Hereditary spastic paraplegia 15 (HSP15) is a rare genetic disease manifesting with progressive muscle spasticity and paralysis of the lower limbs (paraplegia) caused by mutations in the ZFYVE26 gene. When spastic paraplegia is accompanied by retinal degeneration and cognitive impairment, it is known as Kjellin syndrome. We report on ocular manifestations in a case with HSP15 and Kjellin syndrome. We follow a 26-year-old male patient with HSP15 for 6 years. His condition was confirmed by clinical exome sequencing. In addition to regular systemic follow-ups, we performed ophthalmic examinations that included best corrected visual acuity, color vision testing, stereo acuity, visual fields, fundus photography, fundus autofluorescence, optical coherence tomography (OCT), OCT angiography, and corneal topography. Genetic testing in the patient revealed homozygosity for the pathogenic variant c.2114dupC; p. (Glu706Ter) in the ZFYVE26. Although the variant is present in population databases and ClinVar, this is the first report of this variant in HSP15 affected patient. During follow-up the patient's visual acuity declined. Ocular fundus findings comprised of slowly progressive retinal degeneration and a novel ocular phenotype in HSP15 - keratoconus. Corneal topography showed corneal thinning (thinnest location OD: 524 µm OS: 490 µm). Keratoconus was classified as RE: A1B2C0D1, LE: A3B4C1D3 according to Belin Keratoconus Staging System. We describe the clinical and ocular manifestations of a patient with HSP15 and Kjellin syndrome who was diagnosed with a pathogenic variant of ZFYVE26 gene. The patient developed keratoconus that to our knowledge is a novel ophthalmic phenotype in HSP15.

Spastic paraplegia (SPG) is a heterogenous group of neurodegenerative disorders, that may include ocular involvement. Here we report the clinical data of a patient with late-onset Kjellin syndrome, a peculiar form of hereditary SPG with macular dystrophy. Clinical, functional and multimodal retinal imaging data were collected. Genetic testing was performed by Whole Exome Sequencing (WES). A 52-year-old female patient with SPG of unknown origin was referred for a progressive visual acuity loss. Multimodal fundus imaging revealed a peculiar macular dystrophy. Given the specific association of macular dystrophy and SPG, a Kjellin syndrome was suspected and genetic testing performed. WES revealed biallelic pathogenic variants in SPG11, co-segregating with disease in the family. Careful ophthalmological examination prompted the diagnosis and guided molecular testing. This case underlines the importance of a neuro-ophthalmologic assessment in patients with SPG.

A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.