Article Text
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.
- Neurodegenerative Diseases
- Genetic Diseases, X-Linked
- Genetics, Medical
- Neurology
- Phenotype
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Loss-of-function mutations in the endosomal Na+/H+ exchanger 6 protein cause the X-linked neurogenetic disorder Christianson syndrome (CS) in males, characterised by intellectual disability, epilepsy, non-verbal status, postnatal microcephaly and ataxia.
WHAT THIS STUDY ADDS
In the largest group of patients with CS studied to date, we present a large group of new mutations including important new missense mutations. We also conduct genotype–phenotype correlative analyses.
We expand the CS phenotype by presenting the natural history and dynamics of major CS symptoms across the lifespan including growth and motor abilities, as well as adding new diagnostic symptoms, such as high pain threshold.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
In this international natural history study of CS, we define the trajectory of symptoms and the adult phenotype, thereby identifying critical targets for treatment and enhancing clinical readiness for treatment trials.
Introduction
Christianson syndrome (CS) in males results from loss-of-function (LOF) mutations in the X-linked gene SLC9A6 which encodes the endosomal Na+/H+ exchanger 6 (NHE6).1–4 CS is one of the most common forms of X-linked intellectual disability (ID).5 The NHE6 protein modulates intra-endosomal pH and endosomal maturation.6 7 Studies of the pathophysiology of CS in animals and cells lacking NHE6 have identified both neurodevelopmental and neurodegenerative features.6 8–11 In male patients, CS presents early with global developmental delay, lack of language, postnatal microcephaly, ataxia, epilepsy and Angelman syndrome-like and/or autistic features.1 However, little systematic data exists which establishes the life course of symptoms in people with CS into adulthood. In addition to abnormal brain development, progressive neurodegenerative and medical processes unfold with age.1 12
In the initial large pedigree, Dr Arnold Christianson and colleagues reported that early neurodevelopmental abnormalities were followed by a ‘slow regression’ starting in the second decade of life.3 In our prior report of 14 CS probands, we identified a history of regression in 50% of participants.1 Also, CS has been described to involve a progressively worsening ataxia, which appears to be associated with the high prevalence of cerebellar degeneration in patients (atrophy in 30–60% of cases).1–4 13 Further, human neuropathological studies3 12 and NHE6-null mouse and rat models have identified cerebellar Purkinje cell loss, and as well as cortical tissue loss, with tau deposition.8–10 Dr Christianson’s original description of an extended South African pedigree suggested progressive morbidity, thin body habitus, and a potential risk of early mortality3; however, to date the risk of early mortality has not been corroborated in larger studies.
The majority of published NHE6 mutations are nonsense or splice mutations that are thought to result in complete LOF of the NHE6 protein.1–4 Nonsense mutations appear to lead to nonsense-mediated mRNA decay.14 Other mutation types (for example, missense) have also been reported but are less common, yet may be informative to protein function.1 15 Cytoplasmic tail mutations, particularly when missense, could be highly informative given that the function of this part of the protein is not well understood. While mutations were initially reported as inherited in pedigrees, de novo mutations now appear to be a relatively common form of transmission.1
Based on the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study, the current study examined the largest sample to date of CS probands across the lifespan, importantly including longitudinal follow-up data and a large proportion of adults. In total this study includes 44 probands, including 11 adults. This group of patients is more than three times as large as the largest prior report1 with a wider age range of participants (age 2–32 years). With a focus on potential target symptoms for future clinical trials, the three primary aims of this study are to (1) identify new mutations and the range of NHE6 mutations in CS; (2) cross-sectionally and longitudinally examine the clinical phenotype across the lifespan, as well as the adult phenotype and potential early mortality; and (3) longitudinally examine growth and maintenance of healthy weight of the probands across the lifespan. In summary, given the size and the longitudinal design, the current study permits the determination of the CS phenotype across the lifespan into adulthood.
Methods
Procedures
This Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study was approved by the Institutional Review Board (IRB) at Lifespan Healthcare and Brown University. Informed consent was given by the parent/guardian of the participant. The procedures involved the initial enrolment and yearly follow-ups. We generated natural history data through both retrospective medical record review and history taking as well as annual prospective follow-up assessments.
Recruitment and enrolment
Enrolment criteria were adapted from Pescosolido et al 1 and included males at any age wherein: (1) there was a prior clinical genetic diagnosis involving a mutation in the SLC9A6 gene; (2) the participating child had an active clinician; and (3) the clinical phenotype was consistent with CS diagnostic criteria. Participants were recruited through close collaboration with the Christianson Syndrome Association, participation in the biannual international conferences for CS, and via genetic diagnostic labs. Participants were predominantly enrolled remotely due to our international recruitment that spans 11 countries. DNA was isolated from blood or saliva samples. All NHE6 mutations were verified by Sanger sequencing by sequencing all coding exons (1–16) and exon/intron junctions as previously described1 except where indicated in table 1.
Clinical assessment and medical record review
Clinical data were collected by telephone, video-conferencing and/or in-person assessments and through medical record collection. Standardised research assessments were filled out by parents/guardians. The Vineland Adaptive Behaviour Scales-Second Edition (VABS-2)16 assessed adaptive functioning across the following domains: communication, social, daily living, motor, and maladaptive behaviour. Irritability and hyperactivity were assessed via the Aberrant Behaviour Checklist (ABC),17 a parent questionnaire to assess behavioural problems. A detailed medical and family history questionnaire was administered to parents/guardians. Height and weight were obtained from available medical notes. In-person standard neurological examinations were performed by a board-certified neurologist (JSL). Prospective follow-up involved an annual telephone or video interview to collect information regarding changes to medical, neurological, or behavioural symptoms experienced by the proband. VABS-2 and ABC were administered and new medical records were collected.
Statistical analyses
The sample (n=44) was divided into four groups, based on developmental stage at enrolment: toddlers (0–5 years; n=11), children (6–11 years; n=9), adolescents (12–16 years; n=13), and adults (17–32 years; n=11). Analysis of variance and χ² analysis were used to examine group differences across developmental stages, inheritance/de novo, and mutation type. A subset of the group (n=22) completed the VABS-2 at baseline and re-assessment at the study 1 year follow-up. VABS-2 subdomains were used to measure expressive language (communication scale), interpersonal skills (social scale), fine motor skills (motor scale) and gross motor skills (motor scale). The change in raw skills between baseline and follow-up was calculated to examine potential intra-individual decline and analysed using Pearson’s correlation. Raw measurements of height/weight were converted to age-normed percentiles (WHO growth standards for 0–2 years,18 Centers for Disease Control and Prevention (CDC) growth curves for 2–20 years19) and to z-scores. To model physical stature across development, we used a linear mixed model (with random slopes and intercepts) for each variable of interest (ie, height, weight) with the age of the child as the time basis. The model intercept and slope were random effects.
Results
CS-associated mutations
In total, 37 distinct families were enrolled with 44 affected males. 31 unique mutations were identified in the cohort (table 1; figure 1). Of the 31 unique mutations, there were: 15 frameshift and/or nonsense mutations; 4 deleterious missense mutations; 9 splice mutations; 2 copy number variant deletions; and 1 mutation that removes the first methionine residue. Of those with known inheritance (29 of 37 families), 16 cases were inherited (55%) and 13 cases were de novo (45%). Notably, 5 mutations were recurrent (ie, occurred in more than 1 family). Each of the following mutations occurred in 2 distinct families: c.899+1 del (mutation 14), c.1024G>A (mutation 16), c.1148G>A (mutation 17) and c.1710G>A (mutation 30). Mutation 25, c.1498C>T, was found in 3 families. These recurrent mutations were inherited in 3 families not known to be related and were de novo in 5 families. Inheritance was unknown in the 3 remaining families with recurrent mutations. No strong genotype–phenotype associations were evident (online supplemental table 1).
Supplemental material
CS core and associated symptoms across the lifespan
In total, 44 males were evaluated with SLC9A6 mutations, ranging from age 2 to 32 years. In order to consider CS symptoms across developmental stages, cross-sectional analysis was conducted across four age groups (table 2): 0–5 years at enrolment (n=11); 6–11 years (n=9); 12–16 years (n=13); and 17–32 years (n=11). In terms of race and ethnicity: 11% of the sample identified as Hispanic/Latino (n=5); 89% identified as White (n=39); 5% identified as multiracial (n=2); 2% identified as Black (n=1); and 2% identified as other (n=1). Participants were born in 11 different countries and seven different primary languages were represented in these families.
Based on our prior study of 14 patients with CS, we proposed CS core symptoms (present>85%) and secondary symptoms (present in>35%).1 Core symptoms included ID (severe to profound), non-verbal status, epilepsy, ataxia, postnatal microcephaly and hyperkinesis (ie, behavioural hyperactivity).1 The previously proposed core symptoms were upheld here in this larger study on average across ages by combining all age groups (table 2). Specifically, all of the core symptoms were present in greater than 85%, including ID (100%), epilepsy (100%), non-verbal/non-phrase speech (100%), microcephaly (95%), ataxia (95%) and hyperkinesia (93%). Of the 44 participants with CS, 32 never had spoken words. While there were 12 participants with words, generally this reflected five or fewer words and none had phrase speech. For caregivers of the 12 participants with words, nine caregivers also noted the loss of words with time. Notably, we also discerned that high pain tolerance represents a new core symptom when considering all age groups together, present in over 85% (91%).
Secondary symptoms occurred in 35–84% of participants and included current sleep problems (51%), unprovoked laughter (62%), visual acuity problems (52%), current GERD (56%), constipation (55%), eye movement abnormalities (68%), regression (54%), swallowing problems (44%) and contractures (36%) (table 2). Previously identified secondary symptoms such as prior Angelman syndrome diagnosis and Autism Spectrum Disorder (ASD) diagnosis occurred in 29% and 18% of the current sample, respectively. ASD diagnosis and prior Angelman diagnosis were more common in the older groups, perhaps reflecting more access to accurate genetic testing in the younger group. Scoliosis occurred in 39% of participants; two participants had corrective surgeries for scoliosis between 15 and 20 years of age.
While the core symptoms were relatively stable across age groups, there were several changes in frequency across ages that were notable. Absence of phrase speech, ID, ataxia and epilepsy were always observed in all patients. We found that 80% of the youngest age group (strictly below our cut-off for core symptoms) had microcephaly which elevated to 100% in all older age groups, reflecting the idea that the microcephaly in CS has a strong postnatal component (table 3). This variation in head circumference data reflecting decreases across ages approached significance (p=0.089). Similarly, 73% of participants had a high pain threshold in the youngest age group (0–5 years old) which elevated to above 85% (our cut-off for core symptoms) in the older age groups therefore, although prevalent in the youngest age group, high pain threshold may not be considered a strict core symptom in the youngest age group (table 3). In the current group, ataxia was present in 82% of participants in the youngest age group and in 100% of subsequent age groups, again suggesting that ataxia worsens with age. In line with these observations, with regard to the ability to walk, 100% of participants report walking unaided by or before age 5; however, the ability to walk unaided is lost in approximately 20% of participants in the 6–16 groups and 30% are reported as not able to walk unaided in the oldest group (17+ years old). Finally, with regard to hyperkinesis, this core symptom was present in 100% of the participants in the two younger age groups and 92% and 82% of the oldest age group suggesting that hyperkinesis does not meet the cut-off for a core symptom in the oldest age group. Concurrent with these data, we observe that the hyperactivity subscale scores on the ABC are most severe in the younger groups and less prominent in the oldest group (table 2), although this does not reach statistical significance.
There were statistically significant differences across developmental groups for some reported symptoms or phenotypic features that are particularly notable. There were significant group differences in the rate of current constipation, prior history of regression, adaptive function (including social, communication and daily living subscores) and number of hospitalisations (p<0.05). Each of these experiences were most common in the adult group (table 2). Importantly, 100% of participants in the oldest age group reported notable problems with constipation (p=0.002). With regard to regression, reports of any regression at some point in their lifetime increased significantly with age from toddlers (30%), children (44%), adolescents (50%) and adults (90%) (p=0.047). With regard to adaptive functioning, age-normed Vineland scores appeared stable in toddlers and children, and then dropped in the adolescent group and again in the adult group (p<0.001 for communication, p<0.001 social and daily living, and p<0.0005 for adaptive functioning). While not representing a statistically significant difference across groups (p=0.305), it is notable that the highest level of inability to walk is experienced in the adult group at approximately 30% (table 2).
Longitudinal assessment of growth and physical stature across the lifespan in CS
Adult patients with CS have been described as having a thin body habitus3; however, systematic analysis of growth in CS across the lifespan has not been conducted. To study growth in CS across the lifespan, raw measurements of height and weight were converted to age-normed percentiles (WHO growth standards for 0–2 years18; CDC growth curves for 2–20 years19) and to z-scores. To model physical stature across development, we used a linear mixed model (with random slopes and intercepts) for each variable of interest (ie, height, weight) with the age of the child as the time basis. The height (n=24) and weight (n=30) obtained at clinical appointments were analysed via mixed linear modelling of age-based percentiles (figure 2). While height and weight naturally increased with time (figure 2A,B), the age-normalised weight, i.e., the percentile (n=30; total data points=116; range=1–12 points per person) linearly declined over time (slope p<0.001) (figure 2C). Height percentile (n=24; total data points=81; range=1–11 points per person) also linearly declined over time (slope p<0.001). Of note, the predicted intercept for the model at birth was within normal ranges; however, as shown the model demonstrates a progressive slower growth in CS relative to normal growth with age (figure 2). Of relevance to challenges in growth and nutrition, approximately 30% (13/44) of participants had G-tubes placed. Approximately 38%, 23%, 23% and 15% had their G-tubes placed during ages of 0–5, 6–11, 12–16 or 17+years of age. Indications for G-tube placement have been failure to thrive, most often at the younger ages, and inability to eat across all ages, generally related to challenges with swallowing.
Adaptive, behavioural and motor functioning across the lifespan
Cross-sectional findings. Parent-reported adaptive and behavioural data were also available for a subsample of the males (n=27–31). When examining differences across the cohort by current developmental stage (cross-sectional analysis), a statistically significant difference across groups was identified (p<0.0005) in age-normed overall adaptive functioning. Specifically, older participants had lower age-normed abilities than younger participants, in that the younger participants had abilities more similar to their same-aged peers while the abilities of the older participants were further below those of their same-aged peers (table 2). In further examining across these cross-sectional age groups, there were no significant differences between age groups in hyperactivity or irritability at baseline (table 2; ABC).
Adaptive/motor findings. Importantly, we also conducted a longitudinal follow-up analysis through investigation of change in adaptive function in individuals (n=22) at baseline and at a 1 year follow-up time point. The change in skills between baseline and follow-up was correlated with age at enrolment. Results showed that participant age was negatively correlated with a change in fine motor skills (r=−0.50; p=0.028) and gross motor skills (r=−0.63; p=0.002; figure 3). Specifically, 5 of 6 adults (83%) experienced a loss in multiple fine motor skills such as picking up small objects with thumb and fingers and moving objects from one hand to the other. Expressive language and interpersonal skills change were not significantly correlated with age (figure 3). These longitudinal studies suggest that older participants are at risk for losing previously acquired skills, particularly in the motor domain, which is observable by parents/guardians at a 1 year follow-up. Therefore, these longitudinal studies augment the above cross-sectional studies.
Neurological examination. Standardised, in-person motor examination was performed by a board-certified neurologist (JSL). 12 patients were directly examined (online supplemental table 2). The cross-sectional direct assessment of patients additionally supports the interpretation that there is age-related worsening of motor function. Subjects have evidence of cerebellar dysfunction including tremor and truncal ataxia as evidenced by wide-based gait. Importantly, also older patients (ie, age 20 and greater) present with evidence of motor dysfunction with signs of corticospinal tract, i.e., upper motor neuron damage such as increased tone, weakness, increased and abnormal reflexes. Thus, the clinical phenotype includes upper-motor neuron involvement that emerges particularly in adulthood as well as cerebellar dysfunction that is also progressive but presents first in early adulthood.
Supplemental material
Participant deaths
Three of the 44 participants in this described cohort died (6.8%) during the duration of the study. One participant, who also may have had other contributing genetic mutations, died between 6 and 10 years of age due to complications caused by a worsening neurological state and increased seizure frequency. The adult participants died between the ages of 20–25 and 30–35 years in their homes due to conditions related to infirmity and illnesses such as pneumonia.
Discussion
This study represents the largest to date of Christianson syndrome (CS). This also is the first study to date as part of the International Christianson Syndrome and NHE6 (SLC9A6) Gene Network Study presenting longitudinal follow-up and systematic study of CS into adulthood. 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. Among the most prominent results are; first, the large range of mutations wherein there are some notable new missense mutations (discussed below); second, we have also defined the core symptoms of CS and the dynamics of these symptoms across the lifespan, and also, added a novel and important new core symptom, namely the high pain threshold that children exhibit, particularly after age 6; third, we present longitudinal follow-up data demonstrating that patients with CS do show decrease in motor function with age; fourth, we present data exhibiting the challenges in maintenance of a healthy weight and reductions of body mass index with age; and finally, fifth, in this study through longitudinal follow-up, we were able to provide important information with regard to CS features in adulthood and we begin to address the question of life expectancy and mortality. This international CS study has thereby defined future treatment targets and also provides natural history data of the sort that will support future clinical trials.
Genetic diversity in CS and genotype–phenotype relationships
We present 31 unique mutations in 44 affected males with CS. The vast majority are likely complete LOF mutations, with more than 80% as frameshift/nonsense, splice (29% of total) or highly deleterious copy number variants. A minority represent missense mutations which are also likely LOF; however, further study will be needed to address this functionally. In the current dataset, there is no statistical evidence of genotype–phenotype correlations, providing further support that the majority of NHE6 mutations are complete LOF. Prior studies in patient-derived induced pluripotent stem cells (iPSCs) have demonstrated that nonsense mutations are subject to nonsense-mediated mRNA decay.14 Of note, the G383D mutation which has been studied functionally in iPSCs exhibits some residual protein expression.14 Another notable finding, in terms of genetic mutations, is that we present here a patient with the L582P mutation which represents a rare missense mutation in the cytoplasmic tail of NHE6 that is associated with the CS phenotype.
Natural history of primary and secondary CS symptoms with age
Previously established core diagnostic features of CS1 were confirmed including ID (100%), epilepsy (100%), non-verbal/non-phrase speech (100%), postnatal microcephaly (95%), ataxia (95%) and hyperkinesia (93%). All families reported a prior diagnosis of ID and available IQ data are consistent with the profound to severe range. Conducting rigorous IQ testing at this level of function is challenging. Where IQ information was available (n=10) or performed directly by our team (n=5), IQ estimates ranged from 18 to 40. High pain tolerance, not previously identified as a core feature of CS, was present in 91% of probands. Therefore, we support the inclusion of high pain tolerance as a new core diagnostic feature. Clinicians and caregivers should be aware of this symptom in order to understand how people with CS may respond to injury. Overall, with regard to core symptoms of CS, we show here that there is some evolution of these symptoms with age such that microcephaly, ataxia and high pain threshold have lower expression until after age 6. Notably, this provides further support that the microcephaly in CS is indeed postnatal microcephaly. Furthermore, hyperkinesia appears to dissipate with age.
Secondary symptoms of CS1 were also highly represented including GERD (56%), eye movement abnormalities (68%), prior regression (54%) and prior diagnosis of Angelman syndrome (29%) and autism (18%). We suspect a prior diagnosis of Angelman syndrome will become less common in younger CS males in the future due to advances in genetic testing. No toddlers were diagnosed with Angelman syndrome. Importantly, the adult cohort experienced a higher rate of select medical complications, particularly gastrointestinal symptoms such as constipation. Adult patients with CS had significantly greater hospitalisations. Also, importantly, scoliosis occurred in greater than a third of patients which worsens with age and required surgery in a subset. In terms of dysmorphology, Dr Christianson first noted males with prominent straight nose, square prognathic jaw, large ears and sunken eyes.3 These features were found to be somewhat inconsistent, so they are not a focus here. Also noted is the unilateral inward deviation of the eye with eye movement abnormalities consistent with Duane anomaly; this was found in 68% of the current group (table 2) often leading to surgical correction.1
Challenges in maintaining a healthy weight during growth and aging in CS
Clinical records were analysed to examine height and weight growth across development as they represent secondary CS symptoms.1 While probands continued to make raw score gains in pounds and inches across time, their rate of growth relative to normative values resulted in a pattern of decreasing age-normed scores across development for height and weight. Mixed model results estimated height and weight to be in the average or typically developing range at birth. However, height fell to below one SD below the mean by 7 years and two SDs by 19 years old. Weight fell to below one SD by 8 years old and two SDs by 15 years old. While there was little evidence of loss in body mass in our data, models were only calculated from 0 to 20 years (based on available developmental normative data). These analyses of body size highlight abnormalities in growth in CS which call for important future studies. Healthy weight should become a target symptom in growth and adulthood. Studies of nutrition and healthy weight in adulthood are warranted and consideration of the caloric and nutritional requirements of men with CS will need to become a critical subject in future studies.
Longitudinal data in CS demonstrate progression of motor symptoms
The majority of probands (54%) had a history of parent-reported developmental regression that increased in prevalence across development with 30% of toddlers, 44% of children, 50% of adolescents, and 90% of adults experiencing prior regression. This was not specific to any of the subdomains, although 60% of adults had a prior motor regression and 45% of adults had a prior speech regression. This is consistent with our prior study of regression in 50% of CS probands, most notably in speech and motor domains.1 Additionally, loss of social skills was noted in about one-third of children with regressions.
To complement these and prior cross-sectional and retrospective analyses, we examined changes in language, social, and motor functions over a 1 year interval follow-up. Here, we find that there was a negative association between participant age at enrolment and fine and gross motor function loss in that adults experienced a notable loss of motor functions in this 1 year interval. These data identify motor function as a target symptom for treatment and prevention of decline. These prospective follow-up data are particularly notable as we are able to observe a measurable decline in this relatively short time-line of 1 year. This finding is particularly valuable and hopeful as clinical trials that may target the progression of these motor symptoms will benefit from observations of this strong effect size in time frames that appear feasible for a robust trial.
Limitations of this study
While this is the largest study to date on CS, defining more rare events in CS will require a larger sample. While this study does include longitudinal data, many findings still rely on natural history data from retrospective clinical records or a convenience sample. This study does not examine the clinical progression of epilepsy symptoms, treatment and outcome. Our prior study had a detailed cross-sectional analysis;1 an in-depth analysis of epilepsy natural history is beyond the scope of the current manuscript and is being addressed in a parallel study. Dr Arnold Christianson in his original study in a large South African pedigree suggested that there may be a risk of premature mortality in CS. In the course of our study, we have observed the death of three participants.
Summary
We present the largest study to date of male patients with CS. Overall, this study has identified a large range of LOF mutations, including also several novel missense variants. This study is notable for the identification of a new core symptom (high pain threshold) and the natural progression into adulthood. This study has the largest group of adults with CS, and we have defined the clinical progression of motor symptoms. In addition, we identify a decline in body mass index with age as an important treatment target moving forward. In conclusion, this study identifies several target symptoms—particularly healthy weight gain and motor symptoms—that progress with a natural history that may make them amenable to intervention in a future clinical trial. The findings presented here and emerging from this network study will enhance clinical trial readiness as targeted treatments become available.
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Lifespan Healthcare and Brown University, IRB project #: 842130; IRB committee #: 403516.
Acknowledgments
The authors would like to thank the families for participating in this study. We would also like to thank the Christianson Syndrome Association for their help with this study. EMM had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
References
Supplementary materials
Supplementary Data
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Footnotes
Correction notice The article has been corrected since it was published online. A number of typographical errors were corrected, and the Ethics approval statement was corrected for clarity.
Contributors Conceptualisation: BCK, EMM. Data Curation: BCK, JE, CRB, DGSP, MFP, QO, JB, RSB. Formal Analysis: BCK, JSL, RNJ. Writing: BCK, EMM. Guarantor: EMM.
Funding This work was supported by National Institutes of Health Grants R01NS113141, R01NS121618, R01MH102418, R01MH105442, R21MH115392, and R01AG087455 to EMM.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.