Clinical and genetic spectrum of the ZFYVE26 gene: an analysis of 7 patients

Background: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of monogenic diseases characterized by length-dependent corticospinal tract degeneration that manifests as bilateral lower limb spasticity, hyperreflexia and extensor plantar responses. They can be further divided into pure and complex, based on additional clinical features, such as epilepsy or cognitive decline. Their genetic classification uses the designation spastic paraplegia gene (SPG). SPG15/Kjellin syndrome, caused by biallelic pathogenic variants in the ZFYVE26 gene, is the second most common autosomal recessive HSP. While a complex HSP phenotype is described, the clinical spectrum of the ZFYVE26 has expanded over the years, with movement disorders and motor neuron disease being reported as possible clinical features. Objective: Describe the clinical characteristics of 7 patients with genetically proven SPG15/jALS. Results: The average age at onset of symptoms was 16.4 years (range: 9-24 years) and the average age at diagnosis was 27.6 years (range: 14-45 years). Consanguinity was observed on 4 patiens. Two main phenotypes were observed: 3 patients had a clinical presentation compatible with juvenile amyotrophic lateral sclerosis (jALS), while the other 4 patients were diagnosed with a HSP phenotype. Distinguishing features between the two groups were the presence of cerebellar ataxia (75% in the HSP group, none in the jALS group), muscle fasciculations (66% in the jALS group, absent in the HSP group) magnetic resonance imaging (corpus callosum thinning was observed in all patients; the classic “ears of the lynx” sign present in 100% of the HSP patients, more diffuse cortical atrophy and white matter changes in the jALS group). Retinal “yellowish flecks” were observed on two patients (one on each group). Cognitive decline was observed on five patients, ranging from moderate dysexecutive changes on 3 patients in the HSP to dementia resembling frontotemporal lobar degeneration (1 patient in each group). Dystonia was observed as the sole movement disorder in two patients, while a combination of dystonia and parkinsonism was observed in one patient. Conclusion: The ZFYVE26 spectrum ranges from a complex HSP to a disorder resembling FTD-ALS; additional clinical features include dystonia, parkinsonism and cerebellar ataxia. MRI remains an useful diagnostic tool to distinguish between ZFYVE26 HSP/ ALS from other genetic o acquired disorders.