Background

Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain.

Methods

We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected.

Results

Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age.

Conclusions

WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

中文翻译：

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与 WDR45 相关的表型和成像光谱。

背景

X 连锁基因WDR45中的突变会导致神经退行性变，并伴有 5 型脑铁积累。由于大脑中进行性铁积累，整体发育迟缓发生在幼年，缓慢进展为肌张力障碍、帕金森症和痴呆。

方法

我们介绍了 17 例新病例并回顾了 106 例报告的 5 型脑铁积累神经变性病例。收集了与发育史和事件关键时间测量相关的详细信息。

结果

在这个队列中，有 19 名男性。大多数人通过全外显子组检测进行分子诊断。总共在 11 个受试者中鉴定了 10 个新变体。所有个体都受到发育迟缓的影响，最突出的是语言技能。大多数人的运动和认知技能都出现了下降。虽然大多数人都受到癫痫发作的影响，但范围从诱发性癫痫发作到顽固性癫痫。成像结果也各不相同，通常随着时间的推移而演变。在我们的队列中有一半注意到苍白球和黑质中典型的铁积累，并且与图像采集的年龄较大有关，而髓鞘形成异常与年龄较小有关。

结论

WDR45突变导致一种进行性和不断发展的疾病，其诊断常常被延迟。发育迟缓和癫痫发作在儿童早期占主导地位，随后神经功能逐渐下降。具有WDR45突变的个体的临床表型存在可变的表达性，这表明该基因应根据评估时的年龄在对患有髓鞘形成异常、铁沉积、发育迟缓和癫痫的儿童进行诊断评估时考虑。