Severe Neurodevelopmental Disorder in Autosomal Recessive Spinocerebellar Ataxia 13 (SCAR13) Caused by Two Novel Frameshift Variants in GRM1.

IF 2.7 3区 医学 Q3 NEUROSCIENCES Cerebellum Pub Date : 2024-10-01 Epub Date: 2023-10-13 DOI:10.1007/s12311-023-01617-2
Carlo Alberto Cesaroni, Giulia Pisanò, Gabriele Trimarchi, Stefano Giuseppe Caraffi, Giulia Scandolo, Martina Gnazzo, Daniele Frattini, Carlotta Spagnoli, Susanna Rizzi, Claudia Dittadi, Giulia Sigona, Livia Garavelli, Carlo Fusco
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Abstract

Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is a neurological disease characterized by psychomotor delay, mild to profound intellectual disability with poor or absent language, nystagmus, stance ataxia, and, if walking is acquired, gait ataxia. Epilepsy and polyneuropathy have also been documented in some patients. Cerebellar atrophy and/or ventriculomegaly may be present on brain MRI. SCAR13 is caused by pathogenic variants in the GRM1 gene encoding the metabotropic receptor of glutamate type 1 (mGlur1), which is highly expressed in Purkinje cerebellar cells, where it plays a fundamental role in cerebellar development. Here we discuss the case of an 8-year-old patient who presented with a severe neurodevelopmental disorder with balance disturbance, absence of independent walking, absence of language, diffuse hypotonia, mild nystagmus, and mild dysphagia. Whole-exome sequencing revealed a compound heterozygosity for two likely pathogenic variants in the GRM1 gene, responsible for the patient's phenotype, and made it possible to diagnose autosomal recessive spinocerebellar ataxia SCAR13. The detected (novel) variants appear to be causative of a particularly severe picture with regard to neurodevelopment, in the context of the typical neurological signs of spinocerebellar ataxia.

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GRM1中两种新的移帧变体引起的常染色体隐性棘角性共济失调13(SCAR13)的严重神经发育障碍。
常染色体隐性脊髓小脑共济失调13(SCAR13)是一种神经系统疾病,其特征是精神运动迟缓、轻度至重度智力残疾伴语言差或缺失、眼球震颤、体位性共济失调,如果是后天性行走,则为步态共济失调。癫痫和多发性神经病也被记录在一些患者身上。脑MRI上可能出现小脑萎缩和/或心室肥大。SCAR13是由编码谷氨酸1型代谢型受体(mGlur1)的GRM1基因的致病性变体引起的,该受体在浦肯野小脑细胞中高度表达,在小脑发育中起着重要作用。在这里,我们讨论一例8岁的患者,他表现出严重的神经发育障碍,伴有平衡障碍、缺乏独立行走、缺乏语言、弥漫性肌张力减退、轻度眼球震颤和轻度吞咽困难。全外显子组测序揭示了GRM1基因中两种可能的致病性变体的复合杂合性,这是患者表型的原因,并使诊断常染色体隐性脊髓小脑共济失调SCAR13成为可能。在脊髓小脑共济失调的典型神经体征背景下,检测到的(新的)变异似乎是神经发育特别严重的原因。
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来源期刊
Cerebellum
Cerebellum 医学-神经科学
CiteScore
6.40
自引率
14.30%
发文量
150
审稿时长
4-8 weeks
期刊介绍: Official publication of the Society for Research on the Cerebellum devoted to genetics of cerebellar ataxias, role of cerebellum in motor control and cognitive function, and amid an ageing population, diseases associated with cerebellar dysfunction. The Cerebellum is a central source for the latest developments in fundamental neurosciences including molecular and cellular biology; behavioural neurosciences and neurochemistry; genetics; fundamental and clinical neurophysiology; neurology and neuropathology; cognition and neuroimaging. The Cerebellum benefits neuroscientists in molecular and cellular biology; neurophysiologists; researchers in neurotransmission; neurologists; radiologists; paediatricians; neuropsychologists; students of neurology and psychiatry and others.
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