Bischoff et al. Orphanet Journal of Rare Diseases (2015) 10:66 DOI 10.1186/s13023-015-0282-1

RESEARCH

Open Access

Selective cognitive and psychiatric manifestations in Wolfram Syndrome Allison N. Bischoff1, Angela M. Reiersen1, Anna Buttlaire1, Amal Al-lozi1, Tasha Doty1, Bess A. Marshall2,3, Tamara Hershey1,4,5* and Washington University Wolfram Syndrome Research Group

Abstract Background: Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormalities, and neurodegeneration, but has been less clearly linked to cognitive, sleep, and psychiatric abnormalities. We sought to determine whether these abnormalities are present in children, adolescents, and young adults with WFS compared to age- and gender-matched individuals with and without type 1 diabetes using standardized measures. Methods: Individuals with genetically-confirmed WFS (n = 19, ages 7–27) were compared to age- and gender- equivalent groups of individuals with type 1 diabetes (T1DM; n = 25), and non-diabetic healthy controls (HC: n = 25). Cognitive performance across multiple domains (verbal intelligence, spatial reasoning, memory, attention, smell identification) was assessed using standardized tests. Standardized self- and parent-report questionnaires on psychiatric symptoms and sleep disturbances were acquired from all groups and an unstructured psychiatric interview was performed within only the WFS group. Results: The three groups were similar demographically (age, gender, ethnicity, parental IQ). WFS and T1DM had similar duration of diabetes but T1DM had higher HbA1C levels than WFS and as expected both groups had higher levels than HC. The WFS group was impaired on smell identification and reported sleep quality, but was not impaired in any other cognitive or self-reported psychiatric domain. In fact, the WFS group performed better than the other two groups on selected memory and attention tasks. However, based upon a clinical evaluation of only WFS patients, we found that psychiatric and behavioral problems were present and consisted primarily of anxiety and hypersomnolence. Conclusions: This study found that cognitive performance and psychological health were relatively preserved WFS patients, while smell and sleep abnormalities manifested in many of the WFS patients. These findings contradict past case and retrospective reports indicating significant cognitive and psychiatric impairment in WFS. While many of these patients were diagnosed with anxiety and hypersomnolence, self-reported measures of psychiatric symptoms indicated that the symptoms were not of grave concern to the patients. It may be that cognitive and psychiatric issues become more prominent later in life and/or in later stages of the disease, but this requires standardized assessment and larger samples to determine. In the relatively early stages of WFS, smell and sleep-related symptoms may be useful biomarkers of disease and should be monitored longitudinally to determine if they are good markers of progression as well. Trial Registration: Current Clinicaltrials.gov Trial NCT02455414. Keywords: Wolfram syndrome, Cognition, Psychiatry, Behavior, Development, Diabetes mellitus

* Correspondence: [email protected] 1 Department of Psychiatry, Washington University School of Medicine, Campus Box 8225, 4525 Scott Avenue, 63110 St. Louis, MO, USA 4 Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA Full list of author information is available at the end of the article © 2015 Bischoff et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Bischoff et al. Orphanet Journal of Rare Diseases (2015) 10:66

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 midadulthood [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.

Page 2 of 11

Methods Participants WFS

WFS patients were identified through the Washington University International Wolfram Syndrome Registry and were participants in a longitudinal natural history study (Washington University Wolfram Syndrome Research Clinic) involving annual data collection over 5 years. For enrollment in the Research Clinic, patients had to be age 30 or younger and have genetically confirmed WFS (mutations of the WFS1 gene), or diabetes mellitus and optic atrophy diagnoses before age 18. Subsets of these data have been analyzed to answer other questions [8, 10]. For this paper, we analyzed data from the 2013 clinic because that year’s clinic used a wider variety of cognitive, psychiatric, and behavioral measures and had a larger and more diverse patient sample than previous years. Controls

The comparison groups consisted of individuals with type 1 diabetes (T1DM) and non-diabetic healthy controls (HC). The T1DM group was recruited through Washington University’s Pediatric Diabetes Clinic at St. Louis Children’s Hospital and Washington University School of Medicine in St. Louis. All T1DM were clinically diagnosed with T1DM based on disease presentation, physical exam, medical history, and family history. T2DM and monogenic DM were ruled out based on physical exam and personal and family history based on the guidelines established by the American Diabetes Association. The HC group was recruited through the community, or were siblings of participants in the T1DM group. Exclusion criteria included self-reported psychiatric or neurological diagnoses, the use of psychoactive medications, contraindication to MRI, and A, p.W540X

3

8

c.1230_1233delCTCT, p.Val412fsX440

c.1243_1245delGTC, p.Val415del

3

7

c.2002C>T; p.Q668X

c.2002C>T; p.Q668X

4

10

c.739_740delTT, p.Phe247fsX251

c.1243_1245delGTC, p.Val415del

5

10

c.1251_1252delCTinsG; c.1885C>T; p.Arg629Trp p.Phe417Leufsx25

5

17

c.739_740delTT, p.F247Cfs*5

c.1243_1245delGTC, p.V415del

5

15

c.599 T>C; p.L200P

c.695G>C; p.R232P

5

5

c.599delT; p.L200fs286Stop

c.2254G>T; pE752Stop

5

6

c.1230_1233delCTCT; p.Val412fs440Stop

c.1243_1245delGTC: p.Val415del

5

No dx

c.739_740delTT, p.F247Cfs*5

c.1243_1245delGTC, p.V415del

6

7

c.817G>T; P.E273X

c.1839G>A; p.W613X

6

9

c.2648del4; p.F883fs

None identified

7

7

c.320G>A; p.G107E

c.1882C>T; p.R629W

7

8

c.376G>A; p.A126T

c.1838G>A;p.W613X

7

7

c.376G>A; p.A126T

c.1838G>A;p.W613X

13

13

c.1240_1242delTTC; p.F414del

c.1689_1694delCTTCCT; p.F564del;p.L565del

14

12

c.605A>G; p.E202G

c.631G>A; p.D211N

No dx

5

c.2339G>C, p.Gly780Ala

c.2452C>T, p.Arg818Cys

DM diabetes mellitus, OA optic atrophy, No dx No diagnosis in 2013

Parent IQ estimate

p = 0.02), with the WFS group performing better (remembering more words after a 20 min delay) compared to both the T1DM (p = 0.02) and HC groups (p = 0.01).

The average parent WTAR verbal intelligence score did not differ across groups (F2, 49 = 1.31, p = 0.28).

Attention and impulsivity

There was no main effect of group for VIQ (F2, 59 = 0.36, p = 0.70) or SR standard score (F2, 64 = 2.63, p = 0.08). On a trend level, HC performed better on SR than T1DM. WFS did not differ from either T1DM or HC.

Groups did not differ on CPT Hit Reaction Time (F2, 60 = 1.33, p = 0.27). However, there was a main effect of group on CPT Detectability (F2, 60 = 3.15, p = 0.05) with the WFS group showing better attentiveness and lower rates of impulsivity compared to the T1DM group (p = 0.02), but not to HC group (p = 0.12).

Memory

Smell identification

Groups differed at a trend level on LNS (F2, 59 = 2.94, p = 0.06; T1DM > WFS > HC), but did not differ on DS (F2, 57 = 1.33, p = 0.27). Groups also differed at a trend level on CVLT short-term memory (F2, 58 = 2.72, p = 0.07; WFS > T1DM > HC). In addition, there was a main effect of group on CVLT long-term memory (F2, 58 = 4.01,

Groups differed on UPSIT raw score (F2, 63 = 9.38, p < 0.001), with the WFS group scoring lower than both the T1DM (p < 0.001) and HC groups (p < 0.001) (Fig. 1). Upon reviewing the UPSIT raw score data, we identified 3 older WFS patients that were much more impaired than other patients. We analyzed the data

Verbal and spatial intelligence

Bischoff et al. Orphanet Journal of Rare Diseases (2015) 10:66

Page 6 of 11

Table 3 Cognitive assessment adjusted means (±S.E.) Normative average

WFS

T1DM

p

HC

N

M

N

M

N

M

100

14

104.1 ± 2.5

21

105.3 ± 2.0

18

109.2 ± 2.2

0.28

VIQ

100

14

111.8 ± 3.5

25

108.2 ± 2.6

24

108.8 ± 2.7

0.70

Spatial relations scaled scorec

100

17

107.1 ± 2.3

25

104.6 ± 1.9

25

110.7 ± 1.9

0.08

L-N sequencing scaled score

10

14

11.1 ± 0.7

25

12.1 ± 0.6

24

10.2 ± 0.6

0.06

Digit span scaled scorec

10

14

12.1 ± 0.9

25

10.9 ± 0.7

22

12.4 ± 0.7

0.27

CVLT short delay recall z-score

0

14

0.6 ± 0.2

23

0.1 ± 0.2

24

−0.1 ± 0.2

0.07

CVLT long delay recall z-scorec

0

14

0.7 ± 0.2a,b

23

0.0 ± 0.2

24

−0.1 ± 0.2

0.02*

CPT hit reaction t-score

50

13

39.2 ± 2.5

25

38.8 ± 1.8

25

42.8 ± 1.8

0.27

CPT detectability t-scored

50

13

48.1 ± 2.7b

25

56.3 ± 1.9

25

53.3 ± 1.9

0.05*

25

31.0 ± 1.2

24

30.1 ± 1.2

Selective cognitive and psychiatric manifestations in Wolfram Syndrome.

Wolfram Syndrome (WFS) is known to involve diabetes mellitus, diabetes insipidus, optic nerve atrophy, vision loss, hearing impairment, motor abnormal...
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