Objective: Phenotypic variability in Christianson Syndrome

Background: The SLC9A6 gene encodes a sodium-hydrogen exchanger-6 protein involved in endosomal trafficking. Loss-of-function variants in SLC9A6 gene have been associated with Christianson syndrome (CS), an X-linked disorder characterized by intellectual disability, microcephaly, motor regression, epilepsy and behavioral abnormalities.

Methods: Case report.

Results: A 33-year-old male presented for evaluation of parkinsonian features. Born at 36 weeks, he had a normal postnatal course and mildly delayed motor (slower reaction times and slower walking speed) and learning milestones (required special education classes). Neurologic examination was remarkable for bradykinesia, hypomimia, cogwheel rigidity and hyperreflexia. Laboratory evaluation was unremarkable including complete blood count, Vitamin levels, thyroid function tests, serum organic and urine amino acids, CK, ceruloplasmin, lactate and pyruvate levels. Routine cerebrospinal fluid (CSF) analysis was unremarkable; CSF neurotransmitter analysis demonstrated low 5-Hydroxyindoleacetic acid, high neopterin, and borderline low tetrahydrobiopterin. Neuroimaging revealed diffuse parenchymal atrophy, advanced for age. Routine electroencephalogram was normal. A polysomnogram showed obstructive sleep apnea, periodic limb movements of sleep, and loss of REM atonia. Whole exome sequencing demonstrated a hemizygous c.1057G>A (p.V353I) missense pathogenic variant in the SLC9A6 gene on the X-chromosome at Xq26.3, and a pathogenic variant in the RAI1 gene. Both his brothers tested positive for the SLC9A6 pathogenic variant as did his mother and maternal grandfather. His brothers had predominant manifestations of psychiatric, sleep disorders and intellectual delay. His mother had mild learning disabilities and grandfather was asymptomatic.

Conclusions: Parkinsonism has been described in female obligate carriers of pathogenic variants in the SLC9A6 gene in case reports, however our patient is the first male patient with CS and late-onset motor degeneration with a previously unreported missense pathogenic variant in SLC9A6 gene: c.1057G>A (p.V353I) that is predicted to be deleterious by SIFT and PolyPhen2 analysis. The sleep abnormalities of the patient and his brothers may be attributed to the fact that all three carry the RAI1 pathogenic variant, which regulates mammalian circadian genes and the sleep-wake cycle.

References: 1. Riess A, Rossier E, Krüger R, Dufke A, Beck-Woedl S, Horber V, Alber M, Gläser D, Riess O, Tzschach A. 2013. Novel SLC9A6 mutations in two families with Christianson syndrome. Clin Genet 83:596–597. 2. Pierre Sinajon, Deborah Verbaan, Joyce So, The expanding phenotypic spectrum of female SLC9A6 mutation carriers: a case series and review of the literature, Human Genetics, 2016, 135, 8, 841.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsonism-in-christianson-syndrome-a-unique-presentation-of-a-unique-syndrome/