SPG21 – mast syndrome

SPG21, encoding maspardin, is implicated in mast syndrome, a complicated form of hereditary spastic paraplegia characterized by dementia, ataxia, and abnormalities in extrapyramidal motor function. This association was initially identified in a large Old Order Amish pedigree and later confirmed in European families, establishing a consistent autosomal recessive inheritance pattern. Detailed clinical evaluations have revealed not only progressive spasticity and cognitive decline but also neuroimaging findings such as a thin corpus callosum and global brain atrophy. Rigorous segregation analyses in multiple families support the causality of SPG21 mutations in disease expression. The clinical phenotype aligns with disruptions in protein trafficking, a function attributed to maspardin. Overall, these findings form a solid basis for diagnostic decision‑making and future targeted screening strategies.

In the seminal study from the Amish community, 14 affected individuals were identified with mast syndrome (PMID:14564668), where linkage analysis and sequencing revealed a frameshift mutation causing premature termination. This study provided robust genetic evidence based on multi‑family segregation and detailed phenotyping. The mutation spectrum included variants predicted to result in loss of protein function, thereby corroborating the role of SPG21 in the disease. Functional hypotheses were also raised from predicted consequences on protein structure and localization. These data collectively reinforce the pathogenic impact of mutated maspardin. Segregation analysis further underscored the autosomal recessive model.

A follow‑up study in European cohorts reported five additional probands exhibiting similar neurological deficits, including spastic paraplegia, ataxia, and cognitive impairment (PMID:35111129). Comprehensive testing in these families unearthed several types of SPG21 mutations, including missense, frameshift, and splice‑site variants. The replication of the association in non‑Amish populations adds further weight to the genetic evidence. Clinical assessments in these cases were in concordance with the Amish findings, emphasizing a common disease mechanism. The expanded allelic series highlights both recurrent and unique variants contributing to the clinical presentation. This independent cohort strengthens the overall gene‑disease link.

The genetic evidence is compelling, with a diverse mutation spectrum observed across a total of 19 affected individuals (PMID:14564668; PMID:35111129). A representative variant, c.601dup (p.Thr201fs), exemplifies the loss‑of‑function nature of these mutations and follows the recommended HGVS nomenclature with complete coding change and three‑letter amino acid codes. Additional mutations affecting splice sites and generating premature stop codons further substantiate the deleterious impact on maspardin. The recurrence of such mutations across unrelated families dramatically reinforces the association. These findings provide a strong foundation for molecular diagnosis and streamlined clinical screening.

Functional studies have demonstrated that maspardin localizes to intracellular endosomal and trans‑Golgi vesicles, consistent with its critical role in protein sorting and trafficking. Experimental evidence indicates that the truncated proteins fail to maintain proper cellular localization, which likely contributes to the observed neurodegenerative features. Although rescue experiments remain limited, the observed functional deficits align well with the genetic data and clinical phenotype (PMID:14564668). This convergence of genetic and functional evidence underpins a moderate level of experimental support. The combined results enhance our understanding of the disease mechanism and inform both therapeutic and diagnostic approaches.

Integrating the genetic and experimental findings creates a coherent narrative that supports the strong association of SPG21 mutations with mast syndrome. With a broad variant spectrum, clear-cut segregation in distinct populations, and corroborative functional data, the evidence exceeds traditional thresholds for clinical utility. Additional supporting data exist that further consolidate the overall association. The comprehensive evaluation affirms that SPG21 is a robust molecular diagnostic marker, aiding in both genetic counseling and the development of commercial testing assays.

Key Take‑home sentence: SPG21 mutations represent a strong and clinically actionable marker for diagnosing mast syndrome, making them essential for inclusion in diagnostic panels and tailored therapeutic strategies.

References

• American Journal of Human Genetics • 2003 • Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia PMID:14564668
• Frontiers in Neurology • 2021 • Mast Syndrome Outside the Amish Community: SPG21 in Europe PMID:35111129

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