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更新于：2025-05-07

Mental Retardation, X-Linked, Syndromic, Christianson Type

Christianson特异性精神发育迟滞，X染色体连锁

更新于：2025-05-07

基本信息

别名

ANGELMAN-LIKE SYNDROME, X-LINKED、Angelman-Like Syndrome, X-Linked、Christianson Syndrome

+ [16]

简介

An X-linked dominant condition caused by mutation(s) in the SLC9A6 gene, encoding sodium/hydrogen exchanger 6. It is characterized by intellectual disability, delayed development, and difficulty standing or walking.

关联

项与 Christianson特异性精神发育迟滞，X染色体连锁相关的药物

SLC9A6 Gene Therapy (University of Utah)

靶点

SLC9A6

作用机制

SLC9A6 blockers

在研机构

University of Utah

原研机构

University of Utah

在研适应症

Christianson特异性精神发育迟滞，X染色体连锁

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 Christianson特异性精神发育迟滞，X染色体连锁相关的临床结果

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100 项与 Christianson特异性精神发育迟滞，X染色体连锁相关的转化医学

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0 项与 Christianson特异性精神发育迟滞，X染色体连锁相关的专利（医药）

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项与 Christianson特异性精神发育迟滞，X染色体连锁相关的文献（医药）

2025-02-01·Neurology Genetics

SLC9A6 -Linked Parkinson Syndrome in Female Heterozygotes Is Associated With PET-Detectable Tau Pathology

Article

作者: Okusa, Shohei ; Takahata, Keisuke ; Kurose, Shin ; Yamamoto, Yasuharu ; Ueda, Ryo ; Tokuda, Takahiko ; Moriguchi, Sho ; Takiyama, Yoshihisa ; Zhang, Ming-Rong ; Ueno, Yuji ; Tatebe, Harutsugu ; Ito, Daisuke ; Ichihashi, Masanori ; Higuchi, Makoto ; Matsuura, Sayo ; Tagai, Kenji ; Seki, Morinobu ; Endo, Hironobu ; Kawamura, Kazunori

Background and ObjectivesA previous postmortem study of men with Christianson syndrome, a disorder caused by loss-of-function mutations in the gene SLC9A6, reported a mechanistic link between pathologic tau accumulation and progressive symptoms such as cerebellar atrophy and cognitive decline. This study aimed to characterize the relationships between neuropathologic manifestations and tau accumulation in heterozygous women with SLC9A6 mutation.MethodsWe conducted a multimodal neuroimaging and plasma biomarker study on 3 middle-aged heterozygous women with SLC9A6 mutations (proband 1: mid-50s; proband 2: early 50s; proband 3: mid-40s) presenting with progressive extrapyramidal symptoms. Examinations included ¹¹C-PiB PET; ¹⁸F-florzolotau PET; structural MRI; and plasma measures of neurofilament light chain (NfL) polypeptide, glial fibrillary acidic protein, phosphorylated (p)Tau181, Aβ40, and Aβ42. Neuroimaging results of all 3 patients were compared with those of 12 healthy age-matched women (49.8 ± 4.7 years) while plasma biomarker levels of probands 1 and 2 were compared with those of 14 age-matched healthy women (54.1 ± 9.0 years).ResultsProband 1 was diagnosed with Parkinson disease while probands 2 and 3 were diagnosed with atypical parkinsonism. ¹¹C-PiB PET results were negative in all patients. ¹⁸F-florzolotau PET revealed focal tau accumulations in all 3 patients, predominantly in the striatum contralateral to motor symptoms. Moreover, greater extrapyramidal symptom severity was associated with higher standardized uptake value ratios (SUVRs) for ¹⁸F-florzolotau in the striatum. Multiple comparisons showed significantly higher ¹⁸F-florzolotau SUVR values in both the caudate and putamen of proband 1, who exhibited the most severe extrapyramidal signs, while no significant increases in ¹⁸F-florzolotau SUVR values were detected in any brain region of probands 2 and 3. Structural MRI revealed slightly lower regional subcortical and gray matter volumes in all patients but not significant after multiple comparisons. Finally, plasma NfL concentration was significantly higher in probands 1 and 2 compared with healthy controls.DiscussionOur ¹⁸F-florzolotau PET analysis revealed greater tau accumulation in the striatum of heterozygous women with SLC9A6 mutation associated with worsening extrapyramidal symptom severity. The heterozygosity of loss-of-function SLC9A6 mutations further suggests that tauopathy may be a primary contributor to extrapyramidal signs.

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone

Article

作者: McKinney, R Anne ; Orlowski, John ; Ilie, Alina ; Gao, Andy Y L ; Shi, Roy ; Mustian, Jamie ; Sonenberg, Nahum ; Gao, Andy Y.L. ; Popic, Jelena ; McKinney, R. Anne ; Inglebert, Yanis

Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na⁺, K⁺)/H⁺ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.

2024-11-01·Journal of Medical Genetics

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

Article

作者: Bradley, Rebecca S ; Pescosolido, Matthew F ; Kavanaugh, Brian C ; Elacio, Jennifer ; Biedermann, John ; Ouyang, Qing ; Best, Carrie R ; St Pierre, Danielle G ; Morrow, Eric M ; Jones, Richard N ; Liu, Judy S

ObjectivesMutations 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. ResultsWe 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.ConclusionsIn 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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