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

Abstract

Objectives: Mutations 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.

Results: We 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.

Conclusions: In 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.

Keywords: Genetic Diseases, X-Linked; Genetics, Medical; Neurodegenerative Diseases; Neurology; Phenotype.

Figure 1. Christianson syndrome-associated NHE6 mutations. A total of 31 unique NHE6 mutations were identified in 44 CS male probands across 37 families. Pathogenic NHE6 mutations include: Frameshift and/or nonsense (n=15, cyan or orange), deleterious missense (n=4, black), splice (n=9), CNVs (n=2, green) and one that removes the first methionine residue. Out of CS pedigrees with known inheritance (78%, 29 out of 37 families), 55% were inherited (16 out of 29 pedigrees) and 45% were de novo (13 out of 29 pedigrees). A total of 5 mutations were recurrent across multiple pedigrees: c.899+1delGTAA (mutation 14, 2 pedigrees), c.1024G>A (mutation 16, 2 pedigrees), c.1148G>A (mutation 17, 2 pedigrees), c.1498C>T (mutation 25, 3 pedigrees) and c.1710G>A (mutation 30, 2 pedigrees). The following mRNA isoforms are used: NM_001042537.1, NM_006359, NM_001379110.1 and NM_001177651. CS, Christianson syndrome; CNVs, copy number variants; TM, transmembrane.

Figure 2. Changes in height and weight across development. (A) Raw score of height (inches) by age (years) from 24 CS probands spanning <1–19 years. Height increases over time (Pearson’s correlation, R²=0.92). (B) Raw score of weight (pounds) by age (years) from 30 CS probands spanning <1–19 years. Weight increases over time (Pearson’s correlation, R²=0.90). (C) Estimated age-normed height and weight based on liner mixed model analysis. Both age-normed height (slope p<0.001) and age-normed weight (slope p<0.001) significantly decline over time. Raw height (n=24, total data points=81) and weight (n=30, total data points=116) measurements were converted to age-normed percentiles (WHO growth standards for 0–2 years; CDC growth curves for 2–20 years¹⁹) and z-scores. Our linear mixed model (random slopes and intercepts) of age-based percentiles for height and weight modelled the intercept and age at time point as fixed and random effects, respectively. Covariance parameters for height were large relative to their standard errors with statistically significant intercept (slope p=0.003), slope (p=0.016) and covariance of intercept and slope (p=0.046). Covariance parameters for weight were large relative to their standard errors with statistically significant intercept (slope p=0.002), slope (p=0.016) and covariance of intercept and slope (p=0.023). CS, Christianson syndrome; CDC, Centers for Disease Control and Prevention.

Figure 3. Changes in motor, language and social functioning as a function of baseline age over a 1 year period. Parent-rated changes in gross motor (A), fine motor (B), expressive language (C) and interpersonal/social functioning (D) from enrolment to 1 year follow-up (n=22). Each point represents an individual proband. Raw score change between enrolment and 1 year follow-up is plotted by age at enrolment. Changes in gross (A, R²=0.40, p=0.002) and fine (B, R²=0.25, p=0.028) motor is significantly correlated with age; older age is associated with greater loss of motor skills over a 1-year period. There is no association between age and changes in expressive language (C, R²=0.002, p=0.83) or social functioning (D, R²=0.00, p=0.96) over this time span. Pearson’s correlation.