Elsevier

Brain and Development

Volume 35, Issue 2, February 2013, Pages 172-176
Brain and Development

Original article
Novel mutation in SLC9A6 gene in a patient with Christianson syndrome and retinitis pigmentosum

https://doi.org/10.1016/j.braindev.2012.03.010Get rights and content

Abstract

Mutations in the SLC9A6 gene cause Christianson syndrome in boys. This X-linked syndrome is characterized by profound mental retardation with autistic behavior, microcephaly, epilepsy, ophthalmoplegia, and ataxia. Progressive cerebellar atrophy with motor regression is a remarkable feature in some patients. We report on a 22 year-old male patient with Christianson syndrome carrying the novel p.Gln306X mutation. The infantile phenotype suggested pervasive developmental disorder, then profound mental retardation ensued. In later childhood, progressive cerebellar atrophy was diagnosed on serial brain MRIs and motor regression occurred. Furthermore, ophthalmological evaluations showed a retinitis pigmentosum previously unreported in this condition. We conclude that the natural history of the disease in this patient tends to confirm the degenerative nature of Christianson syndrome, and that retinal degeneration may be part of the condition. Before the onset of degeneration, the syndromic association of severe mental retardation, autistic behavior, external ophthalmoplegia, and facial dysmorphism in male patients is a clue to the diagnosis.

Introduction

Christianson syndrome (CS, MIM#300243) is an X-linked mental retardation syndrome affecting males with profound mental retardation (MR), epilepsy, ophthalmoplegia, microcephaly, and ataxia with cerebellar atrophy [1]. Carrier females may have learning difficulties [2]. Mutations in the SLC9A6 gene were recently identified in six families with multiple male cases and in two sporadic male patients [2], [3], [4], [5]. A recent study suggested that disease-causing mutations induce a loss of function of the gene product, the Na+/H+ exchanger protein member 6 (NHE6) [5]. NHE6 is ubiquitously expressed in the membrane of early recycling endosomes, which is essential for the growth of neuronal dendritic spines. As a consequence, mutations in SLC9A6 may impair the neuronal development [5].

Herein, we report on a further patient with CS, who displayed obvious progressive cerebellar atrophy, retinitis pigmentosum and a novel mutation in SLC9A6.

Section snippets

Patient description

This patient, now aged 22 years, was the second child born to non-consanguineous healthy parents (Fig. 1A). His older sister, as well as his mother, had no history of learning difficulties. Pregnancy and delivery were uneventful, and growth parameters at birth were normal, including an occipitofrontal circumference (OFC) of 33 cm.

Initial steps of his motor development did not raise any concern: the patient held his head at three months, sat alone at 8.5 months and walked independently at 18 months.

Mutation analysis

A blood sample from the patient was collected after having obtained written informed consent. Genomic DNA was extracted from peripheral blood lymphocytes using the Flexigene DNA kit (Qiagen, Courtaboeuf, France). The 16 SLC9A6 coding exons and intron–exon junctions were PCR-amplified using 12 primers pairs (sequences available on request). PCR products were then sequenced with Big Dye Terminator cycle sequencing kit and ABI 3730xl automated sequencer (PE Applied Biosystems).

Sequencing revealed

Discussion

Thirty-eight patients with CS, belonging to eight families, are reported to date, and the phenotype has been delineated from the description of 24 examined patients (Table 1). All patients were affected by profound MR except one with moderate MR [2]. We report a new patient affected with CS carrying a novel SLC9A6 mutation.

Behavioral abnormalities suggesting pervasive developmental disorder were the prominent clinical feature in our patient during the first 2 years of life. At that time, he

Ethical standards/Conflict of interest

The authors confirm that the present submitted work complies with the current laws of the country in which it was performed (France).

The authors declare that they have no conflict of interest.

Acknowledgement

The authors thank Dr. Gregor Gilfillan for providing the sequence of primers for SLC9A6 sequencing.

References (8)

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    Despite these observations and the knowledge that untreated sleep disturbances can negatively affect health and daytime functioning, there is little information regarding the nature of these difficulties or their potential associations with the daytime symptoms in individuals with CS. Three previous studies [2–4] mention sleep complaints in individuals with CS but no additional information is provided about the nature of these issues or impact on the individual. Lack of characterization of the sleep disturbances of individuals with CS is a problem because common presenting symptoms of sleeplessness may have different underlying causes that would require different treatments.

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    Thus, all four variants elicit deleterious effects on recycling endosomal function. Progressive cerebellar atrophy, loss of Purkinje neurons, and motor regression are common features of a majority (∼60%) of CS patients examined thus far (1, 2, 6, 7, 10, 14). Less severe neuronal loss and gliosis have been documented in other brain regions, such as the cerebral cortex and hippocampus (6).

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