| Title: |
The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15 |
| Authors: |
Saffari, Afshin; Kellner, Melanie; Jordan, Catherine; Rosengarten, Helena; Mo, Alisa; Zhang, Bo; Strelko, Oleksandr; Neuser, Sonja; Davis, Marie Y; Yoshikura, Nobuaki; Futamura, Naonobu; Takeuchi, Tomoya; Nabatame, Shin; Ishiura, Hiroyuki; Tsuji, Shoji; Aldeen, Huda Shujaa; Cali, Elisa; Rocca, Clarissa; Houlden, Henry; Efthymiou, Stephanie; Assmann, Birgit; Yoon, Grace; Trombetta, Bianca A; Kivisäkk, Pia; Eichler, Florian; Nan, Haitian; Takiyama, Yoshihisa; Tessa, Alessandra; Santorelli, Filippo M; Sahin, Mustafa; Blackstone, Craig; Yang, Edward; Schüle, Rebecca; Ebrahimi-Fakhari, Darius |
| Contributors: |
Deutsche Forschungsgemeinschaft; German Research Foundation; International Centre for Genomic Medicine in Neuromuscular Diseases; Japan Ministry of Health; Labor and Welfare; Research Committee for Ataxic Disease; Italian Ministry of Health; CureAP4 Foundation; CureSPG50 Foundation; Spastic Paraplegia Foundation; Manton Center for Orphan Disease Research; National Institute of Neurological Disorders and Stroke; Boston Children’s Hospital Office of Faculty Development; Wellcome Trust; National Institute for Health Research; University College London Hospitals Biomedical; Intellectual and the Developmental Disabilities Research Center; National Institutes of Health |
| Source: |
Brain ; volume 146, issue 5, page 2003-2015 ; ISSN 0006-8950 1460-2156 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2022 |
| Description: |
In the field of hereditary spastic paraplegia (HSP), progress in molecular diagnostics needs to be translated into robust phenotyping studies to understand genetic and phenotypic heterogeneity and to support interventional trials. ZFYVE26-associated hereditary spastic paraplegia (HSP-ZFYVE26, SPG15) is a rare, early-onset complex HSP, characterized by progressive spasticity and a variety of other neurological symptoms. While prior reports, often in populations with high rates of consanguinity, have established a general phenotype, there is a lack of systematic investigations and a limited understanding of age-dependent manifestation of symptoms. Here we delineate the clinical, neuroimaging and molecular features of 44 individuals from 36 families, the largest cohort assembled to date. Median age at last follow-up was 23.8 years covering a wide age range (11–61 years). While symptom onset often occurred in early childhood [median: 24 months, interquartile range (IQR) = 24], a molecular diagnosis was reached at a median age of 18.8 years (IQR = 8), indicating significant diagnostic delay. We demonstrate that most patients present with motor and/or speech delay or learning disabilities. Importantly, these developmental symptoms preceded the onset of motor symptoms by several years. Progressive spasticity in the lower extremities, the hallmark feature of HSP-ZFYVE26, typically presents in adolescence and involves the distal lower limbs before progressing proximally. Spasticity in the upper extremities was seen in 64%. We found a high prevalence of extrapyramidal movement disorders including cerebellar ataxia (64%) and dystonia (11%). Parkinsonism (16%) was present in a subset and showed no sustained response to levodopa. Cognitive decline and neurogenic bladder dysfunction progressed over time in most patients. A systematic analysis of brain MRI features revealed a common diagnostic signature consisting of thinning of the anterior corpus callosum, signal changes of the anterior forceps and non-specific ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/brain/awac391 |
| DOI: |
10.1093/brain/awac391/48808153/awac391.pdf |
| Availability: |
https://doi.org/10.1093/brain/awac391; https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awac391/48808153/awac391.pdf; https://academic.oup.com/brain/article-pdf/146/5/2003/51077610/awac391.pdf |
| Rights: |
https://academic.oup.com/pages/standard-publication-reuse-rights |
| Accession Number: |
edsbas.6BE8A5CB |
| Database: |
BASE |