Pontocerebellar hypoplasia (PCH) comprises a clinically and genetically heterogeneous group of disorders characterized by hypoplasia and degeneration of the cerebellum and ventral pons. To date at least 18 different clinical subtypes of PCH associated with pathogenic variants in 19 different genes have been described. Only recently, bi-allelic variants in TBC1D23 have been reported as the underlying molecular defect in seven index cases with a suspected non-degenerative form of PCH, PCH type 11 (PCH11).

We used exome sequencing to investigate an individual with global developmental delay, ataxia, seizures, and progressive PCH. Brain volume was evaluated over a disease course of 14 years using volumetric magnetic resonance imaging (MRI). Volume alterations were compared to age-matched controls as well as data from children with PCH2.

We identified a homozygous frameshift variant in exon 9 of 18 of TBC1D23 predicting a loss of protein function. Brain morphometry revealed a pattern of pontine, brain stem, and supratentorial volume loss similar to PCH2 patients although less pronounced. Intriguingly, cerebral MRI findings at the age of 1 and 15 years clearly showed progressive atrophy of the cerebellum, especially the hemispheres. In four of the cases reported in the literature cerebellar hemispheres could be evaluated on the MRIs displayed, they also showed atrophic foliae.

While pontine hypoplasia and pronounced microcephaly are in line with previous reports on PCH11, our observations of clearly postnatal atrophy of the cerebellum argues for a different pathomechanism than in the other forms of PCH and supports the hypothesis that TBC1D23 deficiency predominantly interferes with postnatal rather than with prenatal cerebellar development.

桥小脑发育不全（PCH）包括一组临床和遗传上异质的疾病，其特征在于小脑和腹桥发育不全，变性。迄今为止，已经描述了与19种不同基因中的致病变体相关的PCH的至少18种不同临床亚型。直到最近，TBC1D23中的双等位基因变体才被报道为七个疑似PCH 11型非变性PCH（PCH11）的索引病例的潜在分子缺陷。

我们使用外显子组测序研究了具有全球发育延迟，共济失调，癫痫发作和进行性PCH的个体。使用体磁共振成像（MRI）在14年的病程中评估了脑容量。将体积变化与年龄匹配的对照以及来自PCH2儿童的数据进行比较。

我们在TBC1D23的18外显子9中鉴定了纯合移码变体，预测蛋白质功能的丧失。脑形态计量学揭示了类似于PCH2患者的脑桥，脑干和幕上体积减少的模式，尽管不太明显。有趣的是，在1岁和15岁时的脑部MRI表现清楚地表明小脑，尤其是半球的进行性萎缩。在文献报道的四例小脑半球可以通过显示的MRI进行评估，它们还显示出萎缩性叶状体。

尽管脑桥发育不全和明显的小头畸形与先前有关PCH11的报道相符，但我们对出生后小脑明显萎缩的观察表明，其发病机制不同于其他PCH，并支持TBC1D23缺乏症主要干扰产后而不是干扰产后的假说。产前小脑发育。