Objective: To (1) describe the genetic variability, phenotype and epidemiology of spastin mutation in HSP patients (2) create the UK HSP register with a focus on patients with mutations in the SPAST gene.

Background: Hereditary Spastic Paraplegias (HSP) are a heterogeneous group of rare degenerative diseases that present clinically with a very diverse phenotype. Spastin (SPAST) mutations are the most common cause of HSP and have been classified initially as predominantly “pure” form. Several complex spastin phenotypes have been published recently.

Methods: We analysed, retrospectively, genetic, phenotype and investigations results data from 117 genetically confirmed spastin cases from 98 families from UK population. For each mutation we assessed novelty, pathogenicity and genotype-phenotype correlation.

Results: A total of 74 unique mutations were identified of which 37.8% (28) were novel. 80% of mutations were unique to one kindred only. All types of variants were identified with missense mutations being the most frequent (39%). Males were more frequently affected with M:F ratio 1.7:1. Mean age at onset was 29.5y with a range from birth to 63y. Over 30% of cases had an early onset HSP. Complex phenotype was present in 18.6%. Our results show an unexpectedly high rate (9.8%) of spastin cases associated with psychiatric illnesses of which three cases had autistic spectrum disorders. One mutation, the c.1635_1636insAA was identified in four cases from three unrelated families affected by Asperger, severe depression and schizoaffective disorder. This is a novel Frameshift mutation with a frequency of 3.3% in our cohort. All the mutations associated with psychiatric manifestations are loss of function, produce a truncated protein and are located in the AAA domain.We found that a later onset and a complex phenotype produced a more severe disease and a faster rate of progression. No other genotype-phenotype correlation was possible and a high variability was identified between and within families.

Conclusions: This study, one of the largest collections of genetically confirmed spastin patients to date, provides new insights into SPAST related HSP. In particular, the previously under-recognized association with autism and psychiatric illness needs to be confirmed in other genes and cohorts to determine if this is a specific effect of spastin mutations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/development-of-the-uk-hereditary-spastic-paraplegia-registry-analysis-of-spast-patients-reveals-high-rate-of-psychiatric-comorbidities/