Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

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.

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“…17 Not until recently, the substantial cerebellar ataxia present in many patients with FA2H mutations was systematically recognized. 18,19 …”

Section: Discovering the Phenotypic And Genetic Spectrum From The Extmentioning

confidence: 99%

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

2017

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“…Speech impairment existed in almost all of the patients. The occurrence of optic atrophy and peripheral neuropathy were not correlated, neuropathy was defined in only two reports 8,13 . The presence of seizure and cognitive decline were also not correlated.…”

Section: Discussionmentioning

confidence: 96%

Hereditary spastic paraplegia type 35 caused by a novel FA2H mutation

et al. 2017

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“…FA2H encodes fatty acid 2-hydroxylase, an important enzyme in galactolipid synthesis that is essential for neuronal myelin sheath maintenance. To date, only a few patients with FA2H mutations have been reported [1, 2, 4, 6, 7]. …”

Section: To the Editormentioning

confidence: 99%

Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia

Donkervoort

Dastgir

et al. 2013

Clinical Genetics

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Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

Cited by 57 publications

References 14 publications

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

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

Hereditary spastic paraplegia type 35 caused by a novel FA2H mutation

Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia

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