Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia

Abstract

BackgroundSpinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible.ResultsClinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3–12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort.ConclusionsOur findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0672-7) contains supplementary material, which is available to authorized users.

Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease

“…Most disease-associated mutations in the LBD are missense mutations; however, an insertion (K417_418Ins) and a splicing mutation in exon 14 also both result in early-onset SCA29 (Wang et al, 2017, Zambonin et al, 2017). While the splice mutation is present in 4 individuals of a three-generation, non-consanguineous Chinese family, the K417_418Ins is a sporadic mutation identified in a single individual (Wang et al, 2017, Zambonin et al, 2017).…”

“…While the splice mutation is present in 4 individuals of a three-generation, non-consanguineous Chinese family, the K417_418Ins is a sporadic mutation identified in a single individual (Wang et al, 2017, Zambonin et al, 2017). This variability in how mutations were acquired is also found in specific diseases and residues.…”

“…NPCA, for example, may be caused by de novo heterozygous mutations (A280D and E512K) or inherited mutations (R269W and R241K), while mutations reported in residue R269 have been acquired via both de novo and inherited mutations (Barresi et al, 2017, Zambonin et al, 2017, Das et al, 2017). While patients with R269 mutations exhibited similar symptoms including cerebellar hypoplasia/atrophy, both inter- and intrafamilial variability of intellectual disability was observed making it difficult to correlate genotype and phenotype (Barresi et al, 2017, Zambonin et al, 2017, Das et al, 2017). This is made even more difficult by the presence of multiple amino acid changes are reported at this site.…”

“…This is made even more difficult by the presence of multiple amino acid changes are reported at this site. Reported mutations R269G and R269W result in smaller and larger changes in residue size, respectively; yet, both mutations result in the same disease (Barresi et al, 2017, Zambonin et al, 2017). Thus, it is likely that the loss of positive charge associated with both mutations, rather than change in size, that affects IP 3 R1 function.…”

“…Residues T267 (Zambonin et al, 2017, Sasaki et al, 2015, Ohba et al, 2013), R269 (Barresi et al, 2017, Zambonin et al, 2017, Das et al, 2017), and S277(Sasaki et al, 2015, Fogel et al, 2014) have all been reported in multiple cases of early-onset, non-progressive cerebellar ataxia. Additionally, for residues T267 and R269, the mutations are manifested as multiple amino acid changes.…”