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

Abstract

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.

CAPN1 mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype

“…Increasing availability of next-generation exome sequencing has allowed expansion of the clinical phenotype of various conditions. HSP and SCA are two such conditions in which next-generation sequencing has identified genes that manifest pathology along a continuum of the two disorders 3. This shared genetic background re-contextualises our traditional view of HSP and SCA as being separate clinical entities.…”

“…As more genes are identified in association with these conditions—largely via next-generation exome sequencing—we are seeing increasing genetic overlap between these disorders. This ‘ataxia–spasticity spectrum’ of gene disorders, as described by Synofzik and Schüle, comprises at least 69 genes, mostly inherited in an autosomal recessive manner 3 . CAPN1 is one of these genes that typically manifests as disorders on a spectrum of spasticity and ataxia, often with predominant features of both.…”

“…Additionally, there are seven identified families with CAPN1 mutations with an autosomal recessive variant of hereditary spastic paraplegia (HSP) 3. SCA and HSP have historically been regarded as distinct clinical entities but they are increasingly recognised to have overlapping phenotypes.…”

The genetic nomenclature of recessive cerebellar ataxias

“…For example, the classification of autosomal recessive spinocerebellar ataxias's (SCAR) (for SCA‐recessive) is far from complete, mainly consisting of relatively newer entities (the most common recessive ataxia, Friedreich ataxia, is not included) and also contains unconfirmed entities. Moreover, this SCAR classification is partly paralleled and duplicated, yet with different numbers, by another autosomal recessive cerebellar ataxia (ARCA) classification, the ARCA classification (for a recent criticism of these autosomal recessive ataxia nomenclatures, see the review by Synofzik and Schule). These problems of existing incomplete, inconsistent, and partly parallel nomenclatures are not unique to recessive ataxias, as the classifications of other genetic movement disorders are similarly flawed .…”

Hereditary spastic paraplegia from 1880 to 2017: an historical review

“…Historically, the differentiation between HSPs and inherited ataxias has been the most challenging. The most common ataxia worldwide, SCA3, as well as other autosomal dominant ataxias (examples: SCA1, SCA2, SCA6, SCA7), are frequently accompanied by pyramidal signs, and spastic paraparesis can be the inaugural symptom 8,9,10 . In regard to the AR group, absent reflexes are a hallmark of its most frequent subtype, Friedreich's ataxia.…”