Accepted Manuscript

Swallowing dysfunction in patients with nephropathic cystinosis

A.E. van Rijssel, S. Knuijt, K. Veys, E. Levtchenko, M.C.H.

Janssen

PII: S1096-7192(18)31192-2
DOI: https://doi.org/10.1016/j.ymgme.2019.01.011
Reference: YMGME 6462
To appear in: Molecular Genetics and Metabolism
Received date: 29 December 2018
Revised date: 16 January 2019
Accepted date: 16 January 2019

Please cite this article as: A.E. van Rijssel, S. Knuijt, K. Veys, et al., Swallowing
dysfunction in patients with nephropathic cystinosis, Molecular Genetics and Metabolism,
https://doi.org/10.1016/j.ymgme.2019.01.011

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 ACCEPTED MANUSCRIPT

Swallowing dysfunction in patients with nephropathic cystinosis

AE van Rijssel1, S Knuijt2, K Veys3, E Levtchenko3, MCH Janssen1

1
Department of Internal Medicine, Radboud university medical center, Nijmegen, The
Netherlands
2
Department of Rehabilitation, Donders Institute for Brain, Cognition and Behaviour, Radboud
university medical center, Nijmegen, The Netherlands

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3
Department of Pediatrics & Department of Growth and Regeneration; University Hospitals
Leuven & University of Leuven, Leuven, Belgium

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Corresponding author:
Mirian Janssen MD PhD, Department of Internal Medicine, Radboud university medical center,
Nijmegen, The Netherlands, Huispost 463, Geert Grooteplein 10 6500 HB, PO BOX 9101
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Nijmegen, The Netherlands, E-mail: mirian.janssen@radboudumc.nl, Phone: +31-24-
3614430. Fax: +31-24-3668532
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Keywords: cystinosis, nephropathic, swallowing dysfunction, dysphagia?

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Abstract
Introduction – Nephropathic cystinosis is a rare autosomal recessive lysosomal storage
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disorder caused by mutations in the CTNS gene. Patients with nephropathic cystinosis suffer
not only from renal disease but have also other systemic complications like myopathy and
swallowing dysfunction. Dysphagia for solid food is mentioned in patients with cystinosis, but
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in clinical practice swallowing investigations are only performed when the patient has
complaints. The aim of this study was to explore the swallowing function in patients with
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cystinosis by use of the Test of Mastication and Swallowing Solids (TOMASS), and to compare
their performance with patients with myotonic dystrophy type 1 – a neuromuscular disease in
which dysphagia for solid food is a known problem.
Methods – 20 adult patients with cystinosis (11 men and 9 women, range 19-51 years) and 10
patients with myotonic dystrophy type 1 (5 men and 5 women, range 20-60 years) were
included. All cystinosis patients were treated with cysteamine.
Data of the two groups were compared with normative data using independent-samples t-tests.
In case the variables were not normally distributed, the non-parametric Mann-Whitney U-test
was used.
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Results – There was a significant difference in the number of bites, masticatory cycles,
swallows and total time between the normal values and cystinosis patients. The results of the
cystinosis patients were comparable to those of the patients with myotonic dystrophy.
Discussion and conclusion – Adult patients with cystinosis have significant dysphagia for solid
food. Clinicians treating these patients should be aware of this fact. The TOMASS can be
performed easily in clinical practice to investigate whether patients with cystinosis have
swallowing dysfunction. The swallowing dysfunction can now be diagnosed by use of a non-
invasive, very simple, non-harmful test. It can be discussed whether this should be added to

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the regular care scheme of cystinosis patients in order to regularly follow-up swallowing
function.

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Introduction
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Nephropathic cystinosis is a rare autosomal recessive disease caused by mutations in the
lysosomal cystine transporter cystinosin encoded by the CTNS gene. The disease is
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characterized by lysosomal cystine accumulation throughout the body. Most children present
during the first year of life with generalized proximal tubular dysfunction (renal Fanconi
syndrome). If left untreated, the disease progresses towards end-stage renal disease around
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the age of 10 years. The advent of renal replacement therapy and cysteamine allowed
cystinosis patients to survive into adulthood.
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Cystinosis is treated by administration of the cystine-depleting agent cysteamine, which

slows down the progression of renal failure and prevents the development of extra-renal
complications. Treatment with cysteamine should be initiated as early as possible and
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continued lifelong, even after kidney transplantation in order to protect extrarenal organs.
Life expectancy of cystinosis patients has substantially improved and is now above 50 years
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[1]. Despite treatment with cysteamine numerous extrarenal manifestations of the disease
occur, affecting eyes, endocrine organs, gastrointestinal tract, central and peripheral nervous
systems and muscles.
Dysphagia for solid food was mentioned previously in patients with cystinosis [2,3]. Both
pharyngeal and oral dysfunction were observed and have been attributed to muscle
dysfunction.
In 2017, the Test of Mastication and Swallowing Solids (TOMASS,) was published and
validated [4]. The aim of this study was to objectify the problems of solid food ingestion in
patients with cystinosis, using the TOMASS. We compared the results with normative data
and a patient group in which dysphagia is a prominent symptom: myotonic dystrophy type 1
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(MD1). MD1 is part of a group of inherited disorders called muscular dystrophies [5]. It is a
multisystem disease, characterized by progressive myotonia (prolonged muscle contractions
after use) and muscle weakness. In MD1, follow-up of dysphagia by a speech-therapist is
usual care, while patients with cystinosis are hardly referred to speech-therapists [6].

Methods
Patients
20 patients with nephropathic cystinosis (11 men and 9 women, range 19-51 years) and 10

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patients with myotonic dystrophy type 1 (5 men and 5 women, range 21-66 years) were
included. Sex, age and body mass index were gathered as personal characteristics. All

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patients with cystinosis were treated with cysteamine. They reported no spontaneous
complaints of dysphagia.

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TOMASS
Patients were asked to eat a standardized cracker (Albert Heijn Basic), ‘as quickly as is
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comfortably possible’. The number of bites, masticatory cycles, swallows per cracker and
total time were registered. Before the start of the test, patients have to drink 150 ml water [4].
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In our patients, this was achieved by examining the swallowing speed (see next paragraph).
The normative data from 107 healthy adults between 20 and 70 years of age were derived
from the Dutch database which was used for the development of the TOMASS [4].
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Swallowing speed
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To test the swallowing speed, a timed test of swallowing was used [7]. Patients have to drink
150 ml of water as quickly as possible, but they have to take care and stop if difficulties arise.
The swallowing speed is supposed to be > 10 ml/sec. Below 10 ml/sec is an index of
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abnormal swallowing.
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Statistical analysis
We checked whether the variables were normally distributed using the Shapiro-Wilk test. In
case of normally distributed variables, data of the two patient groups were compared with
normative data using independent-samples t-tests. In case the variables were not normally
distributed, the non-parametric Mann-Whitney U-test was used. The significance of both
tests was set at p < 0.05.
IBM SPSS statistics 22 software (IBM, Chicago) was used to perform the statistical analysis.

Results
Cystinosis patients
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Table 1 shows the characteristics of the cystinosis patients. One patient was not able to
perform the TOMASS. The variables ‘bites’, ‘swallows’ and ‘total time’ were not normally
distributed. In Table 2, the TOMASS results of the cystinosis patients are compared to the
healthy controls. It demonstrates that there is a significant difference in the number of bites
(p < 0.01), masticatory cycles (t = -6.08, p < 0.01), swallows (p < 0.01) and total time (p <
0.01) between the normal values and healthy controls.
The mean swallowing speed was 24.21 ml/sec, which is normal. Looking at individual
patients, only two patients (17 and 18) scored below 10 ml/sec .

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Myotonic dystrophy
In MD1, the variable ‘total time’ was not normally distributed. In Table 2, the results of the

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patients with myotonic dystrophy are compared to the healthy controls. There is a significant

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difference in the number of masticatory cycles (t = -3,71), p < 0.01), swallows (t = -3.30, p <
0.01) and total time (p < 0.01) between the normal values and myotonic dystrophy patients.
The was no significant difference between the two groups regarding the number of bites (t = -
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0.35, p = 0.73).
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Cystinosis vs Myotonic dystrophy

Finally, we compared both patient groups. Only the variable ‘masticatory cycles’ was tested
parametrically. There were no significant differences between the two patient groups
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regarding the number of bites (p = 0.18), masticatory cycles (t = 1.01, p = 0.32), swallows (p
= 0.43) and total time (p = 0.84).
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Table 1: Characteristics of the cystinosis patients

Patient Age Sex Length Weight BMI Kidney Daily
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(yr) (m/f) (cm) (kg) (kg/m2) transplantation cysteamine

(yes/no) dose
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mg/kg
1 25 m 163 57,4 21,6 yes 34,0
2 29 m 169 69,4 24,3 yes 39,1
3 51 f 155 50,2 20,8 yes 30,0
4 18 m 176 59,6 19,4 no 40,2
5 32 m 176 68 21,9 yes 61,8
6 28 m 178 54 17 no 33,3
7 24 f 155 46,8 19,5 yes 43,2
8 26 f 161 58 22,4 yes 33,6
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9 27 f 150 44,6 20 yes 30,1

10 22 m 150 49,4 21,8 no 36,0
11 22 m 170 55,6 19,2 yes 42,8
12 21 m 171 57,6 19,7 yes 36,7
13 38 m 158 62,3 24,9 yes 28,6
14 19 m 184 75,4 22,2 no 50,0
15 24 f 159 53,6 21,2 yes 25,5
16 41 f 150 36,2 16,1 yes 29,2

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17 34 f 140 53 27 yes 30,2
18 43 f 151 59,4 25,5 yes 25,8

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19 37 f 147 67 31 yes 9
20 28 m 168 68 24,1 yes 34,2

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Table 2: TOMASS results of the healthy adults, cystinosis patients and MD1 patients. The p-
values indicate the difference between the patient group and healthy adults.
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Healthy adults Cystinosis MD1

Mean (SD) Mean (SD) Mean (SD)
p-value p-value
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Bites (n) 1.97 (1.11) 2.74 (1.20) 2.10 (0.99)

p<0.01 p=0.73
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Masticatory cycles 34.39 (11.78) 57.53 (28.11) 49.30 (15.69)

(n)
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p<0.01 p<0.01
Swallows (n) 1.65 (0.87) 3.26 (1.59) 2.60 (0.84)
p<0.01 p<0.01
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Total time (sec) 28.53 (10.80) 58.77 (28.89) 53.10 (15.85)

p<0.01 p<0.01

Discussion and conclusion

Since patients with nephropathic cystinosis are currently treated with cysteamine, they have
a better life expectancy [8,9]. When they become older, more extra–renal complications
occur. One of these complications is swallowing dysfunction. In this study we demonstrated
with a simple non-invasive test that cystinosis patients without clear complaints of dysphagia
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need more bites, more mastication cycles, more swallows and more time to eat a small
cracker. In fact, they score equally to patients with MD1, in which dysphagia is a prominent
symptom. In general, cystinosis patients have no difficulties in swallowing liquids.
In cystinosis, one of the long-term major complications is myopathy, beginning with
weakness and atrophy of the hand, extending to the upper extremities, the muscles involved
swallowing, thoracic muscles and eventually the entire body’s musculature. It was
demonstrated that the frequency of myopathy is related to the duration of cysteamine
therapy, but it is not known whether this represents a delay in onset of the myopathy or a

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complete prevention of it [10].
Clinicians taking care of patients with cystinosis should be aware of swallowing dysfunction

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in these patients. The TOMASS is the only non-invasive clinical tool to quantify solid food
ingestion. It is supposed to identify especially problems in the oral (bolus preparation) and

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pharyngeal (pharyngeal pressure generation) stages of swallowing. Radiologic barium
swallowing examination or videofluoroscopy is still seen as the gold standard for dysphagia
assessment, but these examinations are more time consuming, more expansive and use
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radiation and contrast fluid. The TOMASS can be performed easily in clinical practice to
investigate whether patients with cystinosis have swallowing dysfunction. The swallowing
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dysfunction can now be diagnosed by use of a non-invasive, very simple, non-harmful test. It
can be discussed whether this should be added to the regular care scheme of cystinosis
patients. We can regularly follow-up, even from relatively young ages, because the TOMASS
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is also validated in children [11]. If patients experience problems performing the TOMASS,
referral to a speech therapist should be considered for education and awareness, to correct
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inadequate compensations and to learn to apply adequate compensations, like adjustments

of food consistencies, consistently swallowing a bolus twice (double swallow) or drinking
during or after a meal.
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References
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