About Duchenne

Pronounced Doo-shen

Duchenne is a rare genetic disorder affecting approximately 1 in 3500 - 5000 live male births worldwide and in very rare cases 1: 50 million females [1,8,9].

It is caused when there is a ‘fault’ on the X chromosome, this fault is often referred to as a ‘mutation’ which affects the biggest gene in the human genome, the dystrophin gene. The dystrophin gene is only found on the X chromosome and this is why Duchenne is more common in males than females.

Dystrophin is a protein found in all muscles and it provides them with the essential function of a shock absorber providing the stability needed to protect and repair our muscles. So, when the protein is damaged in a person with Duchenne or Becker for example, they do not have functional dystrophin in their muscles so they will experience progressive muscle damage, loss of muscle function and strength. These muscles are not just found in the skeletal muscles such as the pelvic girdle, legs and arms but also the heart, lungs, diaphragm and the smooth muscles used to swallow and for digestion.

Duchenne is also referred to as Duchenne muscular dystrophy or DMD and belongs to a group of disorders known as dystrophinopathies, which is the word used to describe the conditions that are specifically affected by the dystrophin gene, these conditions are:

Duchenne – the most common and most severe form of dystrophinopathie

Becker – characterised like Duchenne by muscle weakness and atrophy of the lower limbs and pelvis; however, it usually progresses slower than Duchenne and is often referred to as milder and a later onset but can be as severe as Duchenne.

Female Carrier – refers to a female that carries the mutation in the dystrophin gene within her DNA and therefore can pass this on to her children. Female carriers are also at an increased risk of cardiomyopathy which is a condition in the heart and so carrier females require regular surveillance by a cardiologist

Manifesting Carrier – refers to a female that experiences some symptoms, these can vary in severity from muscle cramps to a similar phenotype to males with Duchenne such as muscle weakness, loss of function and learning difficulties (see glossary X-Chromosome inactivation) .

Duchenne is usually diagnosed in infancy with the average age of diagnosis in Australia being 4-5 years of age and is confirmed following clinical examination and genetic testing.

There is currently no cure for Duchenne, but there is extensive research and clinical trials underway as the international community of researchers and industry work for effective treatments (see research update).

Genetics 101 – Back to Basics

Genetics is the study of genes, how they are passed down from each generation and how they cause disease. Genetics focuses on a molecule called DNA (deoxyribonucleic acid), which is present in all our cells. DNA is known as the “blueprint of life” and contains all the instructions our cells need to allow us to grow, survive and reproduce. Genes are a specific section of DNA that tell our cells how to do a specific task and determine our characteristics such as our eye colour or height.

Our genes are determined by our parents and we have two copies of each gene. Different versions of the same gene are called alleles. We get half of our genes from mum and half from dad. This means we could have two of the same alleles or two different alleles, one from each parent. Characteristics such as eye colour and height are determined by multiple genes and even the environment can have an impact on how our genes are expressed.

Our DNA is packaged into structures called chromosomes. Chromosomes are long strands of DNA with many genes, all coiled up tightly. Every cell in a human body has 46 chromosomes or 23 pairs. Each pair contains one chromosome from mum and one from dad – each with their respective alleles. One pair of chromosomes, known as our sex chromosomes, determine our sex and can be either XX (female) or XY (male). The remaining 22 pairs are known as autosomes.

Genetics of Dystrophinopathies

Beginning to Understand the Diagnosis

Duchenne is caused by DNA changes, known as pathogenic variants, in the Duchenne gene. Pathogenic variants cause the gene to work incorrectly or stop working all together. The gene (also known as the dystrophin gene) is the largest known human gene and lies on the X chromosome. The Duchenne gene provides instructions for our cells to make a protein called dystrophin, which is present in all our muscles and used for movement. Dystrophin works with other proteins to strengthen muscle fibres and prevent them from wasting away. Dystrophin also acts as an anchor to help stabilise muscle cells and may play a role in cell signalling and communication.

Dystrophin works with other proteins to strengthen muscle fibres and prevent them from wasting away. Dystrophin also acts as an anchor to help stabilise muscle cells and may play a role in cell signalling and communication.

What Causes Duchenne?

Duchenne is an X-linked condition, which means that the fault is found on the X chromosome. The Dystrophin gene is found only on the X chromosome.

In 2/3 cases, a male child will inherit the X chromosome that has a Dystrophin gene variant from their mother, causing Duchenne or Becker [3]. X-linked recessive conditions almost always manifest in males as they only have one X chromosome. Females, however, have two copies of the X chromosome – one from each parent – so if one copy is faulty, they have a second back up copy to produce the dystrophin protein and protect them from developing the condition.

Females who have a fault on the Dystrophin gene variant in one of their X chromosomes are called “carriers”. Carriers have a 50% chance (1 in 2) of passing on the faulty gene to each child - they may pass on the healthy X chromosome or the affected X chromosome. Male children have a 50% chance of being affected and female children have a 50% chance of being a carrier.

With X-linked conditions, an affected father will always pass his affected X chromosome to all his daughters who will be carriers. However, an affected father cannot pass an X-linked gene to his sons because fathers always pass their Y chromosome instead of their X chromosome to male children.

In 1/3 cases, Duchenne and Becker can occur in a child born to healthy parents who have no family history of the condition [3]. This is usually because of a random event, causing a new variant to develop in the child. This is not related to anything the parents do or don’t do during pregnancy. This type of random event is called a de novo mutation or spontaneous mutation.

Duchenne is usually diagnosed in infancy with the average age of diagnosis in Australia being 4-5 years of age and is confirmed following clinical examination and genetic testing.

Carriers and Manifesting Carriers

Carriers and manifesting carries graph

A female who has the Dystrophin gene variant in one of her X chromosomes is called "a carrier". Carriers do not have Duchenne or Becker and most are unaware that they carry this variant unless they have a family history. However, up to 22% of carriers are referred to as “manifesting carriers”, and will show some symptoms such as weakness, fatigue, or muscle cramping [4]. Manifesting carriers also have an increased risk of heart problems, such as dilated cardiomyopathy. The severity of these symptoms varies from person to person but are usually milder than in males.

The reason manifesting carriers get symptoms while others don’t, is because of a natural process called X-chromosome inactivation. This is a random process that happens individually in each of a female’s cells. One X chromosome, from the mother or father, is randomly switched off so that both males and females have only one working copy of the X chromosome in each cell. For manifesting carriers, the X chromosome with the Dystrophin gene variant might be active in most of their cells, causing symptoms. These symptoms can present like in males with increasing muscle weakness. These females are frequently managed the same as the males and will require the same additional medical surveillance and psycho – social supports.

What Happens When a Child Has Duchenne?

Most commonly when a child has Duchenne there will be a delay in them reaching their developmental milestones, such as crawling and walking, and commonly there can also be delays with speech. Parents frequently notice these delays and seek advice.

Sometimes the diagnosis comes when your child was having investigations for another reason and they found that there were abnormal blood results for example.
A child with Duchenne will most commonly lose the ability to walk between the ages of 10-14, requiring an electric wheelchair before their early teens and leading to progressive loss of upper body strength and independence. All the while suffering internal muscle loss and failure of the heart and lungs. By the late teens to early 20’s requiring support with breathing, sometimes requiring ventilatory support 24 hours a day.

There are no approved treatments in Australia and there is no cure. The life expectancy is mid 20’s due to cardiac or respiratory muscle failure.

The Role of Genetic Counsellors in Your Journey

Genetic counsellors provide you and your family with accurate information about Duchenne and dystrophinopathies and how it affects your family.
It is important for females with a family history of Duchenne or Becker to have genetic testing to determine their carrier status. Genetic counsellors help you make an informed decision about genetic testing, and how this may impact you and your extended family or future pregnancies.

They can also help interpret genetic test results and provide you with management and surveillance options based on your situation. Knowing and understanding your child(ren)’s genetic mutation can help you to navigate and better understand research, potential emerging therapies and clinical trial opportunities that are relevant to their specific genetic mutation as there are many variants in mutations of the dystrophin gene.

If you are found to be a carrier and planning a pregnancy, genetic counsellors will help you find the right options for you and give you all the information needed to make informed decisions, such as IVF or pre-implantation genetic diagnosis. It is also important for female carriers of Duchenne to have regular heart monitoring to detect the development of dilated cardiomyopathy.

For more information please visit:

National Human Genome Research institute:
https://www.genome.gov/Genetic-Disorders/Duchenne-Muscular-Dystrophy

Genetic and Rare Disease Information Centre
https://rarediseases.info.nih.gov/diseases/6291/duchenne-muscular-dystrophy

MedlinePlus
https://medlineplus.gov/genetics/condition/duchenne-and-becker-muscular-dystrophy/#inheritance

References

Nowak, K.J. and K.E. Davies, Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO reports, 2004. 5(9): p. 872-876.
Trent, R.J., Mendelian Genetic Traits, in Molecular Medicine (Third Edition), R.J. Trent, Editor. 2005, Academic Press: Burlington. p. 43-II.
Sussman, M., Duchenne Muscular Dystrophy. JAAOS - Journal of the American Academy of Orthopaedic Surgeons, 2002. 10(2).
Brioschi, S., et al., Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype. BMC Medical Genetics, 2012. 13(1): p. 73.
Allen, D.G. and N.P. Whitehead, Duchenne muscular dystrophy – What causes the increased membrane permeability in skeletal muscle? The International Journal of Biochemistry & Cell Biology, 2011. 43(3): p. 290-294.
Giliberto, F., et al., Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization. Journal of the Neurological Sciences, 2014. 336(1): p. 36-41.
Hoffman, E.P., R.H. Brown, Jr., and L.M. Kunkel, Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell, 1987. 51(6): p. 919-28.
Dang, U.J, Ziemba, M., Clemens, P.R, Hathout, Y., Conklin, L.S., CINRG Vamorolone 002/003 Investigators and Hoffman, E.P. Serum biomarkers associated with baseline clinical severity in young steroid-naïve Duchenne muscular dystrophy boys. Human Molecular Genetics, 2020. 29(15): p. 2481-2495.
Nozoe, K.T., Akamine, R. T., Mazzotti, D. R., Polesel, D. N., Grossklauss, L.F., Tufik, S., Andersen, M. L. and Moreira, G.A. Phenotypic contrasts of Duchenne Muscular Dystrophy in women: Two case reports. Sleep Science, 2016. 9(3): p. 129-133.

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