Mental Retardation, X-Linked, Syndromic, Christianson Type

A number sign (#) is used with this entry because the Christianson type of X-linked syndromic mental retardation (MRXSCH) is caused by mutation in the SLC9A6 gene (300231) on chromosome Xq26.

Some clinical features of this disorder show overlap with Angelman syndrome (AS; 105830).

Description

Christianson syndrome is an X-linked neurodevelopmental and progressive mental retardation syndrome characterized by microcephaly, impaired ocular movements, severe global developmental delay, developmental regression, hypotonia, abnormal movements, and early-onset seizures of variable types. Female carriers may be mildly affected (summary by Schroer et al., 2010 and Pescosolido et al., 2014).

Clinical Features

Christianson et al. (1999) described a 5-generation South African family with X-linked mental retardation, comprising 16 affected males and 10 carrier females. The clinical features common to the 16 males included profound mental retardation (100%), mutism despite apparently normal hearing (100%), grand mal epilepsy (87.5%), and limited life expectancy (68.8%). Of the 4 affected males examined, all had mild craniofacial dysmorphism and 3 were noted to have bilateral ophthalmoplegia and truncal ataxia. Three of the 10 obligate female carriers had mild mental retardation. Cerebellar and brainstem atrophy was demonstrated by cranial imaging and postmortem examination. Gilfillan et al. (2008) provided follow-up on the family reported by Christianson et al. (1999). Additional features included microcephaly, absence of expressive verbal language, and slow regression of walking ability. The youngest affected individual had a friendly demeanor.

Gilfillan et al. (2008) reported 3 additional families with the disorder. Affected individuals had profound mental retardation, absence of verbal language, seizures, and ataxia. Three affected males from a Norwegian family showed deceleration of head growth in the first year of life. Epilepsy occurred between 9 and 26 months. All had a happy demeanor with frequent smiling and episodes of unprovoked laughter. Other features included ataxia, hyperkinetic movements, open mouth, drooling, swallowing difficulties, and thin body habitus. Brain MRI of 1 patient showed progressive cerebellar atrophy. An affected Swedish boy had similar features; his carrier mother had severe dyslexia. Three affected boys in a U.K. family also had a long face with pointed jaw, profuse dribbling, poor growth capacity, and variable ambulation. Variable features included swallowing difficulties and flexed arms. Gilfillan et al. (2008) noted that the phenotype in all families was similar to that of Angelman syndrome.

Schroer et al. (2010) reported a large family in which 6 males had Christianson syndrome confirmed by genetic analysis (R468X; 300231.0002). All had profound mental retardation with lack of speech development, and only 1 acquired independent ambulation. Most had hypotonia in infancy, and all had onset of severe seizures by age 2 years. Many had developmental regression during the first decade. Other features included microcephaly, open mouth, and abnormal eye movements. Two had involuntary movements, 1 with hyperreflexia and clonus. Three had a happy demeanor with frequent laughing and smiling. Three carrier females had learning problems. Brain MRI of 3 of the boys showed cerebellar atrophy, and magnetic resonance spectroscopy (MRS) showed a prominent glutamine/glutamate peak.

Pescosolido et al. (2014) reported 14 boys, between 4 and 19 years of age, from 12 unrelated families with MRXSCH confirmed by genetic analysis. One of the families had previously been reported by Schroer et al. (2010). All patients had delayed psychomotor development with absent or very poor speech, and about 50% showed developmental regression at some point. Most (92%) had microcephaly. All patients had truncal ataxia with an unsteady gait, and most (79%) had a history of hypotonia. Cognitive functioning was profoundly impaired. All patients had early onset of variable seizure types between 4 months and 3 years of age, and 4 patients had a phenotype consistent with an epileptic encephalopathy; EEG showed various abnormalities. More than one-third of patients (43%) were originally diagnosed clinically with Angelman syndrome because of movement or balance disorders, lack of speech, mental retardation, a happy demeanor, and unprovoked laughter. Six patients (43%) were initially diagnosed clinically with autism, and 8 of 9 children formally tested met autism criteria. Other common features included abnormal eye movements (79%), sleep problems (64%), gastroesophageal reflux (50%), and hyperkinetic movements (100%). Many parents reported a high pain threshold. Three patients had documented cerebellar atrophy. Female carriers had diverse presentations, including normal functioning, mild to moderate intellectual disability, and psychiatric illness.

Clinical Variability

Masurel-Paulet et al. (2016) reported a family with an attenuated form of MRXSCH. The proband was a 9-year-old boy with mild intellectual disability, severe early language delay that improved with time, normal gross motor development, and postnatal microcephaly (less than third percentile). He had only 1 seizure at age 3 years that was well-controlled. He had no dysmorphic features except strabismus, and no ataxia or cerebellar symptoms, although brain imaging showed mild cerebellar atrophy. A 40-year-old maternal uncle had mild intellectual disability and early speech delay, but worked as a forklift truck driver and was married. He had normal head circumference, no ataxia, and no seizures. The proband's mother and his 3 sisters all had learning difficulties and writing difficulties with features of dyslexia and dysphasia without microcephaly. Targeted genetic sequencing identified a splice site mutation in the SLC9A6 gene (300231.0007) in the proband, his uncle, mother, and the proband's 3 mildly affected sisters. Analysis of proband cells showed that the mutation resulted in the production of 4 different transcripts, with 90% of the transcripts resulting in the skipping of exon 3 and an in-frame deletion that may affect protein folding. Masurel-Paulet et al. (2016) postulated that the milder phenotype in this family may be explained by the residual production of about 10% of the normal transcript.

Diagnosis

Pescosolido et al. (2014) proposed diagnostic criteria for MRXSCH. Core diagnostic symptoms (in over 85% of patients) include early-childhood onset in boys, nonverbal status, moderate to severe intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and/or attenuation in growth of head circumference, and hyperkinetic behavior. Secondary symptoms that are often present (in over 35% of patients) include symptoms of autism and/or Angelman syndrome, eye movement abnormalities, developmental regression, particularly loss of independent ambulation after 10 years of age, low weight for age, and cerebellar vermis atrophy, particularly after 10 years of age.

Pathogenesis

Garbern et al. (2010) reported the neuropathologic findings of 2 adult brothers with X-linked mental retardation due to a hemizygous mutation in the SLC9A6 gene (300231.0005). There was generalized symmetric cerebral atrophy with atrophy of the white matter, and marked neuronal loss and gliosis of the globus pallidus, putamen, substantia nigra, and cerebellar cortex. There were numerous tau (MAPT; 157140)-positive intracellular inclusions in the glial cells throughout the white matter and strongly tau-positive tangle-like inclusions in neurons of the substantia nigra, locus ceruleus, pontine nuclei, basal ganglia, thalami, and cranial nerve nuclei. Tau-positive neurons were also found in the cerebral cortex and hippocampus. The tau proteins were predominantly of the 4R type, were insoluble, and highly phosphorylated. The neuropathologic findings resembled those seen in tauopathies caused by MAPT mutations (FTD; 600274), but no MAPT mutations were found in this family. The phenotype of these patients, and of other affected males in this large family, included profound mental retardation, autistic features, incontinence, and late-onset truncal ataxia. Variable features included small head, mutism, seizures, ophthalmoplegia, and hand-wringing. Dysmorphic features were not noted. Garbern et al. (2010) suggested that the pathogenesis of this disorder resulted from aberrant MAPT processing, suggesting a possible interaction between the SLC9A6 gene function and cytoskeletal elements involved in vesicular transport.

Mapping

By linkage analysis of a South African family with X-linked syndromic mental retardation, Christianson et al. (1999) found linkage to chromosome Xq27.3 between markers DXS424 (Xq24) and DXS548 (Xq27.3) (maximum 2-point lod score of 3.10).

Molecular Genetics

In affected members of 4 unrelated families with Christianson-type X-linked syndromic mental retardation, including the original family reported by Christianson et al. (1999), Gilfillan et al. (2008) identified 4 different mutations in the SLC9A6 gene (300231.0001-300231.0004).

Tarpey et al. (2009) sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation. They identified 2 independent nonrecurring truncating mutations in SLC9A6 that segregated precisely with the phenotype. In addition to X-linked mental retardation, affected individuals had epilepsy and ataxia.

Fichou et al. (2009) did not find any unambiguous pathogenic mutations in the SLC9A6 gene among 59 unrelated boys with a diagnosis consistent with Angelman syndrome who did not have known molecular anomalies, suggesting that mutations in this gene are not a common cause of Angelman syndrome.

Pescosolido et al. (2014) found de novo SLC9A6 mutations in 7 (58%) of 12 families with MRXSCH. All of the mutations were predicted to result in truncation of the protein or splicing defects. No genotype/phenotype correlations were observed, and cellular functional studies were not performed.

Population Genetics

Pescosolido et al. (2014) estimated that MRXSCH due to mutations in the SLC9A6 gene may be one of the most common causes of X-linked developmental brain disorders, affecting from 1 in 16,000 to 1 in 100,000 people worldwide.