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Brain. 2016 Jul;139(Pt 7):1904-18. doi: 10.1093/brain/aww111. Epub 2016 May 23.

Genetic and phenotypic characterization of complex hereditary spastic paraplegia.

Author information

1
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA.
2
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 3 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
3
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 4 School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
4
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
5
5 Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
6
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 5 Department of Neurology and Psychiatry, Assiut University Hospital, Faculty of Medicine, Assiut, Egypt.
7
6 Laboratory of Neurogenetics, NIH/NIA, Bethesda, MD 20892, USA.
8
7 Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
9
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 8 Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.
10
9 Department of Clinical Neuroscience, Royal Free Campus, UCL Institute of Neurology, London, UK.
11
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 9 Department of Clinical Neuroscience, Royal Free Campus, UCL Institute of Neurology, London, UK.
12
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 10 Reta Lila Weston Institute of Neurological Studies and Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
13
11 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
14
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 12 Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.
15
1 Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK 2 Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA h.houlden@ucl.ac.uk.

Abstract

The hereditary spastic paraplegias are a heterogeneous group of degenerative disorders that are clinically classified as either pure with predominant lower limb spasticity, or complex where spastic paraplegia is complicated with additional neurological features, and are inherited in autosomal dominant, autosomal recessive or X-linked patterns. Genetic defects have been identified in over 40 different genes, with more than 70 loci in total. Complex recessive spastic paraplegias have in the past been frequently associated with mutations in SPG11 (spatacsin), ZFYVE26/SPG15, SPG7 (paraplegin) and a handful of other rare genes, but many cases remain genetically undefined. The overlap with other neurodegenerative disorders has been implied in a small number of reports, but not in larger disease series. This deficiency has been largely due to the lack of suitable high throughput techniques to investigate the genetic basis of disease, but the recent availability of next generation sequencing can facilitate the identification of disease-causing mutations even in extremely heterogeneous disorders. We investigated a series of 97 index cases with complex spastic paraplegia referred to a tertiary referral neurology centre in London for diagnosis or management. The mean age of onset was 16 years (range 3 to 39). The SPG11 gene was first analysed, revealing homozygous or compound heterozygous mutations in 30/97 (30.9%) of probands, the largest SPG11 series reported to date, and by far the most common cause of complex spastic paraplegia in the UK, with severe and progressive clinical features and other neurological manifestations, linked with magnetic resonance imaging defects. Given the high frequency of SPG11 mutations, we studied the autophagic response to starvation in eight affected SPG11 cases and control fibroblast cell lines, but in our restricted study we did not observe correlations between disease status and autophagic or lysosomal markers. In the remaining cases, next generation sequencing was carried out revealing variants in a number of other known complex spastic paraplegia genes, including five in SPG7 (5/97), four in FA2H (also known as SPG35) (4/97) and two in ZFYVE26/SPG15 Variants were identified in genes usually associated with pure spastic paraplegia and also in the Parkinson's disease-associated gene ATP13A2, neuronal ceroid lipofuscinosis gene TPP1 and the hereditary motor and sensory neuropathy DNMT1 gene, highlighting the genetic heterogeneity of spastic paraplegia. No plausible genetic cause was identified in 51% of probands, likely indicating the existence of as yet unidentified genes.

KEYWORDS:

Parkinson’s disease; SPG11; gene; hereditary spastic paraplegia; mutation

PMID:
27217339
PMCID:
PMC4939695
DOI:
10.1093/brain/aww111
[Indexed for MEDLINE]
Free PMC Article

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