Hereditary spastic paraplegia : a novel mutation and expansion of the phenotype variability in SPG10

INTRODUCTION Hereditary spastic paraplegias (HSPs) are a group of disorders characterized by slow progressive weakness and spasticity of the lower limbs. HSPs have been divided into pure and complicated forms, depending on the absence or presence of additional neurological or non-neurological features. To date, 72 loci and 55 spastic paraplegia genes (SPGs) have been identified. SPG10 is caused by mutations in the KIF5A gene encoding neuron-specific kinesin heavy chain 5A (NK-HC5A), a member of the kinesin-1 family of motor proteins. In mammals, NK-HC5A is necessary for the anterograde axonal transport of neurofilament subunits, and it has a role in the transport of other anterograde cargoes, such as membrane vesicles. SPG10 is an autosomal dominant HSP (ADHSP), accounting for about 10% of the complicated forms. Peripheral neuropathy and cognitive impairment are the most common additional clinical features. This report describes a novel KIF5A genetic defect in a large Italian ADHSP family with exclusive clinical features. Methods The currently living family members were examined by movement disorder specialists (TLG, GAM, RM and AO). Neurological assessments, including the Spastic Paraplegia Rating Scale (SPRS) Mental Deterioration Battery (MDB) electrophysiology of peripheral nerves, and neuroimaging analyses, were carried out. After informed consent was given, genomic DNA was extracted from peripheral lymphocytes. Genetic analyses were conducted as described in online supplementary data, including linkage studies at the currently known ADHSP loci, PCR-direct sequencing, PCR-restriction fragment length polymorphism (PCR-RFLP) assay, and in silico analysis. Results The RM 551 family is composed of a three-generation kindred with AD inheritance. Eleven individuals were diagnosed as ‘certainly affected’ and classified as having complicated HSP.1 At examination, the age range of the affected individuals was 19–77 years (mean±SD=40.4±17.9 years). Spastic paraparesis was the primary symptom in the clinical course of each patient; age at onset ranged between 12 and 55 years (mean±SD=32.2±15.0 years). The decrease of age at onset between successive generations ranged from 4 to 39 years per generation. The disease was slowly progressive and urinary urgency was a common symptom. Electroneurography of both motor and sensory nerves, as well as electromyography, were normal. MDB did not show cognitive impairment. Other clinical features associated with SPG10 were absent. Interestingly, this variant form of HSP was associated in all affected individuals of the family with varicose veins (VV) of the legs, as well as bilateral Dupuytren's disease (DD) at various stages, according to Clinical-Etiology-Anatomy-Pathophysiology (CEAP) and Tubiana classifications, respectively (table 1 and online supplementary figure S1). DD and VV were absent in all members of the family who did not have gait difficulty. The environmental associations of DD, such as alcohol consumption, tobacco exposure, manual activities, retractile capsulitis, epilepsy, diabetes, HIV and dyslipidemia, were absent in all patients. Obesity and lower limb deep vein thrombosis examined by venous ultrasonography were also absent, suggesting a primary form of VV.

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