Hereditary spastic paraplegias: time for an objective case definition and a new nosology for neurogenetic disorders to facilitate biomarker/therapeutic studies

ABSTRACT

Introduction: Hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders characterized by progressive lower limb weakness and spasticity as core symptoms of the degeneration of the corticospinal motor neurons. Even after exclusion of infectious and toxic mimickers of these disorders, the definitive diagnosis remains tricky, mainly in sporadic forms, as there is significant overlap with other disorders. Since their first description, various attempts failed to reach an appropriate classification. This was due to the constant expansion of the clinical spectrum of these diseases and the discovery of new genes, a significant number of them was involved in overlapping diseases.

Areas covered: In this perspective review, an extensive literature study was conducted on the historical progress of HSP research. We also revised the previous and the current classifications of HSP and the closely related neurogenetic disorders and analyzed the areas of overlap.

Expert opinion: There is undeniable need for objective case definition and reclassification of all neurogenetic disorders including HSPs, a prerequisite to improve patient follow-up, biomarker identification and develop therapeutics. The challenge is to understand why mutations can give rise to multiple phenotypic presentations along this spectrum of diseases in which the corticospinal tract is affected.

KEYWORDS:

• Spasticity
• neurodegenerative diseases
• hereditary spastic paraplegias
• neurogenetic
• motor neuron disease
• phenotype-genotype correlations

Article Highlights

• Hereditary spastic paraplegias are heterogeneous disorders with phenotypic overlap with other neurogenetic conditions.

• Genes mutated in spastic paraplegias are those found mainly in HSP patients (>60) and those mutated in other neurogenetic conditions for which spasticity can occasionally occur as the major clinical presentation.

• Diagnosis is complicated by the occurrence of multiple inheritance modes associated to a given gene, sometimes with the same mutations.

• The lack of phenotype-genotype correlations and of validated biomarkers in most cases is a challenge for future therapeutic opportunities.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

The work of the authors is financially supported by the European Union (H2020 program – SOLVE-RD, to G Stevanin), the Erare program (Prepare, to G Stevanin), the ministry of higher education of Sudan (to L Elsayed), Campus France (to L Elsayed), the Strumpell-Lorrain and Connaitre les Syndromes Cérébelleux patient associations (to G Stevanin), and the Spastic Paraplegia Foundation (to G Stevanin).