CASE 6: JOHN SMITH

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CASE 6: JOHN SMITH

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When is DMD usually diagnosed?

3-6 years old when symptoms begin to show

List some conditions that are screened for during pregnancy

• Sickle cell disease
• Down's syndrome
• Patau's syndrome
• Edward's syndrome
• Thalassemia
• Cystic fibrosis

What are some treatments for DMD?

No medical cure exists for DMD, and the disease has a poor prognosis. Treatment is centered on glucocorticoid therapy, prevention of contractures (physiotherapy), and medical care of cardiomyopathy (ACEIs and beta-blockers) and respiratory compromise.

List things a child aged 4 is expected to be doing at their age (1 for each: gross motor, speech/language, social, fine motor*)

One third of DMD cases are due to {...}

spontaneous mutations of the genome - although, majority of cases are the result of an inherited X- linked recessive trait

Location of the DMD gene?

Xp21 region

Calcium enters the cell and activates calcium-dependent proteases. Usually, protease only break down old, damaged myocytes but when unnecessarily activated by high intracellular calcium activity, they break down functional protein too.

What does calcium do in DMD?

By what age should a child be able to run?

16 months

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What are the main reasons for the low expectancy in DMD?

20-30s - the progressive degeneration results in respiratory insufficiency, pulmonary infection and cardiomyopathy --> death

Explain what pseudohypertrophy is.

Enlarged calf muscles but the muscles iss abnormal - caused initially by the increase in the size of muscle fibres and then as the muscle atrophies, this is replaced by an increase in fatty and connective tissue – these are paradoxically weak.

Millie and David are preparing for a baby boy!! John has DMD whilst Millie is a carrier. What is the chance of their child being able to pass on the recessive allele to his children in the future?

50%

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Out of all the different types of muscular dystrophies, which is most common?

Duchenne's musculardystrophy (DMD) is the most common muscular dystrophy and unfortunately, it's also the most severe

Name some things dystrophin interacts with?

Actin filament, dystrobevin, syntrophins & transmembrane proteins (sarcoglycans & dystroglycans)

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Summarise the aetiology of sickle cell disease

1. Occurs as a result of a substitution mutation (GLU-->VAL) in the haemoglobin beta (HBB) gene found at 11p chromosome
2. HBB mutation produces abnormal version of beta globin known as haemoglobin S (HbS).
3. HbS precipitates in the RBCs when the blood is deprived of oxygen forming crystals that distort the cell into the sickle cell shape which can occlude vessels

By 4 years old what is a child expected to understand in terms of speech/ language?

Complex instructions – “before you put x in y, give z to mummy”

Both have a X-linked recessive inheritance pattern!BMD has a later onset, and the length of survival is longer. Patients typically have higher concentrations of dystrophin protein

What is the difference between Becker's MD and Duchenne's MD?

WINNER!!!

How is child development monitored?

A health visitor will do a new baby review within 10 to 14 days of the birth, where they give advice on the baby's development to parentsAt 9-12 months, another review looking at, among other things, language and learning, safety, diet and behaviour. An ASQ-3 questionnaire will be sent to fill in before this reviewAt 2 to 2-and-a-half years, the child will have another health and development review, along with another ASQ-3 questionnaire to fill out

Within what time frame, in development, is a child expected to be walking independently?

9-18m ; 18m is threshold for worry)

What happens as a result of abnormalities to the DMD gene?

1. Limited production of dystrophin or short dystroophin...
2. Loss of membrane integrity
3. Muscle contractions form rips in the myocyte membrane, allowing various molecules in and out the myocyte – calcium and creatine kinase

Describe the progression of DMD

Histologically, muscle fibres undergo degeneration and are replaced by fibrofatty tissue and collagen (which are unable to contract --> weakening).

What is the histology of muscle in a person with DMD?

By what age should a baby be able to hop on one foot for 3 steps (each foot)?

3 years old

Name some common physical signs of DMD

• Lordosis due to weak back muscles
• Belly sticks out due to weak abdominal muscles
• Pseudohypertrophy
• Arms held back for balance

Michael, Jen, Alicia and Simon are siblings - they each represent one of the 4 boxes of a Punnett square.

• Michael doesn't have DMD
• Jen is a carrier
• Alicia passed on the trait to her son but doesn't have it herself
• Simon doesn't have DMD

Their dad has DMD whilst their mum doesn't (and isn't a carrier)

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Ways to test for DMD?

• Genetic testing - checking for elevated creatine kinase
• Physical exams - Gower's sign...
• Muscle biopsy - analysing proteins in the muscle to see what gene is causing dystrophy
• Comparative genomic hybridization array (CGH) - a sample is taken from an egg or single cell of a blastocyst stage and the embryo is compared to a normal control sample
• Pre-implantation genetic diagnosis (PGD) - genetic profiling of embryos prior to implantation

What are the 4 types of creatine kinase?

Cytosolic creatine kinase:Brain-creatine kinase (BCK)Muscle-creatine kinase (MCK)Mitochondrial creatine kinase:Obiquitous MiCKSarcomeric MiCK

What is the function of the dystrophin?

Dystrophin acts like a shock absorber - aid in transferring the force of contraction to connective tissue (and prevents contraction-induced damage).

What is the most common abnormality to the DMD gene?

Frameshift mutations (especially deletion)

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Explain the relationship between creatine, creatine kinase and creatinine (triangle), explaining what each is

Name some issues with genetic testing for congenital conditions

• Limitations of genetic testing - some genetic tests do not identify all of the possible gene mutations that can cause a particular condition, or they have limited predictive value, therefore couples may have to make difficult decisions without the knowledge of the severity of the disorder
• Sometimes no treatment/ intervention exists, so is there any point even obtaining the information?
• Undesired options after genetic testing - creates additional decisions for the couple, including considerations of invasive testing and the possibility of abortion.
• False positive and false negative results - false positives can lead to further diagnostic testing and even termination.
• Genetic testing predicts increased risk, rather than certainty of disease, making decisions about interventions more difficult for individuals

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