SPAST – Spastic Paraplegia Type 4

Autosomal dominant spastic paraplegia type 4 (SPG4) is caused by pathogenic variants in the SPAST gene, which encodes the microtubule-severing AAA ATPase spastin. The SPAST gene product is essential for axon integrity in corticospinal tracts, and loss of function leads to a retrograde axonopathy characterized by progressive lower limb spasticity. SPG4 (MONDO:0008438) exhibits wide allelic heterogeneity, with truncating, missense, splice-site, and copy number variants reported. Clinical penetrance is high but age at onset and severity vary markedly, suggesting modifier influences. Functional studies link defective microtubule severing to axonal swellings, transport deficits, and synapse loss, supporting a mechanistic basis for disease. Genetic testing of SPAST is therefore recommended in adults presenting with isolated or complicated hereditary spastic paraplegia.

Inheritance of SPG4 is autosomal dominant with robust segregation. In a large multigenerational pedigree (43 members), a novel exon 1 nonsense mutation segregated in 24 carriers (PMID:15197701). An independent Han Chinese family study identified 8 affected probands carrying a heterozygous c.1495C>T (p.Arg499Cys) variant (PMID:37473796). Prodromal biomarker studies in 56 at-risk relatives detected subtle hyperreflexia, Babinski sign, and elevated CSF NfL in 30 mutation carriers, illustrating preclinical stages (PMID:35472722). These data confirm dominant transmission with complete penetrance in adult carriers.

The variant spectrum of SPAST in SPG4 includes predominantly loss-of-function alleles: nonsense (e.g., c.508C>T (p.Lys47Ter)), frameshift, and canonical splice-site changes, as well as missense substitutions clustering in the AAA ATPase domain. A recurrent nonsense change, c.508C>T (p.Lys47Ter), was reported in a patient with spastic paraparesis and neurogenic bladder (PMID:32850101). Deep intronic and CNV events account for ~10% of cases, mediated by Alu-mediated non-allelic homologous recombination. Splice-site variants (e.g., c.1245+1G>A, c.1414-2A>T) have been functionally confirmed to cause exon skipping and premature termination (PMID:38145127).

Mechanistic studies demonstrate that wild-type spastin assembles as a hexamer to sever microtubules, whereas disease-associated mutations impair ATP hydrolysis and severing activity, leading to axonal swellings and transport defects in neurons and mouse models (PMID:15716377; PMID:19453301). Microtubule-targeting drugs rescued axonal swellings in spastin-deficient cortical neurons, underscoring therapeutic avenues (PMID:22773755). Modifier loci, such as SARS2, influence age at onset via mitochondrial pathways, highlighting genetic complexity (PMID:36056923).

Both haploinsufficiency and toxic gain-of-function contribute to SPG4 pathogenesis. Haploinsufficiency is supported by reduced spastin dosage and threshold effects in splice-leaky alleles (PMID:11039577). Conversely, mutant M1 isoforms exert dominant-negative or gain-of-function effects on microtubule stability and dynamics, exacerbating corticospinal degeneration in transgenic models (PMID:30520996). This dual mechanism informs variant interpretation and therapeutic targeting.

Key Take-home: SPAST genetic testing provides a definitive diagnosis for AD-SPG4, enables presymptomatic biomarker monitoring, and guides emerging microtubule-targeted therapies.

References

• Movement disorders : official journal of the Movement Disorder Society • 2004 • Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation. PMID:15197701
• Neuroscience letters • 2023 • Identification of c.1495C T mutation in SPAST gene in a family of Han Chinese with hereditary spastic paraplegia PMID:37473796
• Journal of community hospital internal medicine perspectives • 2020 • Complicated SPG4 presenting with recurrent urinary tract infection. PMID:32850101
• 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 (HSP) and human HSP patients. PMID:19453301
• Frontiers in neurology • 2013 • Cohort analysis of novel SPAST variants in SPG4 patients and implementation of in vitro and in vivo studies to identify the pathogenic mechanism caused by splicing mutations. PMID:22773755
• European journal of human genetics : EJHG • 2000 • Hereditary spastic paraplegia caused by mutations in the SPG4 gene. PMID:11039577

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