SPG11 – Hereditary Spastic Paraplegia

SPG11, encoding the protein spatacsin, is the most common genetic cause of autosomal recessive complicated hereditary spastic paraplegia (ARHSP-TCC), a subtype characterized by progressive lower limb spasticity, thin corpus callosum and cognitive decline. The condition manifests in childhood or early adulthood with pyramidal tract dysfunction leading to gait disturbance, often accompanied by intellectual disability (HP:0001249), seizures (HP:0001250) and abnormal periventricular white matter morphology (HP:0002518). Magnetic resonance imaging typically shows a thin or dysplastic corpus callosum and diffuse white matter changes.

Autosomal recessive inheritance is confirmed by homozygous and compound heterozygous truncating or splice‐site variants identified in multiple consanguineous and non‐consanguineous families. For example, a novel homozygous stop codon mutation c.1492C>T (p.Gln498Ter) was reported in an Egyptian ARHSP-TCC family (PMID:20971220). Variants are predominantly loss‐of‐function, including nonsense, frameshift and splice‐site changes. Extensive co‐segregation in at least 13 families supports pathogenicity.

A large cohort study of 76 index ARHSP-TCC patients found SPG11 mutations in 41% of cases with thin corpus callosum, including 22 truncating alleles segregating in seven isolated cases and 13 families (PMID:18079167). Two recurrent founder mutations were described in Portuguese and North African populations, highlighting population‐specific alleles. Disease onset ranges from the first to third decades, with severity progressing to wheelchair dependence in over half of patients after ~15 years.

Functional studies demonstrate that loss of spatacsin perturbs neurodevelopment and autophagy. Morpholino knockdown of zebrafish spg11 orthologs causes CNS defects and impaired axon tract formation (PMID:20390432). In human cells, SPG11 mutations disrupt autophagic lysosome reformation and endosomal trafficking, whereas ZFYVE26 mutations preferentially impair autophagosome–endosome fusion (PMID:30081747). These findings corroborate a loss‐of‐function mechanism.

Genotype–phenotype correlations indicate that truncating variants confer a homogeneous complicated HSP phenotype with thin corpus callosum, cognitive impairment and upper motor neuron signs. Additional features reported include seizures, polyneuropathy and movement disorders such as tremor or dystonia. No studies dispute the SPG11‐HSP association.

In summary, SPG11 has a definitive gene–disease relationship with autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Genetic testing for SPG11 variants is clinically useful for diagnosis, family counseling and prenatal planning. Targeted therapies remain under investigation.

References

• Brain | 2008 | Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. PMID:18079167
• European Journal of Medical Genetics | 2011 | Expanding the clinical spectrum of SPG11 gene mutations in recessive hereditary spastic paraplegia with thin corpus callosum. PMID:20971220
• Neurogenetics | 2010 | Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish. PMID:20390432
• Autophagy | 2019 | ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. PMID:30081747

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