The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

Abstract

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.

Cardiovascular autonomic testing in the work-up of cerebellar ataxia: insight from an observational single center study

“…Cerebellar ataxias are a heterogeneous group of disorders of both genetic and non-genetic origin [1][2][3][4]. Hereditary forms include a variety of entities with both autosomal dominant and recessive inheritance pattern [1,2], the most common being the spinocerebellar ataxias type 1, 2, 3, and 6, which are caused by a CAG triplet expansion in the respective loci [2]. In several patients with adult-onset ataxia a specific genetic cause cannot be found, suggesting a diagnosis of sporadic degenerative ataxia [4].…”

Recent Advances in the Treatment of Cerebellar Disorders

“…This heterogeneous group of conditions gathers disorders generally manifesting before the age of 30 with progressive gait ataxia [50,51]. ARCAs often exhibit extra-cerebellar neurological symptoms or even extra-neurological deficits.…”

“…ARCAs often exhibit extra-cerebellar neurological symptoms or even extra-neurological deficits. The diagnosis of ARCAs may turn to be very challenging at the beginning of the disease [50,51]. Newly developed therapies designed to manipulate cellular functions have so far failed to show significant improvement in ARCAs.…”

“…However, chelation or replacement therapy is sometimes beneficial especially where metabolic changes lead to accumulation or deficiency of a particular substance ( Table 2). Symptoms of FRDA are related to spinocerebellar degeneration, cerebellar pathology, and peripheral nerve damage [50,51]. Guanine-adenine-adenine (GAA) trinucleotide repeat expansion is inserted in the frataxin (FXN) gene, located on chromosome 9q13 [57].…”

Novel MAG Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype

“…Autosomal recessive cerebellar ataxias are generally associated with peripheral sensorimotor neuropathy and non-neurological features. The most common of these is Friedreich ataxia, but recent advances in genetics, particularly the use of next-generating sequencing (NGS) technologies, have expanded the number of causative genes to more than 50 [3][4][5]. Additionally, HCAs share clinical features and disease mechanisms with hereditary spastic paraplegias (HSPs), with several ataxia-related genes found to cause HSPs and vice versa [6,7].…”