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.
Highlights
The hereditary spastic paraplegias (HSPs) are a diverse group of neurodegenerative diseases with a prevalence of 2–7.4/ 100 000 in most populations (Erichsen et al, 2009; Blackstone, 2012; Noreau et al, 2014)
Four less common distinct phenotypes have been associated with SPG11 mutations, including Kjellin syndrome, which is a rare form of HSP with additional retinal manifestations (Puech et al, 2011; Nowak et al, 2014), slowly progressive amyotrophic lateral sclerosis (Orlacchio et al, 2010; Daoud et al, 2012), syndromes reminiscent of dystoniaparkinsonism (Paisan-Ruiz et al, 2010b; Kara et al, 2013) and syndromes with prominent L-DOPA responsive parkinsonism (Anheim et al, 2009a; Everett et al, 2012a)
We focused on a subset of genes in which mutations have been previously associated with spastic paraplegia, neurodegeneration, ataxia, peripheral neuropathy, Parkinson’s disease and pallidopyramidal syndromes
Summary
The hereditary spastic paraplegias (HSPs) are a diverse group of neurodegenerative diseases with a prevalence of 2–7.4/ 100 000 in most populations (Erichsen et al, 2009; Blackstone, 2012; Noreau et al, 2014) They can be inherited in autosomal dominant, autosomal recessive or X-linked patterns with an age of onset that varies from early childhood to 70 years of age. The most common cause of autosomal dominant spastic paraplegia are SPAST/SPG4 mutations, with patients presenting with a pure form of HSP (Schule and Schols, 2011; Finsterer et al, 2012; Fink, 2014; Noreau et al, 2014). The increasing heterogeneity of spastic paraplegia and the clinical overlap seen with several other conditions suggests that there is still considerable genetic expansion to come in this group of disorders (Beetz et al, 2008; de Bot et al, 2012)
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