Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy

Sakamoto, Masamune; Iwama, Kazuhiro; Sasaki, Masayuki; Ishiyama, Akihiko; Komaki, Hirofumi; Saito, Takashi; Takeshita, Eri; Shimizu‐Motohashi, Yuko; Haginoya, Kazuhiro; Kobayashi, Tomoko; Goto, Tomohide; Tsuyusaki, Yu; Iai, Mizue; Kurosawa, Kenji; Osaka, Hitoshi; Tohyama, Jun; Kobayashi, Yu; Okamoto, Nobuhiko; Suzuki, Yume; Kumada, Satoko; Inoue, Ken; Mashimo, Hideaki; Arisaka, Atsuko; Kuki, Ichiro; Saijo, Harumi; Yokochi, Kenji; Kato, Mitsuhiro; Inaba, Yuji; Gomi, Yuko; Saitoh, Shinji; Shirai, Kentaro; Morimoto, Masafumi; Izumi, Yuishin; Watanabe, Yoriko; Nagamitsu, Shin-Ichiro; Sakai, Yasunari; Fukumura, Shinobu; Muramatsu, Kazuhiro; Ogata, Tomomi; Yamada, Keitaro; Ishigaki, Keiko; Hirasawa, Kyoko; Shimoda, Konomi; Akasaka, Manami; Kohashi, Kosuke; Sakakibara, Takafumi; Ikuno, Masashi; Sugino, Noriko; Yonekawa, Takahiro; Gürsoy, Semra; Çinleti, Tayfun; Kim, Chong; Teik, Keng Wee; Yan, Chan Mei; Haniffa, Muzhirah; Ohba, Chihiro; Ito, Shuuichi; Saitsu, Hirotomo; Saida, Ken; Tsuchida, Naomi; Uchiyama, Yuri; Koshimizu, Eriko; Fujita, Atsushi; Hamanaka, Kohei; Misawa, Kazuharu; Miyatake, Satoko; Mizuguchi, Takeshi; Miyake, Noriko; Matsumoto, Naomichi

doi:10.1016/j.gim.2022.08.007

Cited by 2 publications

(2 citation statements)

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“…Available evidence suggests that the natural history of SCA29 and GLSP is non‐progressive. However, recent publications have provided evidence that superior vermian and/or hemispheric cerebellar atrophy may represent a hallmark of ITPR1 ‐related disorders 32,65 . We report on at least six individuals in whom cerebellar hypoplasia was excluded by early brain imaging (3 months to 2 years) but who later developed cerebellar atrophy without evidence of clinical regression.…”

Section: Discussionmentioning

confidence: 92%

“…However, recent publications have provided evidence that superior vermian and/or hemispheric cerebellar atrophy may represent a hallmark of ITPR1 ‐related disorders. 32 , 65 We report on at least six individuals in whom cerebellar hypoplasia was excluded by early brain imaging (3 months to 2 years) but who later developed cerebellar atrophy without evidence of clinical regression. At least four individuals were shown to have cerebellar hypoplasia shortly after birth.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

Tolonen,

Parolin Schnekenberg,

McGowan

et al. 2023

Movement Disorders

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BackgroundThe ITPR1 gene encodes the inositol 1,4,5‐trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood.ObjectivesWe aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy.MethodsCases were identified using next‐generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction.ResultsWe report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N‐terminal IP3‐binding domain, the carbonic anhydrase 8 (CA8)‐binding region, and the C‐terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression.ConclusionsThis dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%