Variants in the FIG4 gene, which encodes a phosphatidylinositol‐3,5‐bisphosphatase lead to obstruction of endocytic trafficking, causing accumulation of enlarged vesicles in murine peripheral neurons and fibroblasts. Bi‐allelic pathogenic variants in FIG4 are associated with neurological disorders including Charcot‐Marie‐Tooth disease type‐4J (CMT4J) and Yunis‐Varón syndrome (YVS). We present four probands from three unrelated families, all homozygous for a recurrent FIG4 missense variant c.506A>C p.(Tyr169Ser), with a novel phenotype involving features of both CMT4J and YVS. Three presented with infant‐onset dystonia and one with hypotonia. All have depressed lower limb reflexes and distal muscle weakness, two have nerve conduction studies (NCS) consistent with severe sensorimotor demyelinating peripheral neuropathy and one had NCS showing patchy intermediate/mildly reduced motor conduction velocities. All have cognitive impairment and three have swallowing difficulties. MRI showed cerebellar atrophy and bilateral T2 hyperintense medullary swellings in all patients. These children represent a novel clinicoradiological phenotype and suggest that phenotypes associated with FIG4 missense variants do not neatly fall into previously described diagnoses but can present with variable features. Analysis of this gene should be considered in patients with central and peripheral neurological signs and medullary radiological changes, providing earlier diagnosis and informing reproductive choices.

中文翻译：

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新型FIG4相关性合并神经系统疾病的临床和放射学特征。

编码磷脂酰肌醇-3,5-双磷酸酶的FIG4基因变异导致内吞运输受阻，导致小鼠周围神经元和成纤维细胞中的囊泡积聚。在双等位基因变体的致病FIG4与神经病症，包括进行性神经性腓骨肌萎缩症型-4J（CMT4J）和尤尼斯-VARON综合征（YVS）相关联。我们介绍了来自三个无关家族的四个先证者，所有这些都是纯合子，重复发生错义变体c.506A> C p。（Tyr169Ser），具有涉及CMT4J和YVS的特征的新型表型。三例表现为婴儿发作性肌张力障碍，一例表现为肌张力低下。所有人均具有下肢反射低下和远端肌肉无力的情况，其中两项进行了与严重的感觉运动性脱髓鞘性周围神经病变一致的神经传导研究（NCS），并且一项进行了中度/轻度降低的运动传导速度的NCS研究。所有人都有认知障碍，其中三个有吞咽困难。MRI显示所有患者均出现小脑萎缩和双侧T2高强度髓样肿胀。这些孩子代表一种新颖的临床放射学表型，并暗示与FIG4相关的表型错义变体不能很​​好地落入先前描述的诊断中，但是可以具有可变特征。中枢神经系统疾病和周围神经系统症状以及髓质放射学改变的患者应考虑对该基因进行分析，以提供早期诊断并告知生殖选择。