Background
Wolfram Syndrome (WFS) (OMIM #222300) [
1] is a rare autosomal recessive disease typically characterized by diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing and vision loss, motor impairment, neurodegeneration, and a reduced lifespan. WFS can be caused by mutations in the
WFS1 gene, which is known to encode the wolframin protein. Wolframin exists within the endoplasmic reticulum (ER) membrane [
2] and helps to protect cells from ER stress related apoptosis [
3‐
5]. Wolframin deficiency leads to cell death in the insulin producing β-cells in the pancreas, causing diabetes, and is also thought to underlie cell death in the brain [
6]. As cellular studies move towards possible clinical interventions [
7], an understanding of the natural history of WFS is becoming more critical, and the progressive neurological aspects of WFS, including brain structure abnormalities, gait impairment, and cognitive and behavioral difficulties, are receiving increasing attention [
8‐
10].
Recent work has shown that altered brain structure in the brainstem and cerebellum can be detected early in the disease process through in vivo neuroimaging [
8]. Clinical retrospective data and case studies have suggested that neurological symptoms, such as ataxia and cognitive changes, occur from teenage years into mid-adulthood [
11,
12], yet our direct measurements [
9] found that motor neurological abnormalities, such as poor balance and altered gait, are present in childhood and early adolescence. It is unknown at this point whether non-motor, complex, and higher order neurological functions, such as cognition and emotional functions, also follow this pattern, or if those functions are relatively spared early in the disease due to their independence from brainstem and cerebellum function. However, these domains have been poorly quantified in previous studies. While several case studies reported cognitive impairment and depression in adult patients with advanced WFS [
12‐
16], others described patients with normal intelligence [
17,
18]. Studies typically have lacked standardized testing or an age-matched control group for comparison.
Our group has studied a cohort of children, adolescents, and young adults with WFS using standardized and quantified assessments of cognitive, psychiatric, and behavioral abnormalities. We also acquired overlapping measures on age- and gender-matched individuals with and without type 1 diabetes mellitus (T1DM). The goal of this paper is to describe the nature and extent of non-motor abnormalities in a deeply phenotyped cohort of young patients with genetically-confirmed WFS. This information may reveal biomarkers for disease progression, targets for symptomatic treatments, and potential outcome measures for future clinical trials.
Discussion
The purpose of this study was to determine whether there are any cognitive or psychiatric symptoms in relatively early stage WFS. This study advances the literature by directly assessing both WFS patients and age- and gender-matched control groups with standardized, quantitative assessments. Overall, we found selective deficits in WFS patients in smell identification and sleep disturbances, but no impairment in cognitive performance. Based upon a clinical evaluation of WFS patients only, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. However, when self- and parent-reported psychiatric symptom inventories were compared to control groups, there was no difference in rates of these reported symptoms. Smell identification deficits were associated with diabetes duration, but there were no other relationships between proxies of disease severity and assessment results. These results indicate that in relatively early stage WFS, smell tests and sleep questionnaires distinguish WFS from control groups better than cognitive tests or self- or parent-reported psychiatric questionnaires. However, psychiatric interviews of WFS patients suggest that there are diagnosable psychiatric conditions that in some cases are well-managed with pharmacological treatment. Although it is not clear if the rate of diagnosable psychiatric conditions in WFS differ from control groups from this study, longitudinal interview data in our WFS cohort may determine if psychiatric diagnoses are a useful index of disease progression.
Past studies have reported either cognitive impairment (learning difficulties, memory issues, decreased verbal performance) [
12‐
15] or normal cognitive development in WFS patients [
17,
18]. However, many of these studies were case reports without quantitative data on cognitive measures, had very small sample sizes, or were based on clinical impressions of older, more affected patients. In contrast, using structured testing and age- and gender-matched control groups, we found that WFS patients perform similarly to and in some cases better than controls, suggesting that cognitive impairment is not an early or prominent feature of WFS. It is possible, however, that cognitive impairment may evolve in the later stages of the disease. Interestingly, the WFS group performed better on a few tests, which could be due to higher motivation, perhaps to compensate for hearing or vision loss, or because of practice effects, as some had performed these tests in previous years. However, we found that a smaller subset of these WFS patients performed within or above the average range for verbal intelligence, memory, and attention on their first year of clinic [
8], suggesting that even without practice they are performing well. The issues of practice effects or later degeneration of higher order cognitive function are best addressed with longitudinal data from both WFS and controls.
Similar to the cognitive data, our psychiatric and behavioral data yielded results somewhat inconsistent with past literature. Previous reports have indicated that there may be a role of the
WFS1 gene in depression and suicide attempts [
35,
36], as carriers of one
WFS1 mutation had a greater risk for lifetime psychiatric symptoms. Studies of WFS patients have also suggested that WFS patients suffer from high rates of depression and anxiety [
14,
15,
37]. However, these reports were based on overall clinical impressions and self-report of diagnoses rather than standardized measures or structured clinical interviews and lacked appropriate control groups. Notably, during a clinical interview with the study psychiatrist, many of the WFS patients reported previous symptoms consistent with an Unspecified Anxiety Disorder. However, in more than one case, the study psychiatrist noted that the patient’s parent was very concerned about the patient’s anxiety and psychiatric symptoms, but the patient did not agree they had significant symptoms. There is a possibility that this could be influenced by parental anxiety about their child’s symptoms, or it could be due to limited insight of the patient. Furthermore, we did not find elevated psychiatric symptoms in the standardized parent- or self-report of current symptoms in three critical psychiatric domains—Neuro-developmental and Disruptive Behavior, Anxiety, and Mood disorders—as compared to the control groups. The apparent incongruity of results between our findings and previous reports could indicate: (1) younger WFS patients may not experience the same severity of psychiatric issues as older, more impaired WFS patients; (2) that our patients have received appropriate support and treatment for their symptoms; or (3) these standardized assessments did not detect clinically relevant symptoms for this particular cohort of patients. Nevertheless, the psychiatric symptoms the WFS patients may experience are generally treatable and manageable as indicated by the lack of self-reported symptoms.
Consistent with past reports [
17,
15,
38,
39], we saw selective deficits in WFS patients in smell identification. Olfactory dysfunction often is an early indicator of neurodegenerative diseases, such as multiple sclerosis (MS), Parkinson’s disease, and Alzheimer’s disease [
40]. Several WFS studies have reported a range of olfactory issues in patients, including anosmia [
17,
15,
38,
39]. However, these studies did not detail how they assessed patients, did not include control groups, and were primarily case reports of older adults. Our results indicate that smell identification deficits are present early in WFS, even compared to a T1DM control group, and are not explained by differences in cognitive function. Further, since smell deficits were worse in those with greater duration of diabetes, it is possible that smell may be a potential marker of disease progress; however, this hypothesis will need longitudinal data to confirm.
Sleep dysfunction was also common in our WFS group. WFS patients and their parents reported more sleep-related problems, such as snoring, heavy breathing, bed wetting, and sleepiness than controls. Furthermore, the study psychiatrist found that the majority of adolescent and adult (6/10 patients ≥ 13 years of age) WFS patients qualified for hypersomnolence disorder. It is unclear whether these sleep problems are central to WFS or due to the presence of a chronic disease like type 1 diabetes or diabetes insipidus, which can increase the frequency of nocturnal urination and sleep disruption. Sleep problems are prevalent among individuals with type 1 diabetes [
41‐
43]. Matyka et al. found that compared to unaffected children, children with T1DM woke up more during the night and slept less. However, our T1DM and control groups did not differ in sleep problems, so it is unlikely that diabetes per se explains sleep problems in our WFS sample. Sleep studies using actigraphy to record motion and pulse oximetry to monitor respiration could help distinguish between the mitigating clinical and environmental factors altering sleep behavior in WFS and possible underlying neurologic dysfunction. Given that death due to WFS has been ascribed to sleep apnea in some cases [
11], these features deserve closer attention and evidence-based intervention.
The pattern of spared and affected non-motor neurological function that we describe in this paper is generally consistent with the known pattern of structural brain abnormalities in WFS. We have observed striking brain volume differences in lower brain order systems like the brainstem and cerebellum in WFS (including some of the patients represented in this paper), but few differences in cortical volume measurements [
8]. Smell and sleep are mediated by complex interactions between the brain stem, limbic system, hypothalamus, and some cortical regions [
40,
44,
45], whereas cognitive function relies primarily on higher order cortical networks. Further cross-sectional and longitudinal structure-function analyses will be necessary to determine whether these relationships exist in WFS.
Our study was a thorough examination of the cognitive, psychiatric, and behavioral outcomes seen in WFS. The major strengths of the study are the inclusion of an age- and gender-matched control group and the use of standardized measures. However, there were some limitations to the study. First, although our WFS group and control groups performed similarly on the cognitive tasks, we may have selected a WFS cohort that was a high functioning group with access to more resources than the average WFS family. However, a wide range of symptom severity was represented in our WFS group, suggesting that they were not high functioning in all domains. Also, this may be a function of the wide age range in our WFS patients, from early childhood to early adulthood. This age range could also obscure the possibility that psychiatric symptoms and diagnoses are a later emerging issue in WFS. Although we saw no obvious relationship between age and symptoms, aside from a possibly higher rate of hypersomnolence in adolescence and adulthood, our sample is likely too small to detect such a pattern. Second, some of our WFS patients were exposed to the testing measures in previous clinics, while the control groups had not been exposed. However, regardless of practice, our WFS patients still showed significant impairments in smell identification. Third, the WFS group and control groups did not receive the same psychiatric evaluation, and the control group was screened for psychiatric diagnoses and medication use prior to study enrollment. Four WFS patients were currently prescribed psychoactive medication for psychiatric symptoms. These patients may have psychiatric symptoms that were masked by medication use, leading to decreased reporting of symptoms on the psychiatric inventories. Furthermore, we cannot draw conclusions about differential rates of psychiatric diagnosis between the groups due to the exclusion criteria for the control groups. Based upon the discrepancies in psychiatric evaluation, parent-report and self-report psychiatric symptoms are clearly complicated in WFS, and it may be difficult to distinguish what symptoms are related to pathological WFS versus symptoms related to having a severe chronic and degenerative illness with multisensory system effects. Future studies on psychiatric illness in WFS could explore different self-report measures than the ones used in the current study. Nonetheless, these findings indicate that some psychiatric symptoms may be manageable in WFS patients with typical pharmacologic treatments.
Acknowledgements
We thank all of the participants and their families for their time and effort. In addition, we thank Emily Bihun for reviewing the manuscript, Samantha Ranck, the WFS study coordinator, and the rest of the current and former study staff and the Washington University Wolfram Study Group for their support throughout the research and writing process.
Washington University Wolfram Study Group Members: in addition to the authors:
P. Austin, MD (Surgery)
G. Earhart, PhD (Physical Therapy)
S. Eisenstein, PhD (Psychiatry)
J. Hoekel, DO, & L. Tychsen, MD (Ophthalmology)
T. Hullar, MD (Otolaryngology)
R. Karzon, PhD (Audiology & Comm. Sciences)
L. Manwaring, MS (Pediatrics)
A.R. Paciorkowski, MD (Neurology, URMC)
Y. Pepino de Gruev, PhD (Medicine)
K. Pickett, PhD (Physical Therapy, U Wisconsin)
J. Shimony (Radiology)
A. Viehoever, MD (Neurology)
N. H. White MD, CDE (Pediatrics)
F. Urano, MD, PhD (Endocrinology)
S. Ranck, MSW (Psychiatry)
B. Beato, BA (Psychiatry)
E. Bihun, MA (Psychiatry)
J.M. Koller, BSBME (Psychiatry)
H.M. Lugar MA (Psychiatry)
J. Rutlin, BS (Psychiatry)
K. Semenkovich, BA (Pediatric Endocrinology)
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
ANB collected WFS and control data, analyzed the data, and wrote the paper. AMR administered and assessed psychiatric interviews, and reviewed the manuscript. AB assisted in data management and analysis, and manuscript preparation. AA and TD collected control and WFS data, respectively, assisted in data management, and reviewed the manuscript. BAM supervised collection of WFS clinical data and reviewed the manuscript. TH designed the experiments, supervised the research, assisted with data analysis, and reviewed/edited the manuscript. All authors read and approved the final manuscript.