TFG – hereditary spastic paraplegia 57

Hereditary spastic paraplegia 57 (SPG57) is a rare autosomal recessive neurodegenerative disorder characterized by lower limb spasticity, optic atrophy, and peripheral neuropathy. The tropomyosin-receptor kinase fused gene (TFG) encodes a key regulator of endoplasmic reticulum–to–Golgi vesicular transport, and biallelic pathogenic variants disrupt this pathway leading to corticospinal tract axonopathy.

Multiple independent studies have reported homozygous missense variants in TFG in at least 10 probands from eight consanguineous families, confirming autosomal recessive inheritance and segregation of TFG variants with SPG57 ([PMID:30467354], [PMID:33767317], [PMID:38837630]). The first Japanese patient harbored c.197T>C (p.Ile66Thr) ([PMID:30467354]), and a Taiwanese cohort identified c.177A>C (p.Lys59Asn) in an adolescent-onset pure HSP case ([PMID:38837630]).

The spectrum of pathogenic variants includes four homozygous missense alleles—p.Lys14Arg, p.Ile66Thr, p.Lys59Asn, and p.Arg106Cys—affecting PB1 and coiled-coil domains essential for TFG oligomerization. No large deletions or frameshifts have been reported, and recurrent founder alleles have not been observed.

Functional assays demonstrate that the Lys59Asn variant destabilizes TFG monomer affinity, impairs homo-oligomer assembly, and reduces protein secretion and cellular viability in vitro ([PMID:38837630]). In a rat model carrying p.Arg106Cys, ER export delays and axon fasciculation defects were rescued by neuron-specific wild-type TFG expression, supporting a neuron-autonomous mechanism ([PMID:39527745]).

Pathogenic TFG variants cause SPG57 via loss of proper ER-to-Golgi trafficking, leading to corticospinal tract degeneration, optic nerve atrophy, and peripheral sensorimotor neuropathy. No studies dispute this association.

Collectively, genetic and experimental data provide strong evidence for TFG as a definitive cause of SPG57. Biallelic TFG testing should be included in diagnostic panels for early-onset spastic paraplegia and related neurodegenerative syndromes.

Key Take-home: Detection of biallelic TFG missense variants enables definitive diagnosis of SPG57 and highlights ER-to-Golgi transport pathways as potential therapeutic targets.

References

• Journal of human genetics • 2019 • A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. PMID:30467354
• Journal of human genetics • 2021 • Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature. PMID:33767317
• Annals of clinical and translational neurology • 2024 • Characterization of a novel TFG variant causing autosomal recessive pure hereditary spastic paraplegia. PMID:38837630
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • Cell type-specific gene therapy confers protection against motor neuron disease caused by a TFG variant. PMID:39527745

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