Myoclonus-Ataxia Syndromes: A Diagnostic Approach

Abstract

Background: A myriad of disorders combine myoclonus and ataxia. Most causes are genetic and an increasing number of genes are being associated with myoclonus-ataxia syndromes (MAS), due to recent advances in genetic techniques. A proper etiologic diagnosis of MAS is clinically relevant, given the consequences for genetic counseling, treatment, and prognosis.

Objectives: To review the causes of MAS and to propose a diagnostic algorithm.

Methods: A comprehensive and structured literature search following PRISMA criteria was conducted to identify those disorders that may combine myoclonus with ataxia.

Results: A total of 135 causes of combined myoclonus and ataxia were identified, of which 30 were charted as the main causes of MAS. These include four acquired entities: opsoclonus-myoclonus-ataxia syndrome, celiac disease, multiple system atrophy, and sporadic prion diseases. The distinction between progressive myoclonus epilepsy and progressive myoclonus ataxia poses one of the main diagnostic dilemmas.

Conclusions: Diagnostic algorithms for pediatric and adult patients, based on clinical manifestations including epilepsy, are proposed to guide the differential diagnosis and corresponding work-up of the most important and frequent causes of MAS. A list of genes associated with MAS to guide genetic testing strategies is provided. Priority should be given to diagnose or exclude acquired or treatable disorders.

Keywords: genetics, myoclonus, ataxia, movement disorders, diagnosis.

FIG 1

Clinical diagnostic algorithm for myoclonus‐ataxia syndromes with onset in infancy or childhood. For didactic purposes, this figure includes the main myoclonus‐ataxia syndromes (entities where myoclonus and ataxia are prominent and frequent features) and which therefore should be suspected first, before considering disorders where the combination of myoclonus and ataxia is found only occasionally. In addition, next‐generation sequencing techniques can be the first step in the diagnostic process in many cases and the genetic finding can be matched or validated with the clinical features displayed in both figures. Conditions with (possible) faster disease progression are shown in bold. CMA: chromosomal microarray analysis; Del/dupl: deletions and duplications; REA: repeat expansion analysis; SGS: single gene sequencing; TGP: targeted gene panels; WES: whole exome sequencing; LH: luteinizing hormone; FSH: follicle stimulating hormone; CK: creatine kinase. Conditions with (possible) faster disease progression are shown in bold.

FIG 2

Clinical diagnostic algorithm for myoclonus‐ataxia syndromes with onset in adulthood. For didactic purposes, this figure includes the main myoclonus‐ataxia syndromes (entities where myoclonus and ataxia are prominent and frequent features) and which therefore should be suspected first, before considering disorders where the combination of myoclonus and ataxia is found only occasionally. In addition, next‐generation sequencing techniques can be the first step in the diagnostic process in many cases and the genetic finding can be matched or validated with the clinical features displayed in both figures. Conditions with (possible) faster disease progression are shown in bold. CMA: chromosomal microarray analysis; Del/dupl: deletions and duplications; REA: repeat expansion analysis; RRFs: ragged red fibers; SGS: single gene sequencing; TGP: targeted gene panels; WES: whole exome sequencing; FLAIR: fluid attenuated inversion recovery; DWI: diffusion‐weight imaging; LH: luteinizing hormone; FSH: follicle stimulating hormone. Conditions with (possible) faster disease progression are shown in bold.