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Last update 08 May 2025

Mental Retardation, X-Linked, Syndromic, Christianson Type

Last update 08 May 2025

Basic Info

Synonyms

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

+ [16]

Introduction

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.

Drugs associated with Mental Retardation, X-Linked, Syndromic, Christianson Type

SLC9A6 Gene Therapy (University of Utah)

Target

SLC9A6

Mechanism

SLC9A6 blockers

Active Org.

University of Utah

Originator Org.

University of Utah

Active Indication

Mental Retardation, X-Linked, Syndromic, Christianson Type

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Mental Retardation, X-Linked, Syndromic, Christianson Type

100 Translational Medicine associated with Mental Retardation, X-Linked, Syndromic, Christianson Type

0 Patents (Medical) associated with Mental Retardation, X-Linked, Syndromic, Christianson Type

Literatures (Medical) associated with Mental Retardation, X-Linked, Syndromic, Christianson Type

01 Feb 2025·Neurology Genetics

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

Article

Author: 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.

01 Jan 2025·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

Author: 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.

01 Nov 2024·Journal of Medical Genetics

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

Article

Author: 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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Mental Retardation, X-Linked, Syndromic, Christianson Type

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