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Genetic variations in myotonic dystrophy type 1: A case study of cytosine– thymine–guanine repeat expansions across different age groups
Correspondence to SUSMIT KOSTA; susmitkosta@gmail.com
[To cite: Kosta S, Sahu R, Joshi P, Bhandari S. Genetic variations in myotonic dystrophy type 1: A case study of cytosine–thymine–guanine repeat expansions across different age groups. Natl Med J India 2025;38: 000–0 DOI: 10.25259/NMJI_1307_2024]
Abstract
We report 3 cases of myotonic dystrophy type 1 (DM1), highlighting the spectrum of clinical presentations across different age groups and severity levels. DM1 is caused by an expansion of cytosine–thymine–guanine (CTG) repeats in the dystrophia myotonica protein kinase (DMPK) gene, with the number of repeats correlating with disease severity. The first patient, an 11-year-old boy with childhood-onset DM1 presented with progressive muscle weakness, difficulty in walking and muscle stiffness. Genetic testing revealed 900 CTG repeats. He was managed with physical therapy and monitored for systemic complications, such as cardiac issues. The second patient was a 25-year-old man with classical DM1, who experienced worsening muscle weakness, difficulty gripping objects and choking episodes. His creatine kinase (CK) levels were elevated, indicating active muscle damage. Genetic testing confirmed 650 CTG repeats, and a multidisciplinary approach was initiated to manage his symptoms and monitor for respiratory and cardiac complications. The third patient was a 40-year-old man with mild DM1, who presented with generalized fatigue, muscle stiffness and difficulty gripping objects. Despite normal CK levels, electromyographic findings showed mild myotonic discharges. Genetic testing revealed 150 CTG repeats, and the patient was advised to follow a tailored exercise regimen to maintain muscle function. In all 3 patients, early diagnosis, based on clinical, biochemical, and genetic findings, was essential for managing the disease and improving outcomes. Whole exome sequencing (WES) was used to exclude other potential neuromuscular and genetic disorders by analyzing the protein-coding regions of the genome, whereas triplet repeat polymerase chain reaction was done to quantify the CTG repeat expansions in the DMPK gene.
INTRODUCTION
Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, a genetic disorder that affects multiple systems in the body. It is characterized by progressive muscle weakness, myotonia (delayed muscle relaxation after contraction) and complications affecting the cardiac, respiratory, endocrine and nervous systems. DM1 is caused by an abnormal expansion of cytosine–thymine– guanine (CTG) trinucleotide repeats in the 32 untranslated region of the serine–threonine kinase dystrophia myotonica protein kinase (DMPK) gene located on chromosome 19q13.3.1 The severity of the disease is directly correlated with the number of CTG repeats, where larger expansions typically result in more severe clinical presentations.
DM1 is classified into several subtypes depending on the age of onset and the severity of symptoms. These include congenital or childhood-onset DM1, which is usually the most severe form, as well as classical/adult-onset DM1 and mild DM1, which tend to have a later onset and milder symptoms. Congenital DM1 presents early in life, often with severe developmental delays, hypotonia and respiratory issues. Classical DM1 generally manifests in late adolescence or adulthood, with symptoms including muscle weakness, myotonia, and systemic involvement. In contrast, mild DM1 may present with subtle symptoms, such as fatigue or muscle stiffness, and typically occurs later in life.2,3
Globally, DM1 affects an estimated 1 in 8 000–20 000 individuals, with a higher prevalence in individuals of European descent. In India and other parts of Asia, DM1 is considered to be underdiagnosed due to a combination of genetic variability and limited access to diagnostic tools.4 Despite this, available data suggest that the prevalence in India is approximately 1 in 20 000 individuals, although this can vary by region. Underdiagnosis remains a challenge due to overlapping symptoms with other neuro-muscular disorders and the varying degrees of disease severity.
The pathophysiology of DM1 involves the expansion of CTG repeats within the DMPK gene, leading to a toxic RNA gain-of-function effect that disrupts normal cellular processes. The number of repeats correlates with the severity of the disease. Individuals with less than 35 CTG repeats are typically unaffected, while those with 50 or more repeats are at risk of developing DM1. Patients with larger expansions, particularly those with over 1000 repeats, are more likely to develop congenital or early onset forms of the disease.5
The diagnosis of DM1 involves a combination of clinical, biochemical, electrophysiological, and genetic testing. Clinical evaluation often reveals characteristic features of myotonia, muscle weakness and multisystem involvement. Biochemical markers, such as elevated creatine kinase (CK) levels, may indicate muscle damage, though CK levels may be normal in milder cases. Electromyography (EMG) can provide supportive evidence by identifying myotonic discharges and delayed muscle relaxation. However, a definitive diagnosis relies on genetic testing, including whole-exome sequencing (WES) to rule out other potential genetic disorders, and triplet repeat-polymerase chain reaction (TP-PCR) to measure the size of CTG repeat expansions in the DMPK gene.
We report patients of DM1 across different age groups, including childhood, classical, and mild forms, to highlight the variability in clinical presentation and the importance of early detection and personalized management. By integrating clinical findings with advanced genetic testing methods such as WES and TP-PCR, we emphasize the role of genetic diagnosis in optimizing patient care and improving long-term outcomes for individuals with DM1.
THE CASES
We report 3 patients, each diagnosed with DM1, who were treated at our hospital. These patients represent different age groups, with the first one classified as childhood-onset DM1 (11 years old), the second as classical DM1 (25 years old) and the third as mild DM1 (40 years old). Each patient was selected based on clinical presentation, and the diagnosis was confirmed through genetic testing.
Each patient underwent a detailed clinical assessment, including a detailed medical and family history. A comprehensive neurological examination was done to assess muscle strength, tone and reflexes. The presence of myotonia was noted based on delayed relaxation after muscle contraction. Routine biochemical tests were done to measure CK levels as an indicator of muscle damage. EMG was conducted for all three patients to assess muscle function and detect the characteristic myotonic discharges (electrical activity indicating delayed muscle relaxation after contraction) associated with DM1. Genetic testing was done using 2 methods to confirm the diagnosis and assess the extent of CTG repeat expansion in the DMPK gene. WES was used to rule out other potential neuromuscular and genetic disorders by sequencing the protein-coding regions of the genome.TP-PCRwas used to measure the number of CTG repeats in the DMPK gene.
Case 1. Childhood-onset DM1
An 11-year-old boy presented with typical symptoms of childhood-onset DM1, including progressive muscle weakness, difficulty walking and muscle stiffness. Despite having no family history of DM1, the clinical symptoms were suggestive of a neuromuscular disorder. The patient’s symptoms, including lower limb weakness, fatigue and declining school performance, highlighted the early systemic involvement of childhood DM1.
Clinically, the patient exhibited progressive muscle weakness and delayed motor milestones, hallmarks of childhood DM1. The mildly elevated CK levels (400 U/L) indicated ongoing muscle damage, though not severe. EMG confirmed myotonic discharges, a critical diagnostic finding in DM1 (Table 1). Genetic testing using TP-PCR revealed the presence of 900 CTG repeats, indicative of a severe form of childhood DM1, while WES confirmed the absence of other genetic disorders (Table 2).
| Item | Childhood DM1 (begins around 10 years of age) | Classical DM1 (10–30 years) | Mild DM1 (20–70 years) | Normal range |
|---|---|---|---|---|
| Age (years) | 11 | 25 | 40 | – |
| Clinical presentation |
|
|
|
|
| Biochemical findings |
|
|
|
|
| Neurological/EMG findings |
|
|
|
|
| Item | Childhood DM1 (begins around 10 years of age) | Classical DM1 (10–30 years) | Mild DM1 (20–70 years) | Normal range |
|---|---|---|---|---|
| Age (years) | 11 | 25 | 40 | - |
| Whole exome sequencing | ||||
| Dystrophia myotonica protein kinase | No significant mutation | |||
| Chromosomal location | 19q13.32 (OMIM: 605377) | 19q13.32 (OMIM: 605377) | 19q13.32 (OMIM: 605377) | - |
| Inheritance | Autosomal dominant | Autosomal dominant | Autosomal dominant | |
| Cytosine–thymine–guanine trinucleotide repeat size by TP-PCR | ||||
| 900 repeats | 650 repeats | 150 repeats | <35 repeats | |
TP-PCR triplet repeat polymerase chain reaction
Physical therapy was initiated to preserve muscle function, and regular follow-up was recommended to monitor for systemic complications, especially cardiac issues. The high number of CTG repeats correlates with the severity of the disease and predicts a more challenging prognosis, requiring lifelong management. Genetic counselling was provided to the family, despite the absence of a family history, to prepare them for potential future hereditary implications.
Case 2: Classical/adult-onset DM1
A 25-year-old male presented with worsening muscle weakness, difficulty walking and choking episodes. Symptoms began in his late twenties and progressively worsened, a typical presentation of classical DM1. He also reported difficulty gripping objects and climbing stairs, indicating that muscular involvement was present in daily activities.
This patient’s CK levels were significantly elevated (700 U/L), reflecting active muscle damage. EMG confirmed myotonic discharges, and TP-PCR detected 650 CTG repeats, confirming classical DM1. Genetic testing using WES excluded other neuromuscular disorders.
Regular monitoring for respiratory and cardiac issues, along with genetic counselling, was critical for managing this patient’s condition. He was also advised of the hereditary risks of DM1, as future offspring could inherit the disorder.
Case 3: Mild DM1
A 40-year-old male with mild DM1, presented with generalized fatigue, muscle stiffness in his hands and forearms and difficulty gripping objects. The patient had been experiencing symptoms since adolescence, but they had remained manageable. He had no significant rise in CK levels, indicating no active muscle damage; however, EMG studies revealed mild myotonic discharges, which supported a diagnosis of DM1. TP-PCR revealed 150 CTG repeats, confirming mild DM1. He was advised to follow a tailored exercise regimen, with periodic follow-up to monitor for any emerging complications, particularly involving the cardiac and respiratory systems.
DISCUSSION
These patients collectively illustrate the variability in the presentation and severity of DM1 across different age groups and genetic profiles. The number of CTG repeats strongly correlates with the severity of symptoms, with larger expansions leading to more severe forms of the disease. Case 1 (childhood-onset DM1) had the highest number of CTG repeats (900), leading to early and severe symptoms, whereas Case 3 (mild DM1) had the lowest number (150), resulting in a milder and later-onset form of the disease. All the patients highlight the importance of early and accurate diagnosis using a combination of clinical evaluation, biochemical markers, EMG and genetic testing. The role of WES and TP-PCR in confirming the diagnosis of DM1 is particularly crucial, as these provide definitive information about the nature and severity of the disease. WES excluded other genetic disorders, and TP-PCR identified CTG repeat expansions in the DMPK gene, confirming DM1 and its severity. Personalized management strategies, including physical therapy, multidisciplinary monitoring, and genetic counseling, are key to optimizing patient outcomes, regardless of the severity of the condition.
Conflicts of interest
None declared
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