Abstract
BackgroundHereditary spastic paraplegias (HSP) are a composite and genetically heterogeneous group of conditions mainly expressed by the impairment of the central motor system (“pure” forms). The involvement of other components of the central nervous system or of other systems is described in the “complicate” forms. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis.MethodsWe applied a clinical and paraclinical protocol which included tools exploring motor and non motor functioning, neurophysiology and MRI to a composite cohort of 70 molecularly defined HSP patients aged 3 to 65, to define for each indicator its significance in detailing the presence and the severity of the pathology.ResultsClinically increased deep tendon reflexes and lower limb (LL) weakness are constant findings in all patients. The “complicated” forms are characterized by peripheral motor impairment, cognitive and cerebellar involvement. The Spastic Paraplegia Rating Scale efficiently reflects the severity of functional problems and correlates with disease duration. Neurophysiology consistently documents the impairment of the central motor pathway to the LLs. Nevertheless, the upper extremities and sensory system involvement is a frequent finding. MRI diffusion tensor imaging (DTI) highlighted a significant alteration of FA and MD. Combining the sampling of the various portion of the cortico-spinal tract (CST) DTI consistently discriminated patients from controls.ConclusionWe propose a graded clinical and paraclinical protocol for HSP phenotype definition, indicating for each tool the discriminative and descriptive capacity. Our protocol applied to 9 different forms of HSP showed that the functional impairment often extends beyond the CST. The novel DTI approach may add significant elements in disease recognition, staging and mapping.
Highlights
Hereditary spastic paraplegia (HSP) is a clinical entity with a wide heterogeneity in molecular aetiology and a core homogeneous phenotype characterized by pyramidal tract disturbance of the lower limbs (LL) with spasticity and weakness, hyperactive deep tendon reflexes (DTR), extensor plantar responses, mild distal loss of vibration sense, inconstant urinary urgency [1]
In spite of the apparently stereotypical clinical manifestation, a relevant variability is observed even among siblings or relatives in the same family [3]. In some cases this is explained by the association of more than one sequence variation of the same gene (Spastic Paraplegia Gene, spastic paraplegia gene (SPG)) [4,5,6], whereas in others subtle characteristics seem to differentiate one form to another [1, 3]: early onset associated with mutations of atlastin-1 (SPG3a) [7], DDHD1 (SPG28) [8] and REEP1 (SPG31) [9]; cognitive decline with mutations in spastin (SPG4) [10]; cerebellar signs such as ataxia with mutations of paraplegin (SPG7) [11]; axonal motor neuropathy and distal atrophy with mutation in seipin (SPG17) [12] and KiF5A (SPG10) [13, 14]; white matter (WM) magnetic resonance imaging (MRI) abnormalities with mutations of CYP7B1 (SPG5) [15]; thin corpus callosum with a characteristic white matter alteration (“ears of lynx” sign) and intellectual disability in mutations of spatacsin (SPG11) [16]
The motor central conduction time of LL motor evoked responses (MER) was described and reported as informative parameters considering the normative values of each laboratory
Summary
Hereditary spastic paraplegia (HSP) is a clinical entity with a wide heterogeneity in molecular aetiology and a core homogeneous phenotype characterized by pyramidal tract disturbance of the lower limbs (LL) with spasticity and weakness, hyperactive deep tendon reflexes (DTR), extensor plantar responses, mild distal loss of vibration sense, inconstant urinary urgency [1]. Besides these core defining clinical signs, some forms called “complicated” are associated with other signs such as cerebellar ataxia, peripheral neuropathy, cognitive impairment, epilepsy, retinopathy, extrapyramidal manifestations, abnormalities on MRI, cataract and ichthyosis [2]. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
