Duchenne Muscular Dystrophy and Muscle Pathology

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Questions and Answers

What is a consequence of persistent inflammation in the context of muscle damage?

Secondary necrosis (correct)

Reduced calcium influx

Increased muscle fiber regeneration

Primary necrosis

In Duchenne Muscular Dystrophy (DMD), the absence of dystrophin directly causes what?

Reduced chronic inflammation

Decreased calcium influx

Constant degeneration leading to chronic inflammation (correct)

Increased production of antioxidants

What is the approximate concentration of calcium ions outside of a muscle fiber?

100 nM

10 mM

1 mM

2 mM (correct)

In DMD, the damage to the muscle plasma membrane causes an influx of calcium into the muscle fiber. What are two direct outcomes of this?

Calpain activation and increased reactive oxygen species (ROS) production (A) Signup and view all the answers

Which type of muscle fiber is most susceptible to dystrophic pathology in DMD?

Fast glycolic fibers (B) Signup and view all the answers

What is the primary genetic cause for the majority of Cri du chat syndrome cases?

A de novo partial deletion of the short arm of chromosome 5. (B) Signup and view all the answers

In most instances of Cri du chat syndrome arising from a de novo deletion, which parent's chromosome is typically affected?

The paternal chromosome. (D) Signup and view all the answers

Which of the following is NOT a characteristic associated with muscular dystrophies?

Increased muscle mass due to overcompensation. (B) Signup and view all the answers

What is the primary function of PGC-1a?

Master regulator of mitochondrial biogenesis (A) Signup and view all the answers

What is a common feature in the pathophysiology of Duchenne Muscular Dystrophy (DMD)?

Calcium overload in muscle fibers due to a lack of dystrophin. (D) Signup and view all the answers

Which of the following is NOT a consequence of decreased PGC-1a levels?

Promotion of the slow oxidative phenotype (C) Signup and view all the answers

How does Becker's Muscular Dystrophy (BMD) differ from Duchenne Muscular Dystrophy (DMD) at a molecular level?

BMD is caused by abnormal dystrophin, whereas DMD is caused by a complete absence of dystrophin. (A) Signup and view all the answers

Limitations associated with Muscular Dystrophy include all of the following EXCEPT:

Increased muscle strength. (B) Signup and view all the answers

Utrophin is structurally and functionally most similar to which protein?

Dystrophin (C) Signup and view all the answers

In adult muscle, where is utrophin predominantly located?

Myotendinous and neuromuscular junctions (A) Signup and view all the answers

What can be said of the incidence of muscular dystrophies?

They affect approximately 1 in 3500 live male births. (D) Signup and view all the answers

For a female to express a recessive X-linked disease, what must be true of her X chromosomes?

Both X chromosomes must carry the mutated gene. (B) Signup and view all the answers

During which stage of development is utrophin ubiquitously expressed throughout the sarcolemma?

Fetal muscle development (B) Signup and view all the answers

Which of the following modes of inheritance is associated with Hemophilia A?

X-linked recessive. (D) Signup and view all the answers

If a male inherits a mutated X chromosome, what is the likely outcome, assuming the mutation is recessive?

He will express the disease. (C) Signup and view all the answers

What percentage chance does a carrier mother have of passing a mutated dystrophin gene to her son?

50% (B) Signup and view all the answers

What is the primary genetic cause of Duchenne Muscular Dystrophy (DMD)?

Complete absence of dystrophin due to gene deletions or stop codon mutations. (D) Signup and view all the answers

In Duchenne Muscular Dystrophy (DMD), what percentage of cases in boys are inherited from their mothers?

70% (B) Signup and view all the answers

What is the function of dystrophin in muscle cells?

It stabilizes muscle membranes. (D) Signup and view all the answers

Which of the following best describes the inheritance pattern of DMD?

X-linked recessive. (A) Signup and view all the answers

What is the primary consequence of dystrophin loss?

Muscle fragility and degeneration. (B) Signup and view all the answers

What is a common consequence, besides skeletal muscle weakness, seen in individuals affected by DMD?

Mild cognitive impairment. (C) Signup and view all the answers

What is the role of serum creatine kinase (CK) in the context of muscle damage?

It is a marker of muscle damage. (B) Signup and view all the answers

What is a significant cause of mortality in individuals with Duchenne Muscular Dystrophy (DMD)?

Cardiomyopathy. (B) Signup and view all the answers

Which of the following is NOT a type of cell involved in muscle function or dysfunction according to the provided image?

Osteoclasts. (D) Signup and view all the answers

What is crucial for healthy muscle regeneration?

An acute inflammatory response. (D) Signup and view all the answers

Which statement accurately reflects the global incidence of DMD in males?

1 in every 3,500 boys worldwide. (C) Signup and view all the answers

What does a mutation in the dystrophin gene lead to in the context of DMD?

The absence or non-functional dystrophin protein. (B) Signup and view all the answers

According to the content, which specific exon is most commonly involved in the mutations that cause DMD?

Exon 45. (A) Signup and view all the answers

What is the primary function of utrophin in the context of Duchenne Muscular Dystrophy (DMD)?

To act as a substitute for the missing dystrophin. (B) Signup and view all the answers

How does the severity of Becker Muscular Dystrophy (BMD) typically compare to that of Duchenne Muscular Dystrophy (DMD)?

BMD is generally less severe than DMD. (C) Signup and view all the answers

In Becker Muscular Dystrophy (BMD), what is a common molecular consequence that leads to the production of truncated dystrophin?

In-frame skipping of exons leading to a shorter protein. (A) Signup and view all the answers

What is a characteristic clinical feature that is more likely to be observed in Becker Muscular Dystrophy (BMD) compared to Duchenne Muscular Dystrophy (DMD)?

Cardiac abnormalities as an initial sign of disease. (C) Signup and view all the answers

What is the approximate incidence rate of Becker Muscular Dystrophy (BMD) in male births?

1 in 30,000 live male births. (B) Signup and view all the answers

If a patient in their 20's was recently diagnosed with muscular dystrophy, which disease is the most likely diagnosis?

Becker Muscular Dystrophy (A) Signup and view all the answers

What is one direct consequence of the truncated dystrophin protein in Becker Muscular Dystrophy (BMD)?

A 50% shortening of the ‘rod domain’ of the protein. (C) Signup and view all the answers

Which of the following characteristics is consistent with BMD in contrast to DMD?

The disease has a slower progression (B) Signup and view all the answers

Study Notes

Lecture 3: Muscular Dystrophies I

Dr. Kinga Vojnits is the coordinator of the PDHC CREATE program and a research associate in biomedical microbiome research at the University of British Columbia Okanagan Campus.
The lecture covers muscular dystrophies.

End Term Group Project

Groups completed an end-term group assignment.
Research topics were chosen by the groups to examine biochemical understandings of the selected disease.
Diseases addressed by students include: genetic diseases, protein misfolding diseases, metabolic diseases, and hematological diseases.
Proposal submission deadline was March 31, 2025.
Group presentations ran from April 1st to April 8th, 2025.

Recap from Previous Lecture

Congenital disorders are present at birth, even if not apparent at birth.
Congenital disorders can be classified in various ways, including physical anomalies, malformations, and genetic disorders.
Examples of genetic disorders are spina bifida, cleft lip/cleft palate, cystic fibrosis, and Huntington's disease.

Deletions/Translocations

DiGeorge syndrome (1 in 4,000 prevalence) symptoms vary depending on deletion location within chromosome 22q11.2.
22q11.2 deletion can impact various body parts.
Congenital heart disease, defects in the palate, immune system issues, learning disabilities, kidney deficiencies and hearing loss are possible with 22q11.2 deletion.

Cri Du Chat Syndrome

Cri du chat syndrome is identified by a mew-like cry and physical abnormalities observed in patients.
Abnormalities include low birth weight, failure to thrive, hypotonia, psychomotor retardation, microcephaly, and a round face with anti-mongoloid slant of the eyes.
This syndrome occurs at a rate of 1 in every 20,000-50,000 births.
Most cases involve a deletion on the short arm of chromosome 5, with the majority coming from the father.

X-linked Recessive

Hemophilia A is an X-linked recessive disorder involving coagulation factor VIII deficiency.
Duchenne muscular dystrophy is characterized by a lack of dystrophin, resulting in abnormal dystrophin.
Becker's muscular dystrophy is linked to abnormal dystrophin.

Goals of Today's Lecture

The lecture aims to define muscular dystrophies, exploring Duchenne Muscular Dystrophy (DMD), Mode of inheritance, Pathophysiology.
The lecture also examines Becker Muscular Dystrophy (BMD), inflammation, calcium overload, fiber type differences, as well as causes and risk factors.

Muscular Dystrophies

A group of inherited diseases causing degeneration of skeletal and cardiac muscle.
Causes of muscular dystrophy include: inheritance (dominant and recessive genes), and risk factors include a family history.
Approximately 50,000 to 250,000 people are affected annually, roughly 1 in every 3500 live male births is affected.
Different types of muscular dystrophy exist, with Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD) being prevalent types.

Muscular Dystrophies (Pie Chart)

A breakdown of various muscular dystrophy types with percentages. This includes Duchenne Muscular Dystrophy (23%), Becker Muscular Dystrophy (10%), facioscapulohumeral dystrophy (13%), limb-girdle muscular dystrophy (10%), congenital myopathy (7%), Myotonic dystrophy, congenital muscular dystrophy (3%), and hereditary neuropathy (12%).
The data represents percentages from a pie-chart displaying different types of muscular dystrophy.

Muscular Dystrophies, General Information

Muscle weakness and loss of muscle tissue, initiating during childhood.
Can affect muscle strength and action, and involve skeletal muscle and other organs.
Complications associated with muscular dystrophy include difficulty walking, poor posture, muscle spasms, neurological issues, cardiac problems, and/or functional limitations.

Dystrophin

A key protein that muscles need to function correctly.
It acts as a shock absorber/stabilizer for the muscles.
Protects muscle fibers from damage during muscle contraction/relaxation.

DMD Causes

Complete absence of dystrophin.
Large gene deletions in the dystrophin gene
Point mutations (in exon 45 most common)

The Genetic Cause of DMD

The dystrophin gene is one of the largest human genes, with ~2.2 million bases, 79 exons, and >3,500 amino acids.
Over 3,000 human mutations are associated with DMD.

The Dystrophin Gene

A diagram of the dystrophin gene, showing its exons (numbered 1 to 79) and various sections such as the actin-binding domains, rod domains, WW cysteine-rich regions and hinge regions.

Functional Domains of Dystrophin

Dystrophin has several functional domains, including actin binding, hinge, rod, and cysteine-rich domains.
Only four rod domains are necessary for function.
Internal deletions in Becker's muscular dystrophy affect specific regions of the rod domains.

Types of DMD Mutations

One point mutation in the mdx mice, and over 3,000 mutations in DMD patients.
Mutations include exon deletions, point mutations, and duplication.

The Genetic Cause of DMD (diagram)

Presentation of different mutation types that cause muscular dystrophy (DMD).
Both types of diagrams present a visual representation of mutations affecting the dystrophin gene, impacting normal dystrophin protein formation.

Mode of Inheritance, X-Linked Recessive

Mutations occur on the X chromosome within the dystrophin gene—for females, both X chromosomes must be mutated in order for the condition to manifest.
If a female has one mutated X, she is a carrier, not displaying symptoms. However, this carrier status poses a risk for passing the mutated gene onto her male offspring.
Males usually manifest the disease if they inherit the mutated X chromosome from a carrier mother.

Dystrophin Diagram

Diagram depicting the diverse components of the dystrophin protein, including different domains like the actin-binding domain, the central rod domain, and the N-terminal and C-terminal domains.

Dystrophin Stabilizes Muscle Membranes

Dystrophin's role in stabilizing muscle membranes.

Dystrophin: (Muscle Shock Absorber)

Dystrophin's function as a shock absorber beneath the muscle membrane.

Loss of Dystrophin Causes DMD

Shows the difference in appearance between normal and DMD muscle through microscopy. This highlights how the loss of dystrophin negatively impacts muscle health.

Muscle Degeneration

Lack of dystrophin leads to the fragility and deterioration of muscles.
Serum creatine kinase serves as a marker for muscle damage.

Inflammation - Healthy Regeneration

Injury prompts the orchestrated repair of muscle tissue.
Active satellite cells proliferate, differentiate, and fuse with damaged muscle fibers.
Inflammation plays a crucial role in the initial stages by clearing debris.

Inflammation - Healthy Regeneration (Diagram)

Detailed diagram showing the progression of muscle regeneration after injury.

Inflammation - DMD

In DMD, inflammation persists, leading to secondary necrosis due to persistent inflammation.
The absence of dystrophin leads to constant degeneration and chronic inflammation in DMD.

Calcium and Muscle

Diagram depicting the crucial role of calcium within muscle tissue and its impact, accompanied by detailed explanations of each step.

Calcium Influx

Detailed description of calcium levels within and outside muscle fibers, and the role of calcium in DMD.

Reactive Oxygen Species (ROS)

ROS production in muscle tissue and its implications for mitochondrial function and homeostasis.
The impact of ROS on redox homeostasis is explained.

Muscle Physiology - Fiber Types

Diagram showing different components of muscle physiology associated with fiber types (e.g., myogenic progenitor, myoblast, committed myocyte, nascent myotube, myofibril, Myofiber, Slow Type I, fast Type IIa, Fast Type IIx).
Explains the role of genes and proteins in fiber types (MYH7, MYH2, MYH1, MyHC).

Another Key Difference Between Fiber Types

DMD affects fast-glycotic fibers more severely due to factors such as increased muscle stress, mitochondrial biogenesis malfunction related to low PGC-1a, and reduced utrophin levels.

PGC-1 alpha

Description and function of the PGC-1-alpha protein detailing its function as a transcription factor and master regulator of mitochondrial biogenesis.
Role of PGC-1a in regulating oxidative metabolism.

Dystrophin and Utrophin – Do They Look the Same?

Diagram highlighting the structural similarities and differences between dystrophin and utrophin in muscle tissue.
Utrophin serves as a potential compensation mechanism in the absence of dystrophin.

BMD (Becker Muscular Dystrophy)

A milder form of DMD, involving truncated dystrophin.

BMD (Becker), Etiology

In BMD, the cause, or etiology, is a single-gene defect on the short arm of the X chromosome, causing size and amount alterations in dystrophin.

BMD (Becker) Clinical Features

Less common than DMD, affecting 1 in 30,000 live male births.
Symptoms are less severe, including delayed symptom onset (above age 7), and an often atypical family history.

BMD (Becker) - Review Paper

The user is directed to review a specific case report paper regarding a novel splicing mutation in a DMD patient.

Literature

Provides various research documents, articles, and case studies for further study on Duchenne muscular dystrophy (DMD). This includes biochemical and molecular aspects, relevant case reports, and the discovery of dystrophin within muscular dystrophy.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz explores the key concepts and pathophysiology related to Duchenne Muscular Dystrophy (DMD) and other muscular dystrophies. Questions cover genetic causes, physiological consequences, and specific characteristics of muscle fibers affected by these conditions. Test your knowledge on the intricate relationships between genetics, muscle damage, and inflammation.