Comprehensive characterisation established
45 different genetic variants in SPG15 have been discovered so far.
Symptom onset often occurs in early childhood with learning disabilities and/ or speech delay, several years before changes occur in gait. Spasticity typically begins in adolescence, with over half experiencing spasticity in the upper limbs over time. Development of ataxia symptoms is common, as is cognitive decline and bladder problems over time. Brain MRI changes also occur. Markers of disease severity have been established.
Detailed and comprehensive characterisation of SPG 15 HSP has emerged from this study involving a huge collaboration of HSP researchers globally.
Abstract
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, 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 cortical and cerebellar atrophy.
The molecular spectrum included 45 distinct variants, distributed across the protein structure without mutational hotspots.
Spastic Paraplegia Rating Scale (SPRS) scores, SPATAX Disability Scores and the 4-Stage Functional Mobility Score showed moderate strength in representing the proportion of variation between disease duration and motor dysfunction.
Plasma neurofilament light chain levels were significantly elevated in all patients (Mann-Whitney-U test, p < 0.0001) and were correlated inversely with age (Spearman’s rank correlation coefficient r = -0.65, p = 0.01).
In summary, our systematic cross-sectional analysis of HSP-ZFYVE26 patients across a wide age-range, delineates core clinical, neuroimaging and molecular features and identifies markers of disease severity. These results raise awareness to this rare disease, facilitate an early diagnosis and create clinical trial readiness.
SOURCE: Brain. 2022 Oct 31;awac391. doi: 10.1093/brain/awac391. Online ahead of print. PMID: 36315648 © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: [email protected].
The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15
Afshin Saffari 1 2 , Melanie Kellner 3 4 , Catherine Jordan 1 , Helena Rosengarten 1 , Alisa Mo 1 , Bo Zhang 1 5 , Oleksandr Strelko 1 6 , Sonja Neuser 7 , Marie Y Davis 8 9 , Nobuaki Yoshikura 10 , Naonobu Futamura 11 , Tomoya Takeuchi 12 , Shin Nabatame 13 , Hiroyuki Ishiura 14 , Shoji Tsuji 15 16 , Huda Shujaa Aldeen 17 , Elisa Cali 17 , Clarissa Rocca 17 , Henry Houlden 17 , Stephanie Efthymiou 17 , SYNaPS Study Group; Birgit Assmann 2 , Grace Yoon 18 , Bianca A Trombetta 19 , Pia Kivisäkk 19 , Florian Eichler 20 , Haitian Nan 21 , Yoshihisa Takiyama 21 22 , Alessandra Tessa 23 , Filippo M Santorelli 23 , Mustafa Sahin 1 6 , Craig Blackstone 24 , Edward Yang 25 , Rebecca Schüle 3 4 , Darius Ebrahimi-Fakhari 1 26 27 28
1. Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
2. Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital, Heidelberg, Germany.
3. Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany.
4. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
5. ICCTR Biostatistics and Research Design Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
6. Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
7. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
8. Department of Neurology, University of Washington, Seattle, WA, USA.
9. VA Puget Sound Healthcare System, Seattle, WA, USA.
10. Department of Neurology, Gifu University Graduate School of Medicine, Gifu, Japan.
11 Department of Neurology, National Hospital Organization Hyogo-Chuo National Hospital, Ohara, Sanda, Japan.
12. Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Aichi, Japan.
13. Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
14. Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
15. Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
16. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan.
17. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, University College London, London, UK.
18. Divisions of Clinical and Metabolic Genetics and Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
19. Alzheimer’s Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
20. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
21. Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan.
22. Department of Neurology, Fuefuki Central Hospital, Yamanashi, Japan.
23. Department of Molecular Medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.
24. Movement Disorders Division, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
25. Division of Neuroradiology, Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
26. Movement Disorders Program, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
27. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA.
28. Intellectual and Developmental Disabilities Research Center, Boston Children’s Hospital, Boston, MA, USA.