Center for Translational Neuroscience, Robert J. and Nancy D. Carney Institute for Brain Science and Brown Institute for Translational Science, Brown University, Providence, Rhode Island, USA.
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, USA.
J Med Genet. 2024 Oct 23;61(11):1031-1039. doi: 10.1136/jmg-2024-109973.
Mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome (CS). Here, in the largest study to date, we examine genetic diversity and clinical progression in CS into adulthood.
Data were collected as part of the International Christianson Syndrome and () Gene Network Study. 44 individuals with 31 unique mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history.
We present data on the CS phenotype with regard to physical growth and adaptive and motor regression across the lifespan including information on mortality. Longitudinal data on body weight and height were examined using a linear mixed model. The rate of growth across development was slow and resulted in prominently decreased age-normed height and weight by adulthood. Adaptive functioning was longitudinally examined; a majority of adult participants (18+ years) lost gross and fine motor skills over a 1 year follow-up. Previously defined core diagnostic criteria for CS (present in>85%)-namely non-verbal status, intellectual disability, epilepsy, postnatal microcephaly, ataxia, hyperkinesia-were universally present in age 6-16; however, an additional core feature of high pain tolerance was added (present in 91%). While neurologic examinations were consistent with cerebellar dysfunction, importantly, a majority of individuals (>50% older than 10) also had corticospinal tract abnormalities. Three participants died during the period of the study.
In this large and longitudinal study of CS, we begin to define the trajectory of symptoms and the adult phenotype thereby identifying critical targets for treatment.
X 连锁内体 Na+/H+交换蛋白 6（NHE6）的突变导致克里斯蒂安森综合征（CS）。在这里，在迄今为止最大的研究中，我们检查了 CS 进入成年期的遗传多样性和临床进展。
数据是作为国际克里斯蒂安森综合征和 () 基因网络研究的一部分收集的。44 名年龄在 2-32 岁的个体携带 31 个独特的突变，前瞻性随访，在此报告基线、1 年随访和回顾性自然史。
我们根据整个生命周期的身体生长以及适应和运动倒退呈现 CS 表型，包括死亡率信息。使用线性混合模型检查体重和身高的纵向数据。通过发育进行的生长速度较慢，导致成年时身高和体重明显低于年龄标准化值。适应性功能进行了纵向检查；大多数成年参与者（18 岁以上）在 1 年随访中丧失了粗大和精细运动技能。以前定义的 CS 核心诊断标准（>85%存在）-即非言语状态、智力残疾、癫痫、产后小头畸形、共济失调、多动-在 6-16 岁时普遍存在；然而，增加了高耐痛的另一个核心特征（91%存在）。虽然神经学检查与小脑功能障碍一致，但重要的是，大多数个体（>50%年龄大于 10 岁）也有皮质脊髓束异常。在研究期间，有 3 名参与者死亡。
在这项关于 CS 的大型和纵向研究中，我们开始确定症状的轨迹和成年表型，从而确定治疗的关键目标。
