Essay 4: paragraph flashcards

4. Using either Amyotrophic Lateral Sclerosis or Spinal Muscular Atrophy as an example (a) discuss the main genetic causes of the disease (50 %) and (b) describe the current approved treatment options available (50 %).

INTRODUCTION & DISEASE CONTEXT - Why is Amyotrophic Lateral Sclerosis (ALS) a useful model for understanding genetic neurodegeneration?

• ALS is:

  • the most common and severe motor neuron disease

  • characterised by progressive loss of upper and lower motor neurons

• Clinical features:

  • muscle weakness

  • paralysis

  • median survival ~3 years

• Although ~90% of cases appear sporadic:

  • genetic factors contribute across the disease spectrum

• ~10% show clear familial inheritance

• ALS therefore provides:

  • insight into how genetic mechanisms drive neurodegeneration

  • a framework for developing targeted therapies

1st PARAGRAPH: C9orf72 REPEAT EXPANSION (MAJOR GENETIC CAUSE) - How does the C9orf72 hexanucleotide repeat expansion cause ALS?

• C9orf72 hexanucleotide repeat expansion is:

  • the most common genetic cause of ALS

  • responsible for ~40% of familial and ~7% of sporadic cases

• Mutations in SOD1:

  • abnormal expansion of GGGGCC repeats

  • normal alleles contain <35 repeats, pathogenic expansions can reach thousands

• Causes neurodegeneration via three mechanisms:

  • RNA toxicity: repeat RNA forms nuclear RNA foci that sequester RNA-binding proteins

  • Repeat-associated non-ATG (RAN) translation: produces toxic dipeptide repeat proteins

  • Loss of C9orf72 function: impairs autophagy and vesicle trafficking

• These combined effects disrupt neuronal homeostasis and survival.

2nd PARAGRAPH: OTHER KEY ALS GENES (SOD1, TARDBP, FUS) - What roles do SOD1, TARDBP, and FUS mutations play in ALS pathogenesis?

• ALS is genetically heterogeneous, w several other genes contributing to disease pathogenesis.

• SOD1 mutations:

  • account for ~2% of cases

  • cause toxic gain of function

  • leads to oxidative stress, mitochondrial dysfunction, and protein aggregation

• TARDBP mutations:

  • affect TDP-43, a key RNA-binding protein involved in splicing and RNA transport

  • leading to cytoplasmic aggregation

  • widespread RNA dysregulation.

• FUS mutations:

  • disrupt RNA metabolism

  • impair DNA repair mechanisms

• These mutations highlight the central role of RNA and protein homeostasis in ALS

3rd PARAGRAPH: CONVERGENT PATHOGENIC MECHANISMS - How do different ALS-associated genes converge on common disease mechanisms?

• Despite genetic diversity, ALS mutations converge on shared pathways:

  • impaired RNA processing

  • defective proteostasis

  • mitochondrial dysfunction

  • axonal transport failure

• Discovery of these genetic subtypes:

  • blurs distinction between familial and sporadic ALS

  • apparently many sporadic patients carry pathogenic variants.

• This genetic architecture:

  • has enabled development of targeted therapies

  • particularly antisense oligonucleotides (ASOs)

  • shift toward precision medicine in ALS.

4th PARAGRAPH: RILUZOLE (APPROVED THERAPY) - How does riluzole modify disease progression in ALS?

• Therapeutic landscape of ALS evolved:

  • from purely symptomatic management to mechanism-based interventions.

• Riluzole:

  • first approved disease-modifying therapy.

• Mechanism:

  • reduces glutamate-mediated excitotoxicity

  • by inhibiting presynaptic glutamate release

  • and modulates voltage-gated sodium channels

• Clinical effect:

  • modest but significant survival benefit

  • ~19% reduction in mortality risk

  • extends survival by several months

• Represents:

  • foundational but limited disease modification

5th PARAGRAPH: EDARAVONE (OXIDATIVE STRESS TARGETING) - What is the mechanism and clinical benefit of edaravone in ALS?

• Edaravone = complementary approach by:

  • targeting oxidative stress, a key contributor to motor neuron injury.

• As a free-radical scavenger,

  • it slows functional decline in selected patients with early, rapidly progressive disease

  • making 2-3 point benefit on the ALS Functional Rating Scale over 24-48 weeks.

• Oral formulation:

  • improves accessibility

  • reduces treatment burden

6th PARAGRAPH: TOFERSEN & GENE-TARGETED THERAPY - Why is tofersen considered a major advance in ALS treatment despite mixed clinical outcomes?

• Most significant recent advance is Tofersen:

  • antisense oligonucleotide designed to reduce SOD1 mRNA

  • and lower production of toxic SOD1 protein.

• Clinical trials:

  • did not meet primary clinical endpoint

• However, showed strong biomarker effects:

  • ~90% reduction in cerebrospinal fluid SOD1

  • significant reduction in neurofilament light chain

• These biomarker improvements:

  • supported FDA accelerated approval for SOD1-ALS

  • validate gene-targeted therapy in ALS

• Provides:

  • proof-of-concept for precision medicine approaches.

CONCLUSION: How have genetic discoveries reshaped treatment strategies in ALS?

• ALS exemplifies how genetic discoveries can directly inform therapeutic development.

• Current approved treatments:

  • provide only modest benefit

  • but validate key disease mechanisms and establish a framework for precision medicine.

• Continued advances in gene-targeted approaches:

  • particularly antisense therapies

  • offer cautious optimism for improving outcomes in this devastating disease.