The Two Faces of Pediatric SCA2

Abstract

Introduction: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurological disease usually described in adults. Expanded CAG repeats in the ATXN2 gene can lead to pediatric onset. This study aims to describe the natural history of SCA2 in children.

Methods: We analyzed clinical and genetic data from 22 children with SCA2 across 17 institutions and compared them to 20 previously reported cases.

Results: The phenotype of pediatric SCA2 can be divided into two distinct groups based on CAG repeat size and age. In the infantile group (n = 9), developmental delay and seizures were prominent features, along with cerebellar and cerebral atrophy. In the juvenile group (n = 13), the disease was a cerebellar degeneration similar to adults. A threshold of 88 ± 4 CAG repeats distinguished the infantile group from the juvenile group. Pediatric SCA2 type was independent of parental origin; SCA2 was maternally inherited in 22%, including three infantile presentations.

Discussion: This large cohort of pediatric SCA2 disease provides the first comprehensive description of its characteristics, which differ from those of SCA7. Indeed, the phenotypic spectrum of SCA7 in children is continuous, while that of SCA2 is bimodal. Although pediatric SCA2 can be difficult to diagnose by genome-wide sequencing, it is a recognizable disease that can be easily diagnosed with a targeted study of the number of CAGs in ATXN2. Genetic counseling for families should consider the significant proportion of maternal transmission.

Keywords: CAG; SCA2; pediatrics; prognostic; review.

FIGURE 1

Bimodal disease course in 22 individuals with childhood‐onset SCA2. Blue bars represent those who are deceased, red bars those who are living and gray bars those who were lost to follow‐up. The left end of the bar indicates age at onset, the right end age at death (blue), current age (red), and age at last examination (gray). Abbreviations: DD: Developmental delay corresponds to hypotonia with no motor acquisition and poor eye contact; Dys: Dysarthria; E: Epilepsy/Spasm; F: Feeding difficulties; G: Gait trouble; Lex: Large expansion (> 100 CAG); O: Ophthalmoplegia; T: Tremor. Double arrows indicate ages at loss of walking and asterisk indicates age at the onset of epilepsy.

FIGURE 2

Age at onset (AO) and age at death (AD) according to the number of CAG repeats in ATXN2. (A) Number of CAG repeats and AO was known for 33 pediatric SCA2 individuals: 17 from our cohort (blue dots) and 16 from the literature (red triangles). Eight infantile SCA2 individuals carried > 100 repeats (five from our cohort and three from the literature) and are not included. AO was negatively correlated with CAG repeat length (Spearman r = −0.92, p value < 0.00001). (B) Age at death in 13 individuals (seven patients from our cohort, six patients from the literature) was negatively correlated with the number of CAG repeats (r = −0.75, p value < 0.005).

FIGURE 3

Parental transmission according to age at disease onset (AO) in SCA2 children. Blue is for paternal (pat) transmission, red for maternal (mat) transmission, triangle indicate girls, and square indicates boys. Gray is for unknown transmission.

FIGURE 4

Top: Kaplan–Meier survival curves showing the duration of disease in patients with SCA2 (n = 22, blue) and SCA7 (n = 26, red). The x‐axis represents the age at the last examination (censored observations are represented by circles) or at the time of death. SCA7 exhibits a continuous decline in survival, whereas SCA2 demonstrates a bimodal distribution, reflecting two distinct disease progression patterns, corresponding to infantile and juvenile onset forms. Bottom: Density of CAG repeats in SCA2 (n = 39) and SCA7 (n = 36) using ggdist (package R) to visualize data frames following a normal distribution. Blue: Infantile SCA2. Red: Juvenile SCA2. Note the threshold in SCA2 (around 88 ± 4) and the overlay in SCA7 (black arrow). Data for SCA7 children obtained from Bah et al.