Questioning disease classification systems

A mechanistically inspired classification proposed


Rebecca Schüle

Eminent HSP researcher Dr. Rebecca Schüle of Germany and her co-author highlight the deficiencies in the current separate classification systems for the spinocerebellar ataxias and the hereditary spastic paraplegias.


They propose a diagnosis-driven single classification system based on a descriptive, unbiased approach of modular phenotyping, i.e. The basket of symptoms that people present with. Such a mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.



Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene.


The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive, diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing, not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.


SOURCE: Mov Disord. 2017 Mar;32(3):332-345. doi: 10.1002/mds.26944. Epub 2017 Feb 14. © 2017 International Parkinson and Movement Disorder Society. PMID: 28195350


Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways.


Synofzik M1,2, Schüle R1,2.


1 Department of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), University of Tübingen, Tübingen, Germany.

2 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

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