Rare Disease: Diagnosis and Treatment

Question 1

What is considered a rare disease?

Answer 1

• U.K. → 1 in 50,000 people.
• U.S.A. → 1 in 200,000 people

Question 2

What are the two main sources of rare disease mutations?

Answer 2

1 - De novo mutations (spontaneous, germline changes).
2 - Familial mutations (inherited, e.g., sickle cell, cystic fibrosis)

Question 3

What types of de novo mutations can occur?

Answer 3

• SNP → Single nucleotide change.
• Indel → Insertions/deletions of bases.
• CNV → Copy number variations (loss/gain of gene copies).
• SV → Structural variations (inversions, translocations).

Question 4

How has Next-Generation Sequencing (NGS) impacted diagnosis?

Answer 4

• Lower costs → Whole genome sequencing (WGS) becomes routine (~$1,000 per genome).
• Personalized medicine → Tailoring treatments based on genetic makeup.

Question 5

What is trio analysis in rare disease diagnostics?

Answer 5

• Sequencing patient + both parents to determine inheritance pattern.
• Helps identify carrier parents and de novo mutations.

Question 6

What is the difference between WGS vs. WES?

Answer 6

• WGS (Whole Genome Sequencing) → Entire genome (~100%).
• WES (Whole Exome Sequencing) → Only protein-coding exons (~1%).

Question 7

What is the newborn blood spot test (heel prick test)?

Answer 7

Screens for ~10 common conditions (e.g., sickle cell, cystic fibrosis, phenylketonuria)

Question 8

Why is early detection important?

Answer 8

• Early diagnosis allows early treatment, often life-saving.
• Critical for metabolic disorders (e.g., phenylketonuria).

Question 9

Why isn’t every rare disease included in newborn screening?

Answer 9

• Financial limitations → Expanding tests would be costly.
• Cost-benefit debate → If a disease has no treatment, detection may not justify expense.

Question 10

How many rare diseases have treatment options?

Answer 10

Less than 5% have approved therapies.

Question 11

Why do rare diseases lack treatments?

Answer 11

• Low patient numbers → No financial incentive for pharmaceutical companies.
• High research costs → Companies focus on common diseases with larger markets.

Question 12

What is SMA?

Answer 12

• Most common rare genetic cause of infant mortality (~1 in 10,000 births).
• Motor neuron disease, leading to muscle weakness & loss of movement.

Question 13

What gene causes SMA?

Answer 13

SMN1 (Survival Motor Neuron 1)

Question 14

What are early symptoms of SMA?

Answer 14

• Hypotonia (floppy baby syndrome).
• Weak movements & difficulty breathing/swallowing

Question 15

What was the prognosis for SMA before 2016?

Answer 15

• Median survival = 13 months.
• Children with SMA Type 1 were placed into palliative care immediately.

Question 16

Solution 1: SMN2 Splice Modulation by ASOs (Nusinersen)
Q: What is the genetic basis for SMA treatment using SMN2?

Answer 16

• SMN1 mutations prevent functional protein production.
• SMN2 gene exists but lacks exon 7, leading to instability.
• ASO (Nusinersen) blocks splice suppressor binding, allowing functional SMN2 protein to compensate for SMN1 loss.

Question 17

Solution 2: Gene Replacement Therapy (Zolgensma)
Q: How does Zolgensma work?

Answer 17

1 - AAV9 viral vector delivers the SMN gene to motor neurons.
2 - SMN gene integrates into nucleus, forming an episome.
3 - Episome ensures long-term expression of functional SMN protein.

Question 18

What is the cost of Zolgensma?

Answer 18

£1.8 million for a one-time 1-hour infusion.

Question 19

How was epalrestat discovered for PMM2-CDG treatment?

Answer 19

• Yeast & worm models screened for drugs that rescue growth.
• Epalrestat boosts PMM2 enzyme activity.
• Originally used in Japan for diabetes → Repurposed for CDG treatment.

Question 20

What are the benefits of drug repurposing?

Answer 20

• Faster approval since drugs are already tested in humans.
• Lower research costs compared to new drug development.