Spinocerebellar Ataxia type 29 in a family of Māori descent

Abstract

Background Mutations in the Inositol 1,4,5-Trisphosphate Receptor Type 1 (ITPR1) gene cause spinocerebellar ataxia type 29 (SCA29), a rare congenital-onset autosomal dominant non-progressive cerebellar ataxia. The Māori, indigenous to New Zealand, are an understudied population for genetic ataxias. Case presentation We investigated the genetic origins of spinocerebellar ataxia in a family of Māori descent consisting of two affected sisters and their unaffected parents. Whole exome sequencing identified a pathogenic variant, p.Thr267Met, in ITPR1 in both sisters, establishing their diagnosis as SCA29. Conclusions We report the identification of a family of Māori descent with a mutation causing SCA29, extending the worldwide scope of this disease. Although this mutation has occurred de novo in other populations, suggesting a mutational hotspot, the children in this family inherited it from their unaffected mother who was germline mosaic.

Discovery of a de novo ITPR1 missense mutation in a patient with early‐onset cerebellar ataxia: A rare case report of spinocerebellar ataxia 29

“…The initial brain MRI conducted at 2 months revealed a nonspecific brain shape and parenchyma. However, a follow‐up brain MRI at 30 months revealed distinct isolated cerebellar atrophy, with notable effects on the superior cerebellum and vermis, consistent with previous reports on SCA29 (Ngo et al., 2019 ; Romaniello et al., 2022 ; Tada et al., 2016 ). At 4 years of age, brain MRI confirmed the persistence of cerebellar atrophy especially in the superior cerebellum and vermis (Figure 1 ).…”

“…The elder sibling first achieved a crutches gait at 7 years and had an IQ of 54 at the school age, whereas the younger sibling attained a crutches gait by 3.5 years and had an IQ of 73 at the school age. Most cases of the c.800C>T (p.Thr267Met) variant have been found to be sporadic; however, an exome sequencing test in this family detected low levels of the variant in the unaffected mother (2/242 reads), suggesting that she was a germline mosaic for the variant (Ngo et al., 2019 ).…”

“…The current literature on the clinical characteristics of SCA is limited, including for past cases of congenital non‐progressive ataxia without a diagnosed mutation in the ITPR1 gene (Steinlin et al., 1998 ). Previous cases of SCA29 caused by de novo heterozygous mutations in the c.800C>T (p.Thr267Met) locus (Table 2 ) (Ngo et al., 2019 ; Sasaki et al., 2015 ; Synofzik et al., 2018 ; Zambonin et al., 2017 ) have shown that the phenotype can be rather diverse. One case report described a patient, who had dysarthria at 6 months, was able to stand with support at 2 years, but remained unable to walk for 6 years in addition to mild intellectual deficits (Sasaki et al., 2015 ).…”

“…Brain MRI showed pronounced atrophy in the superior cerebellum and anterior vermis consistent with our findings, as well as progressive atrophy of the pontine tegmentum. Another study reported a case of two siblings presenting with early onset‐nonprogressive ataxia (Ngo et al., 2019 ). The elder sibling first achieved a crutches gait at 7 years and had an IQ of 54 at the school age, whereas the younger sibling attained a crutches gait by 3.5 years and had an IQ of 73 at the school age.…”

Rare CACNA1A mutations leading to congenital ataxia

“…It is highly expressed in cerebellar PCs and opens to allow Ca 2+ efflux from the ER following the binding of IP 3 , a second messenger produced upon the activation of G-protein-coupled receptors at the plasma membrane [6,83]. Multiple missense mutations in IP 3 R1 have been reported in association with CA [5,18,40,55,57,89,91,100,106,143]. In agreement with the increased intracellular Ca 2+ signaling produced by CA-linked CA8 genetic variants, some of the IP 3 R1 mutations produce channel gain-of-function, either by preventing the inhibitory binding of CA8 or by improving IP 3 binding affinity [2,18].…”