Hereditary ataxias represent a broad group of diseases caused by dysfunction of the cerebellum and/or its main connections. Clinically they manifest as a balance disorder and lack of coordination that affects walking, and often also hands, speech, and eye movements.
The prevalence of spinocerebellar ataxias (SCAs) in the population is estimated at 2.7/100,000 (Ruano et al., 2014). Friedreich’s ataxia is the most common hereditary ataxia in Caucasians, with an estimated incidence of 1/29,000 individuals and a carrier frequency of 1 in 85. Between 2-13% of cases of late-onset and sporadic ataxia are caused by nucleotide expansions detectable by specific study by PCR/TP-PCR (Abele et al., 2002). Anticipation, consisting of a disease with an earlier onset and/or a more severe course in subsequent generations, is a characteristic phenomenon. In addition to the analysis of nucleotide expansions, we have designed NGS panels for the detection of point variants and CNVs in genes responsible for SCA (SPG7, SETX, SACS, AFG3L2 or SYNE1, among others; Galatolo et al., 2017), which we offer structured according to the mode of inheritance (autosomal dominant or autosomal recessive).
The overlap of ataxia with muscle tone disorder (either spasticity or dystonia, not always easy to differentiate on neurological examination) is a well-established finding in the case of spasticity and is increasingly described in the case of dystonia. , so we propose a joint approach using the panel of spastic ataxias and ataxia-dystonia syndromes.
The presentation of ataxia through recurrent episodes lasting minutes to hours would be an indication for conducting a panel of episodic ataxias. The most common and best characterized form is caused by heterozygous pathogenic variants in the CACNA1A gene.
We have designed a panel for the study of congenital or neonatal-onset disorders that present with ataxia associated with malformations of the cerebellum and that can also affect the brain stem. Intellectual and motor disabilities are present in all of them; Other possible associated symptoms are progressive microcephaly and seizures. This is a selection of the most relevant genes related to Joubert syndrome (characterized by the image of the “molar tooth sign”), pontocerebellar hypoplasia and some congenital glycosylation disorders that prominently affect the cerebellum.
The general ataxia panel includes, in addition to all those previously mentioned (with the exception of expansions), other ataxias with a metabolic, mitochondrial basis and due to defects in DNA repair.