CASE 6: JOHN SMITH

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CASE 6: JOHN SMITH

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3-6 years old when symptoms begin to show

When is DMD usually diagnosed?

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

List some conditions that are screened for during pregnancy

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.

What are some treatments for DMD?

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

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

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

Xp21 region

Location of the DMD gene?

What does calcium do in DMD?

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.

16 months

By what age should a child be able to run?

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

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

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.

Explain what pseudohypertrophy is.

50%

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?

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

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

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

Name some things dystrophin interacts with?

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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

Summarise the aetiology of sickle cell disease

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

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

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

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

WINNER!!!

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 review At 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

How is child development monitored?

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

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

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

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

Describe the progression of DMD

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

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

3 years old

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

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

Name some common physical signs of DMD

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

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

What are their parent's genotypes?

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• 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

Ways to test for DMD?

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

What are the 4 types of creatine kinase?

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

What is the function of the dystrophin?

Frameshift mutations (especially deletion)

What is the most common abnormality to the DMD gene?

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

• 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

Name some issues with genetic testing for congenital conditions

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