Flashcards in Duchenne muscular dystrophy Deck (12):
What are the signs of DMD?
Floppy muscles, delay in walking or toe walking, clumsiness, Gower sign (climbing up to get up from the lying down position), muscle pseudohypertrophy (muscle being replaced with excess fat and connective tissue) and lumbar lordosis and prominent abdomen.
Why does pseudohypertrophy of the calves occur?
Because DMD sufferers walk on their toes (dorsiflexion), there is increased use leading to hypertrophy of the calf muscles. This muscular hypertrophy is short-lived, and the muscle in the calves is very quickly replaced with fat and connective tissue instead. This is why it is called pseudo, or fake, hypertrophy.
What causes DMD?
The muscular dystrophy is caused by progressive muscle degeneration. DMD sufferers have a mutation in the gene encoding for the dystrophin protein. Dystrophin is found in all muscles of the body, and whilst its role is not fully understood, it is said to form an important link between actin filaments and the extracellular matrix.
What is the biochemical process behind the progression of DMD?
The absence of or presence of altered dystrophin causes membrane instability. Membrane instability causes a huge calcium influx into the cell, and the calcium ions activate many proteolytic and lipolytic enzymes that start to degrade the muscle cells. The muscle degradation is followed by attempted muscle regeneration by the body. However, this attempted muscle regeneration is eventually overwhelmed by the degradation resulting in the disease.
What are the side effects of having DMD?
Scholiosis of the spine, wheelchair dependent by age 12, respiratory and cardiac problems that progress to kill them.
What is the difference between Duchenne and Becker muscular dystrophies?
Becker muscular dystrophy is a much milder version of Duchenne muscular dystrophy.
How is Duchenne muscular dystrophy inherited?
It is an x-linked recessive gene, meaning that if you are a girl and you have the gene mutation, your second healthy x-chromosome would stop the onset of the disease.
It is only prevalent in boys, because they only inherit one x-chromosome, from their mother, and if it is affected, then they have no other x-chromosome to protect them.
2/3 of DMD cases are from maternal inheritance whilst 1/3 are from spontaneous, random mutations to the gene.
How does the dystrophin mutation occur?
The dystrophin gene is one of the biggest in the genome. Thus, deletions in the dystrophin gene cause problems in the transcription of the entire gene with the reading frame. Duchenne MD has an out-of-frame deletion, which means that the reading frame is ruined for all the other genes and the produced dystrophin protein is non-functional. With Becker MD, the deletion is an in-frame deletion, so only one small section within the huge dystrophin gene is mutated. This results in a significantly milder change to the dystrophin protein, making it atleast partially functional.
What is the biomarker for DMD diagnosis?
Creatine kinase levels. Because of the rapid muscle degeneration and regeneration, there are excessive amounts of creatine kinase levels in the blood of a DMD sufferer.
How does a MLPA probe detect the presence of deletions in the muscular dystrophy gene?
The MLPA probes work by targeting a particular DNA sequence in the genome, in this case the dystrophin gene and creating a primer that should fit perfectly with the dystrophin base pairs. So, if the MLPA probe fits with the exon, then there are no mutations and no DMD. If the probe doesn't fit, then there are mutations and there is DMD.
What is linkage analysis and when is it used to diagnose DMD?
It used when no deletions can be found in the DMD sufferer, and so they do a heirarchical family tree of genetic testing to look for mutations.