The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics

Abstract

ABSTRACT:The inherited cerebellar ataxias are a diverse group of clinically and genetically heterogeneous neurodegenerative disorders. Inheritance patterns of these disorders can be complex with autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance demonstrated by one or more ataxic syndromes. The broad range of mutation types found in inherited ataxia contributes to the complex genetic etiology of these disorders. The majority of inherited ataxias are caused by repeat expansions; however, conventional mutations are important causes of the rarer dominant and recessive ataxias. Advances in sequencing technology have allowed for much broader testing of these rare ataxia genes. This is relevant to the aims of the Human Variome Project, which aims to collate and store gene variation data through mutation databases. Variant data is currently located in a range of public and commercial resources. Few locus-specific databases have been created to catalogue variation in the dominant ataxia genes although there are several databases for some recessive genes. Developing these resources will facilitate a better understanding of the complex genotypephenotype relationships in these disorders and assist interpretation of gene variants as testing for rarer ataxia genes becomes commonplace.

SPG7 mutations explain a significant proportion of French Canadian spastic ataxia cases

“…HSPs are characterized by a predominant progressive spasticity and weakness in the lower limbs due to degeneration of the corticospinal tracts, 1 whereas the main feature of cerebellar ataxias is progressive cerebellar degeneration leading to impaired balance, gait and speech. 2 Both HSP and hereditary ataxias can be associated with other neurological and non-neurological features, resulting in complex phenotypes with frequent intra-and inter-familial variability. Significantly, cerebellar ataxias are very often associated with pyramidal involvement leading to 450% of recessive ataxias manifesting as spastic ataxias.…”

Advances in genetic diagnosis of neurological disorders

“…Different mutations within a single gene can cause the same disease (allelic heterogeneity), and mutations in several different genes can be related to the same clinical expression (locus heterogeneity). For example, a large number of genes have been identified in neuropathies (7), myopathies (8) and ataxias (9).…”

Databases for neurogenetics: Introduction, overview, and challenges

“…The broad molecular heterogeneity of Charcot-Marie-Tooth disease, the spinocerebellar ataxias (SCA) or the hereditary spastic paraplegias (HSP)-a group of disorders affecting upper motor neurons-are just some examples of this. While Hersheson et al (2012) review the broad genetic heterogeneity among inherited ataxias, Bettencourt and collaborators revise cases from the literature and from their own experience with mutations in the SCA genes presenting with a phenotype closer to HSP than to the ataxias [Bettencourt et al, 2012]. Abel et al (2012) further illustrate the evolving landscape of genotype-phenotype relationships in motor neuron diseases, leading to the evolution of the ALSoD database from a single-gene LSDB to a multigene and bioinformatics analysis installation.…”

“…A model for the storage, curation, and usage of the large amount of information emanating from both targeted and genome-wide association studies are described by Lill and Bertram (2012), as exemplified in the PDGene and AlzGene databases. Both complex disease and monogenic neurogenetic databases will have to be prepared to deal with the "nextgeneration" sequencing (NGS) technologies, which represent a new challenge for genetic information storage and interpretation [Hersheson et al, 2012;Lill and Bertram, 2012]. In such scenario, the foreseeable difficulties for interpreting the pathogenic relevance of rare variants will only be worked out with the availability of curated LSDBs and databases of rare variants seen in healthy individuals in various ethnic backgrounds.…”