Overview
This lecture covers Myotonic Dystrophy Type 1 (DM1), including its genetics, symptoms, inheritance patterns, symptom management, and emerging treatments.
Epidemiology & Disease Variability
- DM1 affects more people than previously thought, with about 1 in 2,100 carrying the genetic mutation in the US.
- The disease is highly variable; symptoms can appear anytime from birth to old age.
- Symptom type and severity vary widely among individuals, even within families.
Genetics & Inheritance
- DM1 is caused by expanded CTG repeats (>50) in the DMPK gene on chromosome 19.
- Inheritance is autosomal dominant; each child of an affected parent has a 50% chance of inheriting the mutation.
- The number of repeats can increase with each generation ("anticipation"), especially via maternal transmission.
- Somatic instability means repeat size can increase in tissues over a person's life.
Disease Mechanism
- Expanded CTG repeats are transcribed into RNA with extra CUG repeats, forming toxic clumps in cell nuclei.
- These RNA clumps trap RNA-binding proteins, disrupting RNA splicing in many genes.
- Mis-splicing affects multiple organ systems, causing muscle, cardiac, metabolic, and cognitive symptoms.
Symptoms & Management
- Myotonia: Delayed muscle relaxation (e.g., trouble releasing a fist); can be treated with medications like mexiletine, after EKG screening.
- Muscle Weakness: Affects distal muscles (hands, lower legs), neck, face, and breathing muscles; no FDA-approved treatments; physical activity is encouraged.
- Assistive Devices: Increasing use of ankle braces, walkers, and wheelchairs with age.
- Cardiac Issues: Mostly affects electrical conduction; annual EKG is essential, with possible need for pacemaker.
- Excessive Daytime Sleepiness: Can result from sleep apnea, weak breathing muscles, or direct brain effects; managed by sleep studies, noninvasive ventilation, or stimulants.
- GI Symptoms: Can affect the whole digestive tract; managed by tailoring treatment with a GI specialist, recognizing that triggers and therapies differ by person.
Other Considerations
- People with DM1 are more sensitive to anesthesia and certain drugs.
- There is an increased risk of cancers (skin, uterine, thyroid, colon) in DM1; follow age-appropriate screening.
- New treatments are being developed to target the disease at the genetic and RNA levels, including RNA-directed therapies.
Key Terms & Definitions
- DM1 (Myotonic Dystrophy Type 1) — A genetic disorder caused by CTG repeat expansion in the DMPK gene.
- Myotonia — Delayed relaxation after muscle contraction.
- Anticipation — Worsening and earlier onset of symptoms in successive generations.
- Somatic Instability — Growth of CTG repeats in tissues over time.
- RNA-binding proteins — Proteins that regulate RNA processing and are disrupted in DM1.
- Autosomal dominant — Inheritance where one mutated gene copy is sufficient for disease.
Action Items / Next Steps
- Ensure annual EKGs and regular cardiac monitoring.
- Consult therapists and doctors familiar or willing to learn about DM1.
- Engage in safe, regular physical activity.
- Discuss GI symptoms and management with a GI specialist.
- Use MDF care and anesthesia guidelines during surgeries or procedures.
- Attend additional lectures on GI management in DM1.
- Maintain routine cancer screenings and dermatology visits.
- Monitor for updates on new DM1 therapies.