-36 score for bodily pain was significantly (p = 0.04) lower in DM2, indicating more body pain in DM2. DM2 did not differ from DM1 on any other SF-36 scales. In comparison to the Dutch population, DM2 patients reported lower scores (indicating worse clinical condition) on the physical functioning, role functioning-physical, bodily pain, general health, vitality, social functioning, and role functioning-emotional scales (p < 0.01 on all scales). The difference was most profound for the physical functioning scale. In the DM2 group the severity of pain was significantly correlated with SF-36 scores for bodily pain (p = 0.003). Fatigue was significantly correlated with the SF-36 scores for role functioning-physical (p = 0.001), general health (p = 0.02), and vitality (p = 0.02). The impact of DM2 on a patients' physical, psychological and social functioning is significant and as high as in adult-onset DM1 patients. From the perspective of health-related quality of life, DM2 should not be considered a benign disease. Management of DM2 patients should include screening for pain and fatigue. Symptomatic treatment of pain and fatigue may decrease disease impact and help improve health status in DM2, even if the disease itself cannot be treated.

Dutch myotonic dystrophy type 2 patients and a North-African DM2 family carry the common European founder haplotype.

Myotonic dystrophy type 2 (DM2) is a progressive multisystem disease with muscle weakness and myotonia as main characteristics. The disease is caused by a repeat expansion in the zinc-finger protein 9 (ZNF9) gene on chromosome 3q21. Several reports show that patients from European ancestry share an identical haplotype surrounding the ZNF9 gene. In this study, we investigated whether the Dutch DM2 population carries the same founder haplotype. In all, 40 Dutch DM2 patients from 16 families were genotyped for eight short tandem repeat markers surrounding the ZNF9 gene. In addition, the single-nucleotide polymorphism (SNP) rs1871922 located in the first intron of DM2 was genotyped. Results were compared with previously published haplotypes from unrelated Caucasian patients. The repeat lengths identified in this study were in agreement with existing literature. In 36 patients of our population, we identified three common haplotypes. One patient showed overlap with the common haplotype for only one marker closest to the ZNF9 gene. The haplotype from a family originating from Morocco showed overlap with that of the patients of European descent for a region of 222 kb. All patients carried at least one C allele of SNP rs1871922 indicating that all patients carry the European founder haplotype. We conclude that DM2 patients from the Netherlands, including a North-African family, harbor a common haplotype surrounding the ZNF9 gene. This data show that the Dutch patients carry the common founder haplotype and strongly suggest that DM2 mutations in Europe and North Africa originate from a single ancestral founder.