Browsing by Author "Perić, Stojan (35750481700)"

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

Background/Aim. Chronic low back pain syndrome (CLBPS) is the most common cause of functional disability and loss of working ability in developed countries. Some research shows that neuropathic pain (NP) is present in almost 50% of patients with CLPBS. The aim of this study was to determine the characteristics of NP and its impact on quality of life (QoL) in patients with CLBPS. Methods. Patients were tested using three questionnaires for NP: Pain Detect Questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, and Douleur Neuropathique 4 questions. Thirty-two patients diagnosed with NP based on current clinical criteria and with positive results for NP on all three NP questionnaires formed an experimental group. A control group consisted of 32 patients with CLBPS who did not fulfill clinical criteria for NP and were negative for NP on all three questionnaires. Hamilton depression and anxiety rating scales (Ham-D and Ham-A, respectively) and Short Form (SF)-36 questionnaire were also applied. Results. According to magnetic resonance imaging (MRI), disc herniation was typically detected in the experimental group, while degenerative changes were commonly found in the control group. Patients from the experimental group had significantly greater intensity of pain, pain radiation in the legs, and the pain was usually presented as episodes of sudden attacks with mild pain between them. The most distinctive features of NP were allodynia, electric shock sensation, and hypoesthesia to prick. Patients from the experimental group also had significantly higher depression and anxiety scores, as well as worse QoL compared to the control group, especially in mental domains. Predictors of worse QoL in the patients with CLBPS were a higher level of anxiety and depression. Conclusion. The presence of allodynia, electric shock-like sensations, and hypoesthesia to prick in patients with CLBPS suggest NP. CLBPS patients with NP had worse scores in mental domains of QoL compared to CLPBS patients without NP. © 2022 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Introduction. Histopathological findings of various inclusions were reported in the central nervous system of amyotrophic lateral sclerosis (ALS) patients but not in the peripheral nerves. Case report. We present a 66-year-old man with lower limb weakness, with later development of weakness in the upper limbs and loss of sphincter control. Neurological examination showed the affection of both upper and lower motor neurons. He had paresthesia on the left side of his body and socks-distribution numbness. Histopathology of the sural nerve and genetic report showed basophilic periodic acid-Schiff (PAS)-positive intra-axonal inclusions and heterozygous L144F mutation in the exon 5 of the SOD1 gene. Conclusion. It seems that the presence of the basophilic peripheral nerve inclusions may suggest a diagnosis of SOD1-positive ALS. © 2023 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes—among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients. © 2017, Springer-Verlag Berlin Heidelberg.

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes—among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients. © 2017, Springer-Verlag Berlin Heidelberg.

[No abstract available]

Amyotrophic lateral sclerosis (ALS) is characterized by weakness, fatigue, loss of balance and coordination. The purpose of the study was to examine gait in ALS patients. Gait was compared in ALS with spinal and bulbar onset, while performing dual mental and motor tasks. Dual-task walking was performed by 27 ALS patients, 13 with spinal- and 14 with bulbar-onset disease. Twenty-nine healthy subjects were used as a control group. The subjects performed a basic, simple walking task, dual-motor task, dual-mental task, and combined motor and mental tasks. Results showed that dual-task paradigm has an effect on gait in ALS patients. Gait was differently affected in spinal and bulbar onset of ALS by some of the given tasks. Mental tasks had a larger effect than motor tasks in all gait parameters. In conclusion, both ALS forms have impaired gait in dual tasks. Simple walk in patients with spinal onset shows higher variability of certain gait parameters compared to bulbar-onset patients and controls. Differences in gait could also indicate postural instability and possible falls in complex walking situations. © 2014 Informa Healthcare.

Amyotrophic lateral sclerosis (ALS) is characterized by weakness, fatigue, loss of balance and coordination. The purpose of the study was to examine gait in ALS patients. Gait was compared in ALS with spinal and bulbar onset, while performing dual mental and motor tasks. Dual-task walking was performed by 27 ALS patients, 13 with spinal- and 14 with bulbar-onset disease. Twenty-nine healthy subjects were used as a control group. The subjects performed a basic, simple walking task, dual-motor task, dual-mental task, and combined motor and mental tasks. Results showed that dual-task paradigm has an effect on gait in ALS patients. Gait was differently affected in spinal and bulbar onset of ALS by some of the given tasks. Mental tasks had a larger effect than motor tasks in all gait parameters. In conclusion, both ALS forms have impaired gait in dual tasks. Simple walk in patients with spinal onset shows higher variability of certain gait parameters compared to bulbar-onset patients and controls. Differences in gait could also indicate postural instability and possible falls in complex walking situations. © 2014 Informa Healthcare.

Guillain–Barré syndrome (GBS) in pregnancy may be a serious disease associated with high maternal and perinatal morbidity and mortality. Herein, we present the long-term maternal and fetal outcomes of five pregnant GBS patients from our center. The mean age of pregnant GBS patients was 29.8 ± 3.1. Two patients had a severe disability at admission. Three patients were treated with intravenous immunoglobulins, while the remaining two were treated with symptomatic therapy. One year after disease onset, one patient had a mild disability, while the remaining four had normal neurological findings. All babies born were healthy and developed normally. GBS in pregnancy may affect both maternal and neonatal outcomes. Early diagnosis and treatment are essential for the outcome. Most patients and their babies have a favorable long-term outcome. © 2021 Japan Society of Obstetrics and Gynecology.

Background: Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by a primary deficiency of α-glucosidase and the associated accumulation of glycogen in lysosomal vacuoles. The deficiency of α-glucosidase can often be detected using an inexpensive and readily accessible dried blood spot test when Pompe disease is suspected. Like several neuromuscular disorders, Pompe disease typically presents with progressive weakness of limb-girdle muscles and respiratory insufficiency. Due to the phenotypic heterogeneity of these disorders, however, it is often difficult for clinicians to reach a diagnosis for patients with Pompe disease. Six hundred and six patients from a European population were recruited onto our study. Inclusion criteria stipulated that index cases must present with limb-girdle weakness or elevated serum creatine kinase activity. Whole exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. A panel of 169 candidate genes for limb-girdle weakness was analysed for disease-causing variants. Results: A total of 35 variants within GAA were detected. Ten distinct variants in eight unrelated index cases (and four siblings not sequenced in our study) were considered disease-causing, with the patients presenting with heterogeneous phenotypes. The eight unrelated individuals were compound heterozygotes for two variants. Six patients carried the intronic splice site c.-13 T > G transversion and two of the six patients also carried the exonic p.Glu176ArgfsTer45 frameshift. Four of the ten variants were novel in their association with Pompe disease. Conclusions: Here, we highlight the advantage of using whole exome sequencing as a tool for detecting, diagnosing and treating patients with rare, clinically variable genetic disorders. © 2017 The Author(s).

Background: Since the outbreak of the coronavirus disease 2019 (COVID-19), an increasing number of Guillain–Barré syndrome (GBS) cases following the infection has been reported. The aim of our study was to detect patients with GBS treated in our hospital over a 1-year period and to compare the characteristics and outcomes of those triggered by COVID-19 with the rest of GBS patients. Our prospective study included 29 patients who were diagnosed with GBS from March 2020 to March 2021. Based on the preceding event, patients were stratified as post-COVID-19 and non-COVID-19. The GBS disability scale (GDS) was used to assess functional disability. Results: We identified 10 (34.5%) patients with post-COVID-19 GBS and 19 (65.5%) patients with non-COVID-19 GBS. The median time from the preceding event to the symptoms onset was longer in post-COVID-19 than in non-COVID-19 GBS patients (p = 0.04). However, the time from the symptom onset to the nadir did not differ (p = 0.12). GDS at admission, as well as at nadir, did not differ between these two groups. The level of proteinorrachia was higher in post-COVID-19 GBS patients (p = 0.035). The most frequent subtype of GBS in both groups was acute inflammatory demyelinating polyneuropathy (AIDP). GDS score at discharge (p = 0.56) did not differ between two study groups. Conclusions: There was no difference in clinical and electrophysiological features, disease course, and outcome in post-COVID-19 compared with non-COVID-19 GBS patients. © 2022, The Author(s).

Background: Since the outbreak of the coronavirus disease 2019 (COVID-19), an increasing number of Guillain–Barré syndrome (GBS) cases following the infection has been reported. The aim of our study was to detect patients with GBS treated in our hospital over a 1-year period and to compare the characteristics and outcomes of those triggered by COVID-19 with the rest of GBS patients. Our prospective study included 29 patients who were diagnosed with GBS from March 2020 to March 2021. Based on the preceding event, patients were stratified as post-COVID-19 and non-COVID-19. The GBS disability scale (GDS) was used to assess functional disability. Results: We identified 10 (34.5%) patients with post-COVID-19 GBS and 19 (65.5%) patients with non-COVID-19 GBS. The median time from the preceding event to the symptoms onset was longer in post-COVID-19 than in non-COVID-19 GBS patients (p = 0.04). However, the time from the symptom onset to the nadir did not differ (p = 0.12). GDS at admission, as well as at nadir, did not differ between these two groups. The level of proteinorrachia was higher in post-COVID-19 GBS patients (p = 0.035). The most frequent subtype of GBS in both groups was acute inflammatory demyelinating polyneuropathy (AIDP). GDS score at discharge (p = 0.56) did not differ between two study groups. Conclusions: There was no difference in clinical and electrophysiological features, disease course, and outcome in post-COVID-19 compared with non-COVID-19 GBS patients. © 2022, The Author(s).

Background/Aim. The prevalence of diabetes mellitus in general population is constantly increasing. On the other hand, the number of diabetic patients with neuropathic pain is large. The aim of the study was to examine influence of neuropathic pain on quality of life (QoL) in patients with diabetic sensorimotor polyneuropathy (DSPN) who did not have any other diabetic complication or any other significant comorbidity. Methods. A total of 32 patients with DSPN and definitive neuropathic pain were compared with 32 patients with DSPN without neuropathic pain. The respondents were matched according to age, gender, and duration of illness. The following scales were used: the Pain Detect Questionnaire, Leeds Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique EN 4 Questions, Hamilton depression and anxiety rating scales, Neuropathy Impairment Score of the Lower Limb (NIS-LL), and the Short Form 36 Health Survey Questionnaire (SF-36). Results. Patients with neuropathic pain had significantly more severe DSPN measured with NIS-LL (p < 0.01). They were more likely to be engaged in physical work (p < 0.05), and had more symptoms of depression (p < 0.05) than patients without neuropathic pain. Patients with neuropathic pain had significantly lower QoL in both physical and mental domains (p < 0.01). Independent predictors of worse QoL in DSPN were presence of depression (beta=-0.58, p < 0.01) and presence of neuropathic pain (beta = -0.23, p < 0.05) - R2adjusted = 0.48. Conclusion. Independent predictors of QoL in patients with DSPN were presence of depression and neuropathic pain, which signifies importance of their early recognition and early treatment. © 2021 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration. Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.

Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration. Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.

Objectives: The aim of our study was to determine if redox imbalance caused by the activities of antioxidant enzymes existed in erythrocytes of type 1 myotonic dystrophy (DM1) patients. Methods: The activities of erythrocyte superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were measured in 30 DM1 patients and 15 healthy controls (HCs). The obtained values were correlated with the Muscular Impairment Rating Scale (MIRS) score and creatine kinase (CK). Results: Superoxide dismutase and catalase activities were lower in DM1 patients compared to HCs. A positive correlation was found between disease duration and MIRS score as well as with glutathione reductase activity. In DM1 patients, there were positive correlations between catalase, glutathione peroxidase, and glutathione reductase activities. After sub-dividing DM1 patients according to CK levels, superoxide dismutase activity was still statistically different from HCs. However, catalase activity was significantly lower only in DM1 patients with increased CK. Discussion: Undesirable alterations in antioxidant enzyme activities during DM1 disease progression may result in conditions favoring oxidative stress and changes in metabolism which together could contribute to muscle wasting. © 2016 Taylor & Francis.

Objectives: The aim of our study was to determine if redox imbalance caused by the activities of antioxidant enzymes existed in erythrocytes of type 1 myotonic dystrophy (DM1) patients. Methods: The activities of erythrocyte superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were measured in 30 DM1 patients and 15 healthy controls (HCs). The obtained values were correlated with the Muscular Impairment Rating Scale (MIRS) score and creatine kinase (CK). Results: Superoxide dismutase and catalase activities were lower in DM1 patients compared to HCs. A positive correlation was found between disease duration and MIRS score as well as with glutathione reductase activity. In DM1 patients, there were positive correlations between catalase, glutathione peroxidase, and glutathione reductase activities. After sub-dividing DM1 patients according to CK levels, superoxide dismutase activity was still statistically different from HCs. However, catalase activity was significantly lower only in DM1 patients with increased CK. Discussion: Undesirable alterations in antioxidant enzyme activities during DM1 disease progression may result in conditions favoring oxidative stress and changes in metabolism which together could contribute to muscle wasting. © 2016 Taylor & Francis.

CTG expansions in DMPK gene, causing myotonic dystrophy type 1 (DM1), are characterized by pronounced somatic instability. A large proportion of variability of somatic instability is explained by expansion size and patient’s age at sampling, while individual-specific differences are attributed to additional factors. The age at onset is extremely variable in DM1, and inversely correlates with the expansion size and individual-specific differences in somatic instability. Three to five percent of DM1 patients carry repeat interruptions and some appear with later age at onset than expected for corresponding expansion size. Herein, we characterized somatic instability of interrupted DMPK expansions and the effect on age at onset in our previously described patients. Repeat-primed PCR showed stable structures of different types and patterns of repeat interruptions in blood cells over time and buccal cells. Single-molecule small-pool PCR quantification of somatic instability and mathematical modeling showed that interrupted expansions were characterized by lower level of somatic instability accompanied by slower progression over time. Mathematical modeling demonstrated that individual-specific differences in somatic instability had greater influence on age at onset in patients with interrupted expansions. Therefore, repeat interruptions have clinical importance for disease course in DM1 patients due to stabilizing effect on DMPK expansions in somatic cells. © 2018 Pešović, Perić, Brkušanin, Brajušković, Rakŏcević-Stojanović and Savić-Pavićević.

CTG expansions in DMPK gene, causing myotonic dystrophy type 1 (DM1), are characterized by pronounced somatic instability. A large proportion of variability of somatic instability is explained by expansion size and patient’s age at sampling, while individual-specific differences are attributed to additional factors. The age at onset is extremely variable in DM1, and inversely correlates with the expansion size and individual-specific differences in somatic instability. Three to five percent of DM1 patients carry repeat interruptions and some appear with later age at onset than expected for corresponding expansion size. Herein, we characterized somatic instability of interrupted DMPK expansions and the effect on age at onset in our previously described patients. Repeat-primed PCR showed stable structures of different types and patterns of repeat interruptions in blood cells over time and buccal cells. Single-molecule small-pool PCR quantification of somatic instability and mathematical modeling showed that interrupted expansions were characterized by lower level of somatic instability accompanied by slower progression over time. Mathematical modeling demonstrated that individual-specific differences in somatic instability had greater influence on age at onset in patients with interrupted expansions. Therefore, repeat interruptions have clinical importance for disease course in DM1 patients due to stabilizing effect on DMPK expansions in somatic cells. © 2018 Pešović, Perić, Brkušanin, Brajušković, Rakŏcević-Stojanović and Savić-Pavićević.