The discovery of genetic factors underlying familial ALS (FALS) has provided profound insight into the molecular pathogenesis of both familial and sporadic forms of the disease. Causative genetic mutations are identified in approximately 5% to 10% of total ALS cases, highlighting crucial pathways involved in motor neuron degeneration.
Key Causative Genes in Familial ALS
The identification of SOD1 mutations in 1939/1993 represented a landmark breakthrough. Subsequent genetic research expanded the causative gene spectrum:
Familial ALS Gene Distribution:
├── C9ORF72 mutations ( > 30% )
├── SOD1 mutations ( 20% )
├── TARDBP & FUS mutations ( 4–5% )
└── Other rare genes (Alsin, SETX, SPG11, VAPB, ANG, FIG4, OPTN, VCP, UBQLN2, SIGMAR1)
| Gene Symbol | Chromosomal Locus | Encoded Protein | Inheritance | Key Clinical Features / Subtype |
| SOD1 | 21q22.1 | Cu/Zn SOD-1 | AD / AR | Typical ALS (ALS1) |
| ALSIN | 2q33-2q35 | Alsin | AR | Slowly progressive juvenile onset; PLS/IAHSP (ALS2) |
| SETX | 9q34 | Senataxin | AD | Slowly progressive distal motor neuropathy (ALS4) |
| SPG11 | 15q15-21 | Spatacsin | AR | Slowly progressive juvenile course (ALS5) |
| FUS | 16p11.2 | Fused in Sarcoma | AD / AR | Typical juvenile/adult onset (ALS6) |
| VAPB | 20q13.3 | VAPB | AD | Typical and atypical ALS / SMA (ALS8) |
| ANG | 14q11.2 | Angiogenin | AD | Typical ALS, FTD, Parkinsonism (ALS9) |
| TARDBP | 1p36.2 | DNA-binding protein | AD | Typical ALS (ALS10) |
| FIG4 | 6q21 | Phosphoinositide-5-phosphatase | AD | Rapidly progressive with prominent corticospinal signs |
| OPTN | 10p13 | Optineurin | AD / AR | Slowly progressive limb onset (ALS12) |
| VCP | 9p13.3 | VCP | AD | Adult onset with or without FTD (ALS14) |
| UBQLN2 | Xp11 | Ubiquitin 2 | XD | UMN signs preceding LMN signs (ALS15/ALSX) |
| C9ORF72 | 9p21 | C9ORF72 | AD | Strong association with FTD (ALS-FTD2) |
Genetic Susceptibility in Sporadic ALS (sALS)
In non-familial cases, specific gene variants, single nucleotide polymorphisms (SNPs), and repeat expansions modulate susceptibility:
APEX1: DNA repair enzyme 1 (14q11.2) - SNP associations.
ATXN2: Ataxin-2 (12q24.12) - PolyQ repeat expansions.
NEFH / PRPH: Neurofilament Heavy and Peripherin alterations.
SMN1 / SMN2: Survival Motor Neuron gene copy number variations.
VEGF / PGRN: Promoter SNPs and deletions impacting neurovascular support.
Key Takeaways
C9ORF72 (>30%) and SOD1 (20%) are the most common genetic causes of familial ALS.
UBQLN2 is uniquely linked to X-linked dominant inheritance.
FIG4 mutations lead to rapidly progressive disease with corticospinal signs.