ZFYVE26 – Hereditary Spastic Paraplegia 15

Hereditary spastic paraplegia 15 (HSP15; MONDO:0010044) is an autosomal recessive neurodegenerative disorder characterized by progressive lower-limb spasticity, thin corpus callosum, variable cognitive impairment, and retinal degeneration in Kjellin syndrome. The ZFYVE26 gene (HGNC:20761) encodes spastizin, a FYVE‐domain protein involved in endolysosomal trafficking. Biallelic loss‐of‐function or missense variants disrupt autophagy and endosome fusion, leading to axonal degeneration.

Genetic evidence includes eight unrelated families with homozygous or compound heterozygous truncating and splice variants segregating with HSP15 ([PMID:18394578]). Two additional case reports describe a Saudi patient with compound heterozygous c.7411A>G (p.Asn2471Asp) and c.5417G>A (p.Arg1806Lys) ([PMID:36540605]), and a Kjellin syndrome patient homozygous for c.2114dup (p.Glu706Ter) ([PMID:40400141]).

The variant spectrum comprises predominantly loss‐of‐function alleles (n>60 truncating/splice, frameshift) and rare missense changes affecting the FYVE and coiled‐coil domains. No recurrent or founder variants have been reported outside consanguineous populations. Population frequency is extremely low, consistent with recessive inheritance.

Functional studies support a loss‐of‐function mechanism. Patient‐derived cells and knockout mice exhibit accumulation of immature autophagosomes, lysosomal enlargement, and progressive corticospinal and Purkinje cell loss, mirroring human HSP15 ([PMID:30081747]; [PMID:24367272]). Rescue of autophagy defects by constitutively active RAB5A underscores disrupted endosome–autophagosome fusion.

No significant conflicting evidence has been reported. All reported families display consistent segregation, phenotype, and cellular/murine concordance.

In summary, the body of genetic and experimental data meets ClinGen criteria for a Strong gene–disease association. Key take-home: ZFYVE26 testing enables definitive diagnosis of HSP15 and guides early management and genetic counseling.

References

• Maedica • 2022 • Adult-Onset Hereditary Spastic Paraplegia 15 in a Saudi Patient with A Compound Heterozygous Variant in the ZFYVE26Gene. PMID:36540605
• Ophthalmic genetics • 2025 • Keratoconus in hereditary spastic paraplegia 15 and Kjellin syndrome: a case report. PMID:40400141
• American journal of human genetics • 2008 • Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. PMID:18394578
• Autophagy • 2019 • ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis. PMID:30081747
• PLoS genetics • 2013 • A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the endolysosomal system. PMID:24367272

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