Ataxia and atrophy/pontocerebellar hypoplasia panel [31 genes]

Hereditary ataxias represent a large group of diseases caused by the dysfunction of the cerebellum and/or its main connections. Clinically they manifest as a balance disorder and lack of coordination affecting gait, and often also hands, speech, and eye movement.

The prevalence of spinocerebellar ataxia (SCA) in the general population is estimated to be 2.7 per 100,000 individuals (Ruano et al., 2014). Friedreich ataxia is the most common hereditary ataxia in Caucasians, with an estimated incidence of 1/29,000 individuals and a frequency of 1/85 carriers. Between 2% and 13% of late-onset and sporadic ataxia cases are caused by nucleotide expansions detected by specific PCR/TP-PCR studies (Abele et al., 2002). Anticipation, consisting of early-onset and/or more severe disease in subsequent generations, is a characteristic phenomenon of ataxias. Apart from testing for nucleotide repeat 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 a muscle tone disorder (spasticity or dystonia, which are not always easy to identify during a neurological examination) is a well-established finding in the case of spasticity and is described more often in the case of dystonia, which is why we propose a combined study via the spastic ataxia and ataxia-dystonia syndromes panel.

The presentation of ataxia through recurrent episodes with a duration from minutes to hours would call for the use of the episodic ataxia panel. 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 disorders and disorders with a neonatal onset whose presentation includes ataxia associated with cerebellar malformations and that can also affect the brainstem. Intellectual and motor disability is present in all of them; other possible associated symptoms are progressive microcephaly and seizures. The panel consists of a selection of the most relevant genes related to Joubert syndrome (characterized by the so-called molar tooth sign), pontocerebellar hypoplasia, and some congenital disorders of glycosylation which prominently affect the cerebellum.

Our ataxia comprehensive panel covers, apart from the previously mentioned ones (except for the expansions), other ataxias that have metabolic or mitochondrial basis, or are due to defects in DNA reparation.