Received: 9 May 2019

Revised: 14 July 2019

Accepted: 17 July 2019

DOI: 10.1002/jmd2.12073

RESEARCH REPORTIntellectual functioning in alpha-mannosidosis
Sara S. Cathey1| Sara M. Sarasua1,2| Richard Simensen1 | Katie Pietris3 |Gordon Kimbrell4 | David Sillence5 | Callum Wilson6 | Lucia Horowitz1
1

Greenwood Genetic Center, Greenwood,
South Carolina

2

Clemson University, School of Nursing,
Clemson, South Carolina

3

InSite Solutions, Washington, District ofColumbia

4

Private Practice, Mt Pleasant, South
Carolina

5

Genetic Medicine, Westmead Hospital,
Westmead and Genomic Medicine, Facultyof Medicine and Health, University ofSydney, New South Wales, Australia

6

Starship Children's Hospital, Auckland,
New ZealandCorrespondence
Sara S. Cathey, MD, Greenwood Genetic
Center, 3520 W. Montague Ave, Suite
104 N. Charleston, SC 29418.
Email: scathey@ggc.org

Abstract
Alpha-mannosidosis is a rare inherited metabolic disorder (OMIM #248500) caused by mutations in the enzyme α-mannosidase encoded by the gene MAN2B1.
Patients have distinct physical and developmental features, but only limited information regarding standardized cognitive functioning of patients has been published. Here we contribute intellectual ability scores (IQ) on 12 patients with alphamannosidosis (ages 8-59 years, 10 males, 2 females). In addition, a pooled analysis
was performed with data collected from this investigation and 31 cases obtained
from the literature, allowing a comprehensive analysis of intellectual functioning inthis rare disease. The initial and pooled analyses show that patients with alphamannosidosis have variable degrees of intellectual disability but show decline in
IQ with age, particularly during the first decade of life. Patients treated with hematopoietic stem cell transplantation tend to show stabilized cognitive abilities.
KEYWORDS
alpha-mannosidosis, glycoproteinoses, intellectual disability, IQ

Communicating Editor: Carla E. Hollak
Funding information
International Society for Mannosidosis andRelated Disorders; National Center for
Advancing Translational Sciences, Grant/Award Number: U54NS065768; National
MPS Society, Grant/Award Number: NA

1 | INTRODUCTION
Alpha-Mannosidosis (OMIM #248500) is caused by a genedefect in the enzyme α-mannosidase encoded by the gene
MAN2B1. The disorder is inherited in an autosomal recessive
manner. The condition is characterized by developmental delay
and intellectual disability, coarse facies, hearing impairment,
mild dysostosis multiplex, and immune deficiency. There is aspectrum of severity but three types were described in the older
literature prior to genotyping. Those labeled with type 3 had

the most severe course with earliest onset and shortest survival.
We now know there is no clear genotype-phenotype correlation.1-4 All of our patients were symptomatic at diagnosis andwithin the first 2 years of life with concerns for hearing loss,
developmental delays or regression, and frequent infections.
Far fewer detailed clinical reports have been published on
patients with alpha-mannosidosis as compared to othergroups of lysosomal diseases with approved therapies suchas Pompe, Gaucher, Fabry, and the mucopolysaccharidosis(MPS) disorders. At the time of this writing, no approved

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original
work is properly cited.
© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
JIMD Reports. 2019;1–6.

wileyonlinelibrary.com/journal/jmd2

1

CATHEY ET AL.

2treatment is on the market in the United States of America.
However, hematopoietic stem cell transplant (HCT) has beenshown to positively impact developmental outcome in alphamannosidosis in several patients.5,6 More recently, enzyme
replacement therapy has been approved for treating the nonneuropathic features of the disease in the EU with orphan
drug designation.2,7,8
Reports on intellectual function in alpha-mannosidosis are
scarce. One set of measures of effectiveness of therapies is
impact on IQ. In this study, we measured IQ in 12 patients withalpha-mannosidosis to assess severity and changes with age.

2 | MATERIALS AND METHODS

Synopsis
Alpha-mannosidosis patients show rapid decline incognitive function during the first two decades of life.

2.4 | Statistical methods
Data were analyzed using the SAS software (Cary, North
Carolina, 2009) to perform linear regression and repeatedmeasures linear regression. A P-value less than .05 was considered statistically significant.

2.1 | Participants

3 | RESULTS

Twelve patients with alpha-mannosidosis were evaluated bylicensed and/or certified clinical or developmental psychologists. One patient had previously been treated with cord bloodtransplantation. Evaluations took place at the Greenwood
Genetic Center, South Carolina, in 2009 and 2012 and in
New Zealand and Australia in 2009.9 Patients were enrolled
in the study “Longitudinal Studies of the Glycoproteinoses,”with IRB approved protocol and consent. This data is from across-sectional component of the larger study.

3.1 | Analysis of cognitive abilities in newpatients

2.2 | Assessment
2.2.1 | Cognitive functioning
Patients were assessed with either the Kaufman-Brief Intelligence Test––2nd Edition (K-BIT-2),10 the Developmental
Assessment of Young Children (DAYC),11 or the Peabody
Picture Vocabulary Test––4th Edition12 depending on thepatient's age, severity of intellectual impairment, and fine
motor abilities. Scores on the K-BIT-2, DAYC, and PPVT-4
are presented as standard scores (mean = 100, SD = 15).
Values below 70 indicate cognitive impairment.

2.3 | Pooled data from the literature on
cognitive function
To better understand the changes in cognitive function withage in a larger sample size of this rare disease, the literature
was reviewed to identify case reports for a pooled analysis.
Literature-based data were only included in the pooled analysis if the age at measurement was provided and the IQ wasquantified rather than estimated. Fifteen publications withcognitive data on 31 patients were identified.5,6,13-25 The
data were analyzed separately for those who had and had notundergone HCT. The Table S2 includes the patient age, IQ,
and cognitive test instrument for patients identified in theliterature.

Twelve patients with alpha-mannosidosis (10 males, 2 females)
were evaluated in either 2009 or 2012 (Table 1, Table S1).
Patient ages at assessment ranged from 8 to 59 years withaverage age of 34 years. The youngest patient in this cohort
was the only patient who had undergone HCT and had a significantly higher IQ standard score of 95. Among theuntreated alpha-mannosidosis patients (ages 25-59 years), theaverage IQ was 37 (range 20-48, Figure 1). Using simple linear regression, a cross-sectional decline of 0.74 IQ points per
year of age was observed across the ages of 25 to 59 years(P = .0426) in patients who were not treated with HCT.
Removing the oldest patient, potentially an outlier, made theage range 25 to 41 years and did not affect the estimated slopeof the regression line but it became nonsignificant (β = 0.76,
P = .3009). Medical records for patient 07 included four IQ
measurements over 19 years, documenting significant decline
in functioning. IQ was in the “low average range” before age
6, “borderline” at age 6 years, in the mildly intellectually disabled range (IQ = 57) at 19 years, and in the moderately disabled range at age 25 with IQ score of 40. Only the twoquantified IQ scores were utilized in data analysis.
Five of six patients with alpha-mannosidosis assessed with
the K-BIT-2 had higher Nonverbal than Verbal IQ scores
TABLE 1Age, gender, and IQ scores for 12 new patients withalpha-mannosidosis

FeatureTreated withhematopoietic stem celltransplantation (n = 1)

Untreated(n = 11)
Mean (range)

Gender

1 male9 males, 2 females

Age, years8

36.8 (25-59)

IQ standard score95

36.7 (20–48)

CATHEY ET AL.

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FIGURE 1

IQ by age for patientswith alpha-mannosidosis. Data points forindividuals with multiple evaluations(n = 15) are connected by a line. Patientsfrom the literature (n = 27) are represented
with circles and new patients (n = 11) arerepresented with triangles. See Section 2
for literature citations

indicating better visual than verbal problem-solving skills.
This discrepancy may be largely related to the hearing loss
commonly associated with alpha-mannosidosis. The DAYC
was administered to three patients (ages 36-40 years) whose
low functioning precluded use of the K-BIT-2. The weakest
subtest scores were physical and communication domains,with average age-equivalent scores of 9.7 and 22 months,
respectively. These individuals required wheelchairs, hadmoderate to severe hearing loss, and had limited speech. The
PPVT-4 was administered to two patients who were nonverbal. Both patients scored 20, the lowest standard score possible on this assessment.

3.2 | Pooled analysis of IQ change with age in
new and literature-based untreated patients
Twenty-seven untreated patients with measured IQ derived
from multiple instruments were identified in the literature(Figure 1). The literature patients were substantially younger(median age 8 years, range of 0.6-26 years) than the newpatients in our cohort (range 25-59 years). Serial measures
were available for 14 patients from the literature and 1 patientfrom our cohort (range of 2-6 IQ measures per patient). The
longitudinal data for these patients show greater declines in
the first decade of life with smaller decline in the second
decade. A pooled analysis of our cohort and all untreated literature patients (n = 38) was then performed. Because IQ
appears to decline more quickly in the first two decades oflife, the analysis was performed separately for patients underage 20 years and patients 20 years and older. For thoseunder age 20 years, using a repeated measures linear

regression model, IQ declines at a rate of 1.89 points per
year of age (P = .0007, intercept = 76.5). In the group aged
20 years and older, only one individual had a second measure so a standard linear regression model was used to estimate age-related cognitive decline in a cross-sectionalmanner. The decline in IQ with age after age 20 years is
0.56 IQ points per year of age (P = .0567, intercept = 64.7).

3.3 | Pooled analysis of changes in IQ with age
in patients treated with HCTThis study includes 1 new transplanted patient and 10 literature patients who had undergone transplantation (Figure 2,
Tables S1 and S2). IQ measures were available both preand post-transplantation for six of these patients. Transplantation was preceded by substantial declines in IQ. All four
patients transplanted before age 10 years showed gains or
stabilization in the borderline average to average range of IQ(IQ >70) post-transplant. The two patients transplanted afterage 10 years showed small losses in IQ post-transplant. Of
the five patients without serial measures, two had IQ in theborderline average to average range (IQ > 70) after transplantation. In the transplanted group, eight of 10 (80%)
patients ≤20 years of age had an IQ > 50 whereas 15 out of
27 (54%) had an IQ > 50 in the untransplanted group.

4 | DISCUSSION
Often the diagnosis of a rare disease is accompanied by a
medical prognosis, but families are equally interested in afunctional prognosis regarding expected levels of school

CATHEY ET AL.

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FIGURE 2

IQ by age for pooled
patients pre- and post-HCT. Data obtained
from the literature (n = 10) and the present
study (n = 1). Data points for individuals
with multiple evaluations are connected bya line. Six patients had pre-transplant IQ
measures, which are also included in
Figure 1

achievement and potential independence throughout thelifespan. We found IQ to vary widely among patients withalpha-mannosidosis with most, but not all, showing intellectual disability. Untreated patients showed a steep decline in
IQ before age 20 years, particularly during the first decadeof life, followed by a nonsignificant decline after age 20 inagreement with findings by Autio et al.15 Larger longitudinalstudies, preferably using a single standardized instrument,
are needed to elucidate the pattern of decline.
Borgwardt et al assessed cognitive profiles of 35 patients
between 6 and 35 years of age in a cross-sectional mannerusing the Leiter International Scale-Revised.26,27 Their crosssectional analysis used age-equivalent or developmental scores
rather than standardized IQ scores. Patients show positive cognitive development until age 10 to 12 years and then littlechange. Still, affected individuals fall increasingly further
behind their same-aged normal peers. This divergence fromsame-aged unaffected peers is consistent with our analysis,
which showed steep declines in IQ (an age-normed measure)in the first decade of life with tapering of declines in adulthood. Their patients had a similar range of IQ scores as ourcohort with a mean IQ of 42 and a range from 20 to 81, withmost patients being in the moderate level of intellectual disability. Borgwardt et al used age-equivalent and raw developmental scores which have the advantage of describing absolutechanges in cognitive development (positive, arrested, or
regression) rather than performance relative to same-aged normal peers.26 However, three advantages of using standardized
IQ measures as presented in the cohort here are the scores are
age-normed for comparison to typical peers, standardized IQ

scores are more frequently reported in the alpha-mannosidosis
literature, and these measures are stable in adulthood.

4.1 | Hematopoietic stem cell transplant
In this study, we report on cognitive scores of 11 patientswith HCT. IQ appears to stabilize after HCT, however, multiple post-transplant IQ measures were only available forthree patients, highlighting the need for future publications
on this topic. Newly diagnosed alpha-mannosidosis patientsare now routinely referred to transplantation centers, butpublished outcome data are still lacking and HCT carries
risk.5 Wall et al were the first to report stabilization ofneurocognitive function in an alpha-mannosidosis patient
treated with bone marrow transplantation.6 Over the last
15 years case reports and small series of patients treated withtransplantation have been published.5,13,18,24 Conditioning
regimens varied from patient to patient as did source of stem
cells (cord blood, bone marrow, peripheral blood stem cells)
and the types of donors (HLA matched or mismatched,related or unrelated to the patient). Follow-up measures areneeded for patients post-transplantation to confirm the maintenance or improvement in cognitive function long term.

4.2 | Strengths and limitations
An inherent limitation of studies of individuals affected witha severe rare disease is that disability level may impact participation in such studies. Because this disorder is uncommon and severely affected patients may have shortened lives
or difficulties traveling, large cohorts are difficult toCATHEY ET AL.

assemble. This concern was addressed by testing a relatively
large number of patients (n = 12) and pooling data obtained
from the literature to create an even larger study size.
Another limitation in assessing age-related changes is thereliance on cross-sectional rather than longitudinal data. Additional longitudinal assessments using a single standardized
instrument will allow for better delineation of the trajectory of
decline, whether it be linear, logarithmic, or multiphasic. The
literature often uses broad qualitative descriptors (eg, impaired+ or −, “mild,” “moderate”) which obscure the disease progression. A strength of this study was the use of quantitative,
measured IQ scores. In future longitudinal studies, use of ageequivalent scores may be useful for describing cognitive
developmental patterns.

5 | CONCLUSION
Alpha-mannosidosis is a complex, progressive disorder. The
data presented here provide benchmarks of cognitive functioning in a large cohort of patients with alpha-mannosidosis. The
natural history of untreated disease is rapid decline in cognitive
function during the first two decades of life. Early HCT
appears to stabilize cognitive functioning but timing,
preconditioning regimens, and preferred stem cell source havenot been fully defined. Too often, assessments of cognitive
functioning abilities are omitted from clinical reports, yet these
are as important as radiographs and echocardiograms when
considering disease progression and effectiveness of interventions. Future studies of alpha-mannosidosis should include
serial measures of cognitive function to provide useful information to patients, families, and clinicians who care for them.
ACKNOWLEDGMENTS
The authors are grateful to the patients and their families forparticipating in the research. Funding for the LongitudinalStudies of the Glycoproteinoses has been provided in part by
the patient advocacy groups International Society for
Mannosidosis and Related Disorders (ISMRD) and the
National MPS Society and the Lysosomal Disease Network.
The Lysosomal Disease Network (U54NS065768) is a part of
the NCATS Rare Diseases Clinical Research Network(RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through collaboration between NCATS, NINDS, and NIDDK.
C ON T R IB UT IO N S O F A UT H OR S
S.S.C. designed and managed the study, interviewed andexamined patients, interpreted results, wrote the article, andserves as guarantor. S.M.S. managed data, performed statistical analysis, and wrote the article. R.S., K.P., G.K., D.S.,

5

C.W. performed psychological testing and approved the article. L.H. co-designed the study, performed psychologicaltesting, managed data, and wrote the article.

CO M P L IA NC E A ND E T H I CA L S T A ND AR D S
Sara S. Cathey, Sara M. Sarasua, Richard Simensen, Katie
Pietris, Gordon Kimbrell, David Sillence, Callum Wilson,
Lucia Horowitz declare they have no conflict of interest.

IN F O RM E D C ON S E N T
Written informed consent was obtained from the patient or
his/her legally authorized guardian(s) prior to participationin this study. The study was approved by the Institutional
Review Board of the Self Regional Health System.

AN IM A L R IG H T SThis article does not contain any studies with animal subjects performed by the any of the authors.

OR CI D
Sara S. Cathey https://orcid.org/0000-0002-5580-7683
Sara M. Sarasua https://orcid.org/0000-0002-1625-7404

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S UP P OR T I N G I NF OR M A T I ON
Additional supporting information may be found online in
the Supporting Information section at the end of this article.
Table S1 Data for 12 Patients with Alpha Mannosidosis
Intellectual Functioning in Alpha Mannosidosis.
Table S2 Alpha-Mannosidosis Patients from the LiteratureIntellectual Functioning in Alpha-Mannosidosis.
How to cite this article: Cathey SS, Sarasua SM,
Simensen R, et al. Intellectual functioning in alphamannosidosis. JIMD Reports. 2019;1–6. https://doi.
org/10.1002/jmd2.12073