Christianson syndrome across the lifespan: genetic mutations and longitudinal study in children, adolescents, and adults.

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-10-23 DOI:10.1136/jmg-2024-109973
Brian C Kavanaugh, Jennifer Elacio, Carrie R Best, Danielle G St Pierre, Matthew F Pescosolido, Qing Ouyang, John Biedermann, Rebecca S Bradley, Judy S Liu, Richard N Jones, Eric M Morrow
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Abstract

Objectives: 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.

Method: Data were collected as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study. 44 individuals with 31 unique NHE6 mutations, age 2-32 years, were followed prospectively, herein reporting baseline, 1 year follow-up and retrospective natural history.

Results: 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.

Conclusions: 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.

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克里斯琴森综合征:儿童、青少年和成人的基因突变和纵向研究。
目的:X连锁内体Na+/H+交换子6(NHE6)突变会导致克里斯蒂安森综合征(CS)。在这项迄今为止规模最大的研究中,我们研究了CS的遗传多样性和成年后的临床进展:数据收集是国际克里斯琴森综合征和 NHE6(SLC9A6)基因网络研究的一部分。我们对年龄在 2-32 岁、具有 31 种独特 NHE6 基因突变的 44 名患者进行了前瞻性随访,在此报告基线、1 年随访和回顾性自然病史:结果:我们提供了关于 CS 表型的数据,涉及整个生命周期的身体发育、适应性和运动退行,包括死亡率信息。我们使用线性混合模型对体重和身高的纵向数据进行了研究。在整个发育过程中,生长速度缓慢,导致成年后年龄标准身高和体重显著下降。对适应功能进行了纵向研究;大多数成年参与者(18 岁以上)在一年的随访中丧失了粗大运动和精细运动技能。以前定义的 CS 核心诊断标准(85% 以上存在)--即非语言状态、智力障碍、癫痫、产后小头畸形、共济失调、运动机能亢进--在 6-16 岁时普遍存在;但是,又增加了一个核心特征,即高疼痛耐受性(91% 存在)。虽然神经系统检查与小脑功能障碍一致,但重要的是,大多数患者(超过 50% 年龄大于 10 岁)还存在皮质脊髓束异常。研究期间,有三名参与者死亡:在这项关于 CS 的大型纵向研究中,我们开始确定症状的发展轨迹和成人表型,从而确定关键的治疗目标。
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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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