SPART – Troyer Syndrome

SPART has been robustly implicated in Troyer syndrome, an autosomal recessive form of complicated hereditary spastic paraplegia. Clinically, Troyer syndrome is characterized by a constellation of features including mild intellectual disability, spastic paraplegia and muscular dystrophy, which have been observed in diverse populations including Amish, Turkish, Omani, and Filipino kindreds (PMID:26003402).

Multiple independent case reports and series have identified a spectrum of deleterious SPART variants such as frameshift, nonsense, and missense mutations. Notably, a recurrent two-nucleotide deletion, reported as c.364_365delTA (p.Met122ValfsTer2), has been observed in at least two unrelated families, underscoring a recurrent mutational event rather than a founder effect (PMID:26003402).

Segregation analyses in several consanguineous families provide strong evidence of autosomal recessive inheritance, with multiple affected siblings and additional affected relatives demonstrating cosegregation of SPART variants with the Troyer syndrome phenotype (PMID:28679690).

The genetic evidence is further strengthened by the observed variant spectrum. Cases have reported both null mutations and missense changes across SPART, with the recurrent c.364_365delTA mutation confirming its role in disrupting protein function. These studies report a combined total of more than 20 probands from several unrelated families, providing robust support for causality (PMID:15372254).

Functional studies provide a compelling biological rationale, demonstrating that loss-of‐function of spartin adversely affects mitochondrial protein import and bioenergetics. Patient-derived fibroblasts and cellular models of SPART deficiency exhibit impaired mitochondrial respiration, decreased complex I activity, and altered calcium homeostasis, which mirror the pathophysiological features observed in Troyer syndrome (PMID:16945107; PMID:31314595).

In summary, the converging genetic and functional evidence supports a strong association between SPART mutations and Troyer syndrome. This integrated narrative reinforces the clinical utility of genetic testing for SPART variants in patients with spastic paraplegia and related neuromuscular features, while also guiding future therapeutic research focused on ameliorating mitochondrial dysfunction.

References

• Molecular and cellular probes • 2015 • Recurrent null mutation in SPG20 leads to Troyer syndrome PMID:26003402
• Cold Spring Harbor molecular case studies • 2017 • SPG20 mutation in three siblings with familial hereditary spastic paraplegia PMID:28679690
• Journal of neurochemistry • 2006 • The hereditary spastic paraplegia protein spartin localises to mitochondria PMID:16945107
• FASEB journal • 2019 • A novel mutation in SPART gene causes a severe neurodevelopmental delay due to mitochondrial dysfunction with complex I impairments and altered pyruvate metabolism PMID:31314595
• Journal of neurology • 2004 • Troyer syndrome revisited: A clinical and radiological study of a complicated hereditary spastic paraplegia PMID:15372254

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