Genetic and phenotypic diversity of NHE6 mutations in Christianson syndrome

Abstract

Objective Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na+/H+ Exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. Methods Twelve independent pedigrees (14 boys, ages 4 to 19) with mutations in NHE6 were administered standardized research assessments and mutations were characterized. Results The mutational spectrum was composed of 9 single nucleotide variants (SNVs), 2 indels and 1 CNV deletion. All mutations were protein-truncating or splicing mutations. We identified two recurrent mutations (c.1498 c>t, p.R500X; and c.1710 g>a, p.W570X). Otherwise, all mutations were unique. In our study, seven of 12 mutations (58%) were de novo, in contrast to prior literature wherein mutations were largely inherited. We also report prominent neurological, medical and behavioral symptoms. All CS participants were non-verbal and had intellectual disability, epilepsy and ataxia. Many had prior diagnoses of autism and/or Angelman syndrome. Other neurologic symptoms included eye movement abnormalities (79%), postnatal microcephaly (92%) and MRI evidence of cerebellar atrophy (33%). Regression was noted in 50%, with recurrent presentations involving loss of words and/or the ability to walk. Medical symptoms, particularly gastrointestinal symptoms, were common. Height and body mass index measures were below normal ranges in most participants. Behavioral symptoms included hyperkinetic behavior (100%) and a majority exhibited high pain threshold. Interpretation This is the largest cohort of independent CS pedigrees reported. We propose diagnostic criteria for CS. CS represents a novel neurogenetic disorder with general relevance to autism, intellectual disability, Angelman syndrome, epilepsy and regression.

Complex Neurological Phenotype in Female Carriers of <b><i>NHE6</i></b> Mutations

“…Notable neurological symptoms reported in a subset of CS patients include cerebellar/brainstem atrophy and eye movement problems (closest to Duane syndrome Type I, i.e. an inward gaze deviation), as well as regressions in adaptive and/or motor functioning [2, 3, 5]. Female carriers in these CS pedigrees exhibit heterogeneous phenotypes, ranging from unaffected to presenting with mild-moderate ID/DD, neuropsychiatric disorders including attentional difficulties, mild ataxia, and/or microcephaly [1-8].…”

“…Female carriers in these CS pedigrees exhibit heterogeneous phenotypes, ranging from unaffected to presenting with mild-moderate ID/DD, neuropsychiatric disorders including attentional difficulties, mild ataxia, and/or microcephaly [1-8]. Recurrent developmental features of female carriers include learning problems, difficulty in school, speech disorder, and/or behavioral problems [2-4, 7]. However, the full phenotypic spectrum in females with NHE6 mutations, particularly across the lifespan, is currently unknown.…”

“…For example, symptoms that may develop and/or worsen with age include cerebellar/brainstem atrophy, motor decline/ataxia, cognitive/behavioral regressions, and low weight/height [2, 3, 9]. Postmortem examination of 2 CS males in their 40s and 50s found widespread neuronal and glial loss, as well as accumulation of tau-positive tangle-like inclusions [9].…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Although the exact prevalence is not known, CS is estimated to affect between 1 in 16,000 and 1 in 100,000 individuals [52]. A majority of CS individuals are nonverbal and present with epilepsy, ID, and ataxia.…”

“…Additional core symptoms are postnatal microcephaly and hyperkinetic behavior. Additional symptoms may include eye movement dysfunction, gastroesophageal reflux disease, low muscle tone, cerebellar atrophy, and phenotypic regression [51][52][53]. In one study of phenotypic diversity within CS, 43% of affected individuals received a clinical diagnosis of autism, and a majority of patients present with autistic symptoms [52].…”