Understanding ALS: Genetic Mutations and Key Genes Involved. Decoding ALS: Genetic Mutations Driving Disease and Emerging Therapies

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. While most cases are sporadic, up to 10% are familial, driven by inherited genetic mutations. Identifying these gene defects is crucial for early diagnosis and targeted therapies.

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Decoding ALS: Genetic Mutations Driving Disease and Emerging Therapies

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by progressive loss of motor neurons. While ~90% of cases are sporadic, up to 10% are familial—driven by inherited gene mutations. Understanding these genetic factors is key to early diagnosis, personalized treatment, and the development of targeted therapies.

Genetic Landscape of ALS

• Sporadic vs. Familial

  Familial ALS (fALS) accounts for ~10% of cases; mutations in known ALS genes explain ~76% of fALS and ~25% of sporadic ALS  .

• Major Culprit Genes

  
  

  • C9orf72: Hexanucleotide repeat expansions here are the most common cause of fALS, leading to toxic RNA foci and dipeptide repeat proteins  .

  • SOD1: Mutations in superoxide dismutase 1 disrupt oxidative stress defense, accounting for ~20% of fALS cases  .

  • TARDBP (TDP-43): Missense mutations cause TDP-43 protein aggregation—a hallmark in ~3–5% of fALS and ~1% of sporadic ALS  .

  • FUS: FUS mutations lead to RNA-binding protein mislocalization in ~2–4% of fALS cases  .

  
  

• Less Frequent but Significant Genes

  
  

  • OPTN and VCP also contribute to familial and sporadic ALS, affecting autophagy and protein homeostasis  .

  • Emerging ALS Genes such as TBK1, SQSTM1, PFN1, and UBQLN2 expand our understanding of hereditary risk factors  .

  
  

From Gene Discovery to Targeted Therapies

Antisense Oligonucleotide (ASO) Therapy. Understanding ALS: Genetic Mutations and Key Genes Involved. Decoding ALS: Genet

• Tofersen (Qalsody™): The first FDA-approved ASO for SOD1-ALS, it lowers mutant SOD1 protein synthesis by targeting SOD1 mRNA—slowing neurofilament release and neuronal damage  .

Gene Therapy & RNA Interference

• Ongoing clinical trials are testing ASOs and RNAi against C9orf72 repeats, TARDBP, and FUS mutations, aiming to reduce toxic RNA/protein aggregates  .

Precision Medicine Approaches

• Genetic Testing Panels covering 4–54 ALS genes enable personalized risk assessment and trial matching; 50% include C9orf72 analysis, reflecting its prevalence  .

Towards Early Detection & Personalized Care

1. Early Genetic Screening

   Identifies at-risk individuals before symptom onset, guiding monitoring and lifestyle interventions.

2. Biomarker-Driven Trials

   ctDNA and neurofilament light levels serve as biomarkers to track treatment response in real time.

3. Multi-Omics Integration

   Combining genomics with transcriptomics and proteomics to build comprehensive disease models and refine therapeutic targets.

4. AI-Enhanced Diagnosis

   Machine learning algorithms accelerate variant interpretation, predicting disease progression based on mutation profiles.

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📚 Sources

1. Mutations in known ALS genes explain ~76% of fALS and ~25% of sporadic ALS; major genes are C9orf72, SOD1, TARDBP, FUS. 

2. TARDBP missense mutations cluster in exon 6 and cause TDP-43 pathology in ~3–5% fALS. 

3. Recent review summarizing over 40 ALS genes and gene therapy targets (C9orf72, SOD1, FUS, TARDBP, ATXN2). 

4. FDA approval of Tofersen for SOD1-ALS based on reduction in neurofilament light. 

5. Clinical ALS genetic testing panels (4–54 genes; 50% include C9orf72). 

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