We presented 6 new cases of SCA19 in Latin American patients, harboring three different missense variants, one of them not previously reported (KCND3:c.1070C > G). This case series reflects the clinical heterogeneity in SCA19. A spectrum of severity can be observed going from the milder late-onset and slowly progressive pure ataxic clinical presentation in Chilean family 1, through the young onset ataxia accompanied with milder neurocognitive symptoms in the Chilean family 2 twins, to the early onset ataxia associated with significant neurodevelopmental features in the Mexican patient.
The three male relatives from Chilean family 1 with the KCDN3:c.1070C > G variant represent the most classical presentation of SCA19, that affects approximately 65% of the cases, with an adult late onset slowly progressive pure ataxic presentation [4, 9]. A relevant feature, not previously mentioned in the literature, is the very long-standing duration of the disease and keeping most autonomous daily living activities even after 50-years of ataxia in the father of the proband. Whether this more favorable prognosis is distinctive of this variant, cannot be concluded at this time since this is the first time it has been reported. The follow-up of the proband and his brother will share some light, along with possible future new reported cases.
The Chilean twins with the KDND3:c.1150G > A variant have an intermediate phenotype with young adult onset ataxia associated with cognitive impairment and other neurological symptoms such as DD, head tremor and spasticity of the lower limbs. A Japanese patient previously reported with the same variant, with de novo inheritance presented cerebellar ataxia from early adulthood (18–24 yrs) associated with intellectual disability (ID), myoclonus, dystonia and spasticity in the lower extremities [9] resembling the clinical presentation of the family in this report. The inheritance of the variant in the Chilean family cannot be confirmed as de novo, since the patient's father is deceased. Interestingly, there were phenotypic differences in the severity of the presentation between the twins, one of them having a milder course, raising the possibility of an epigenetic or environmental influence in the phenotype.
The Mexican patient with a de novo KCND3:c.1111G > A (p.Gly371Arg) variant, resembles a previously reported case of a Spanish patient with the same change, also with a de novo mode of inheritance. In that case, the presentation was of very early-onset with DD, cerebellar ataxia from infancy associated with autism spectrum disorder (ASD), dysarthria and sialorrhea [8]. In both cases the patients underwent extensive genetic testing before WES was performed and SCA19 was diagnosed. Also, for both of these patients clinical presentation was on the more severe side of the SCA19 spectrum associated with a de novo variant, possibly related to genetic fitness.
This clinical heterogeneity and the differentiation between different phenotypes in early and late-onset SCA19 was raised by previous authors, but no clear genotype-phenotype correlation has been established yet [3]. The exact molecular mechanism by which KCDN3 loss of function (LoF) variants cause the disease is still unknown [3, 10], and a hypothesis is that specific variants at different loci may lead to different protein change consequences and clinical prognosis [4].
It is noteworthy that all cases in this report were diagnosed by WES, in some of them after previous genetic examinations and in others (Chilean family 2), directly. The continuously expanding genetic spectrum of causes of SCA poses a challenge for clinicians when it comes to deciding upon a particular genetic test. The advances in Next Generation Sequencing (NGS) have allowed the discovery of novel loci associated with SCA [11, 12] and WES has become an important tool with a good diagnostic yield in ataxia ranging from 19–39% [11–14]. Still, in American countries the most frequent SCAs remain the subtypes caused by triplet expansion, which cannot be diagnosed by NGS nowadays [6]. Nonetheless this epidemiology might change in the future since monogenic causes of ataxia were not routinely studied before the wider use of NGS started not so long ago. For early onset cases with neurodevelopmental alterations associated it might be reasonable to consider WES as a first tier genetic test to avoid the diagnostic odyssey, as it went down in both cases with the KCND3:c.1111G > A variant [15].