Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants
Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants
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DOI：
10.1007/s00415-019-09466-y
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发表时间：
2019-11-01
影响因子：
6
通讯作者：
Travaglini, Lorena
中科院分区：
文献类型：
--
作者：
Nicita, Francesco;Stregapede, Fabrizia;Travaglini, Lorena
DDHD 2的隐性突变导致SPG 54，这是一种复杂的遗传性痉挛性截瘫（HSP），全世界报道的患者不到40例。在这项回顾性多中心研究中，我们描述了另外8例SPG 54携带纯合子或复合杂合子DDHD 2变异的病例。最后，我们回顾了SPG 54的文献数据，目的是更好地定义表型和脑磁共振成像（MRI）模式以及基因型-表型相关性。SPG 54的典型特征是早发性（即，先天性或更常见的婴儿期）运动和认知里程碑延迟，伴随或随后出现痉挛。成人发病病例中不存在认知障碍。痉挛随着时间的推移而发展。在大约50%的病例中发现的异常眼球运动是最常见的与痉挛和发育迟缓相关的特征。小脑性共济失调是包括本研究中的一名成人在内的几名患者的突出体征，这表明在痉挛性共济失调综合征的鉴别诊断中包括SPG 54。脑MRI显示胼胝体薄和非特异性脑室周围白色病变分别约占90%和70%。脑磁共振波谱显示异常脂质峰在90%的调查患者。迄今为止已报道了21种致病性变化，其中许多是无义或小缺失/重复。大多数突变似乎是私人的，只有两个突变在三个（即，R287*）或更多家族（即，D660H）。9种新变体的鉴定扩展了DDHD 2相关HSP的分子谱，并证实了尽管基因型不同，但临床和神经放射学表型相当均一的概念。
Recessive mutations in DDHD2 cause SPG54, a complex hereditary spastic paraplegia (HSP) with less than forty patients reported worldwide. In this retrospective, multicenter study we describe eight additional SPG54 cases harboring homozygous or compound heterozygous DDHD2 variants. Finally, we reviewed literature data on SPG54, with the aim to better define the phenotype and the brain magnetic resonance imaging (MRI) pattern as well as genotype-phenotype correlations. SPG54 is typically characterized by early-onset (i.e., congenital or, more frequently, infantile) delay in motor and cognitive milestones, coupled or followed by appearance of spasticity. Cognitive impairment is absent in adult-onset cases. Spasticity progresses over time. Abnormal eye movement, found in about 50% of cases, is the feature most frequently associated with spasticity and developmental delay. Cerebellar ataxia is a prominent sign in several patients, including one adult of this study, suggesting to include SPG54 in the differential diagnosis of spastic-ataxia syndromes. Brain MRI shows thin corpus callosum and non-specific periventricular white matter lesions in about 90% and 70% of cases, respectively. Brain MR spectroscopy reveals abnormal lipid peak in 90% of investigated patients. Twenty-one pathogenic changes have been reported so far, many of which are nonsense or small deletion/duplication. Most mutations appear to be private, with only two mutations recurring in three (i.e., R287*) or more families (i.e., D660H). The identification of nine novel variants expands the molecular spectrum of DDHD2-related HSP and corroborates the notion of a quite homogeneous clinical and neuroradiological phenotype in spite of different genotypes.