SPAST – Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder characterized by progressive lower limb weakness, spasticity, hyperreflexia, and corticospinal tract degeneration. Autosomal dominant SPG4 (SPAST) was the first SPG locus identified at chromosome 2p, with a seminal splice-site mutation (c.1005-2A>C) reported in a large American pedigree confirming activation of a cryptic acceptor and frameshift truncation of spastin (PMID:12023066).

Genetic Evidence
Numerous unrelated cohorts have validated the SPAST–HSP association, including 76 probands screened by SSCP and sequencing for SPG4 mutations, identifying eight novel variants across missense, nonsense, frameshift, and splice classes (PMID:11843700). In a large Italian pedigree, a novel nonsense mutation segregated in 24 affected relatives, correlating clinical features such as hyperreflexia, ankle clonus, and pes cavus with mutation status (PMID:15197701). The variant spectrum exceeds 200 alleles, spanning missense, splice, and truncating changes, with recurrent founder alleles (e.g., p.Arg562Gly in European cohorts).

Case Reports & Variant Spectrum
SPAST-related HSP presents typically as pure spastic paraplegia but can include complex phenotypes such as dysplastic corpus callosum or cognitive impairment. Variants include novel missense (c.1031T>A (p.Ile344Lys)) identified in a Korean family with pure AD-HSP (PMID:12202986), splice-donor disruptions, and large exon deletions revealed by MLPA. Pathogenic alleles are found in ~40–50% of AD-HSP families globally.

Functional & Experimental Evidence
Spastin is an AAA ATPase that severs microtubules, essential for axonal maintenance. Disease-associated mutations abrogate ATPase activity and severing, with mutant spastins decorating microtubules and acting dominantly to inhibit severing (PMID:15716377). In a mouse SPG4 model, loss of spastin caused axonal swellings, impaired anterograde transport of mitochondria and APP-containing vesicles, paralleling human pathology (PMID:19453301).

Mechanism & Clinical Utility
Evidence supports a haploinsufficiency and gain-of-function paradigm: truncated or ATPase-deficient spastins fail to sever microtubules, disrupting axonal transport and leading to corticospinal tract degeneration. Modifier alleles (e.g., p.Ser44Leu) influence age at onset. Microtubule-targeting drugs rescue axonal swellings in spastin-deficient neurons, underscoring therapeutic potential.

Key Take-home: SPAST variants cause autosomal dominant HSP via loss-of-function microtubule-severing defects and dominant microtubule binding, establishing SPAST testing for diagnosis, genetic counseling, and targeted therapy trials.

References

• Neuroscience letters • 2002 • A novel mutation in the spastin gene in a family with spastic paraplegia PMID:12023066
• Archives of neurology • 2002 • Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia PMID:11843700
• Movement disorders • 2004 • Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation PMID:15197701
• Journal of human genetics • 2002 • A novel missense mutation (I344K) in the SPG4 gene in a Korean family with autosomal-dominant hereditary spastic paraplegia PMID:12202986
• The Journal of cell biology • 2005 • Linking axonal degeneration to microtubule remodeling by Spastin-mediated microtubule severing PMID:15716377
• Journal of neurochemistry • 2009 • Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia PMID:19453301

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