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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 6  |  Page : 1224-1231
Neurocognitive functions and behavioral profiles in children with nephropathic cystinosis

1 Department of Pediatrics-Center of Pediatric Nephrology and Transplantation, Cairo University, Cairo, Egypt
2 Department of Pediatrics-Center of Pediatric Nephrology and Transplantation, Cairo University; Egyptian Group for Orphan Renal Diseases, Cairo, Egypt
3 Department of Psychiatry, Cairo University, Cairo, Egypt

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Date of Web Publication10-Nov-2014


Children with nephropathic cystinosis (NCTN) have evidence of defective intellec­tual functions and behavioral disorders. This prospective study was performed to detect the cognitive dysfunctions in patients with this rare hereditary lysosomal storage disease, define their behavioral phenotypes, and study the findings on magnetic resonance imaging (MRI) of the brain. Thirteen patients with confirmed diagnosis of cystinosis (mean age ± SD 5.9 ± 3.0, range 1.5 - 12 years) were subjected to the Stanford Binet test, Porteus Maze test, Child Behavior Checklist, and MRI brain. Thirteen age- and sex-matched children served as the control subjects (mean age ± SD 5.9 ± 2.9, range 1.7 - 12 years). The intelligence quotient (IQ) was significantly lower in patients with cystinosis (P <0.001), with a significant defect in verbal (language, memory, and compre­hension) and non-verbal abilities (visual perception and visiospatial and motor performance). A discrepancy between both abilities was detected - the non-verbal ability being lower; however, it did not reach statistical significance. Furthermore, analysis revealed the visiospatial ability to be significantly lower compared to the visual perception. In comparison to healthy controls, children with NCTN had evidence of increased incidence of behavioral problems, mainly social (P = 0.023). An MRI of the brain revealed varying degrees of atrophic changes in seven patients. Patients with NCTN need a wider scope of attention and care, encompassing not only the metabolic multisystem derangement, but also the neuropsychological impairment in the context of multidisciplinary management. This approach is crucial in formulating comprehensive plans for social and educational rehabilitation.

How to cite this article:
Aly R, Makar S, Bakri AE, Soliman NA. Neurocognitive functions and behavioral profiles in children with nephropathic cystinosis. Saudi J Kidney Dis Transpl 2014;25:1224-31

How to cite this URL:
Aly R, Makar S, Bakri AE, Soliman NA. Neurocognitive functions and behavioral profiles in children with nephropathic cystinosis. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2020 Apr 5];25:1224-31. Available from: http://www.sjkdt.org/text.asp?2014/25/6/1224/144256

   Introduction Top

Infantile nephropathic cystinosis (NCTN) is an autosomal recessive lysosomal storage disease, caused by a defect in CTNS gene coding for cystinosin, [1] a lysosomal carrier protein resul­ting in intralysosomal cystine accumulation throughout the whole body system, with dete­rioration of function. The kidney is the first organ to be involved with the resultant renal Fanconi syndrome, at about six months of age, [2] associated with growth failure and prog­ressive decline in the glomerular filtration rate (GFR) that may end in renal failure. Diagnosis is ascertained by Corneal Cystine Crystal Scoring (CCCs) and the measurement of cystine in the leukocytes. The treatment falls into two categories; supportive treatment and specific therapy with cysteamine, which effec­tively depletes the cystine. [3]

With the advent of treatment, the multi-sys­temic nature of the disease has been empha­sized and the life expectancy increased. This has allowed studying of the neurological, cog­nitive, and behavioral functions of such individuals. [4],[5] Intellectual disorders and behavioral dysfunction have been observed in children with NCTN in the previous studies; however, the cause of such disorders is not yet known. [4],[5]

This study was performed to determine the cognitive profile and behavioral characteristics of children with NCTN and to study the accompanying brain magnetic resonance imaging (MRI) findings as well.

   Materials and Methods Top

Thirteen pediatric patients with NCTN were enrolled in this study. The diagnosis of NCTN was confirmed in 11 cases by slit lamp exami­nation, which revealed the pathognomonic CCCs. The other two infants with negative slit lamp examination, having suggestive criteria of NCTN, were diagnosed by the presence of a high leukocyte cystine assay. Thirteen age-and sex-matched healthy children served as the control subjects.

The study cases were recruited from the Inhe­rited Renal Diseases Clinic, Center of Pediatric Nephrology and Transplantation (CPNT), Cairo University Children's Hospital. Patients who had uncontrolled hypothyroidism or were with a pre-existing neurodevelopmental dis­order were excluded from the study. Three ca­ses were with end-stage renal disease (ESRD) and on regular hemodialysis, while others had preserved renal functions. All the investi­gations were performed when the participants were in good balance. Most of the children were on cysteamine, on a dose ranging from 20 - 40 mg/kg/day, in four equally divided doses, at the time of the study, and all the children were taking electrolyte replacement supplements as well.

The control subjects had normal develop­mental and medical histories and were recrui­ted from the Outpatient Clinics of the Cairo University Children's Hospital, through physi­cian referrals. They were either brother/sister of a diseased child or having a common cold, tonsillitis or allergic rash. All the controls re­ported negative for present, past, or family history of renal diseases.

An informed written consent was taken from the patients' and controls' care providers prior to the study. The current study agreed with and was first approved by the Ethical Standards of the Committee on Human Experimentation, in the Center of Pediatric Nephrology and Trans­plantation (CPNT), Cairo University Children's Hospital, and then again received the approval of the Research and Scientific Committee of the General Pediatric Department, Cairo Uni­versity, and agreed with the Declaration of Helsinki and its revisions.

   Methods Top

The children with NCTN and the controls completed the Stanford Binet (SB) test, Porteus Maze test (PMT), while their parents com­pleted the Child Behavior Checklist (CBCL) questionnaire. Cognitive and behavioral tests were conducted in the Child Psychiatry Unit, Cairo University, for subjects of both the case and control groups. Brain MRI was performed only for patients with NCTN at the Radiology Department, Cairo University.


The SB test accurately assesses low-func­tioning, normal intelligence, and high functio­ning individuals. The test is suitable for chil­dren of age three years or above. Children less than three years were subjected to the Vineland test. The Arabic version of the SB test (second edition) was used for testing visual perception, performance (non-verbal scale), memory, language, and comprehension (verbal scale). [6]

The PMT is a non-verbal test of intelligence that measures the visuospatial and visuomotor coordination in children of age three years and above. It consists of a set of paper forms with drawn mazes of varying complexity. The subject has to trace paths in the maze with no back-tracking, and avoiding blind alleys and dead ends. [7]

The Arabic translated version of the Achenbach of the CBCL has been used for children aged four to twelve years. It is a well-standardized parental report questionnaire that has satisfactory validity and reliability. [8] The CBCL is a 113-item questionnaire rated on a scale between 0 and 2, where 0 = not true, 1 = somewhat or sometimes true, and 2 = very true or often true. From these items, the following nine behavioral problem scales were derived: withdrawn, somatic complaints, anxious/dep­ressed, social problems, thought problems, attention problems, delinquent behavior, aggres­sive behavior, and sexual problems. An inter­nalizing score is derived by combining scores from the withdrawn, somatic complaints, and anxious/depressed scales, and an externalizing score is derived by combining the scores of the delinquent behavior and aggressive behavioral scales. A total behavioral problems score is obtained by the addition of scores on all the nine behavioral problem scales. The raw scores have been translated to T scores, with scores above 70 indicating clinically significant Numerical data were summarized using means and standard deviations. Categorical data were summarized as percentages. Comparisons bet­ween cases and controls, with respect to nume­rical variables, were performed using the Mann-Whitney test, a non-parametric test equivalent to the t-test, for use when the sample size is small. Comparisons between the categorical data were performed using the chi-square or Fisher's exact test in view of the small sample size. Comparisons between visual perception and spatial and visuomotor perception were performed using the signed rank test, a non-parametric test equivalent to the paired t-test, in view of the small sample size. The Pearson correlation coefficient was used to measure the strength of association between the two nume­rical variables. All P-values were two-sided. P-values <0.05 were considered significant.

   Results Top

The NCTN and control participants were not significantly different in the demographic va­riables of age, sex, socioeconomic status, and schooling. Consanguinity was significantly higher among patients with NCTN (P = 0.018), while SDS for weight and height were significantly lower in the patients than in the control subjects (P <0.001).

Neuropsychological evaluation was achieved through a battery of investigations aimed at identifying the cognitive and behavioral phenotype of NCTN patients. The overall IQ, tested from SB as well as all subscales of the test (visual perception, comprehension, memory, and lan­guage and performance abilities), was signifi­cantly lower in the NCTN patients (all with P <0.001) [Table 1], [Table 2], and [Table 3].
Table 1: Basic characteristics of patients with cystinosis.

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Table 2: Scores in percent of different intellectual functions with their IQ in percent measured through the Stanford Binet Test, and the visuospatial function determined through the Porteus Maze Test.

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Table 3: Comparison between patients and controls: IQ and intellectual functions (by Stanford-Binet) and visuospatial and visual perceptual functions.

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Visuospatial ability and visuomotor coordi­nation, determined with the PM test, were sig­nificantly lower in the cystinotic patients than in the control group (P = 0.003) [Table 3], in which the most common part affected was the first one-third of the maze (P = 0.028). Although both were affected, visuospatial per­ception, on comparison, was found to be signi­ficantly lower than visual perception (P = 0.023).

As NCTN patients had evidence of existing verbal (74.3 ± 12.3) and non-verbal (72 ± 11.8) disabilities, further analysis revealed a discrepancy between both disabilities (2.2 ± 3.9), with non-verbal being insignificantly lower (P = 0.06).

A negative correlation was found between the GFR and both age at diagnosis and age at evaluation (r = -0.622, P = 0.023 and r = -0.584, P = 0.036, respectively), while GFR positively correlated with the IQ (r = 0.571, P = 0.042).

[Table 4] lists the mean T scores and the percentage of children who obtained a T score of 67 (a cutoff score) or above, for each of the scales, in each of the two groups. On com­parison of the NCTN group with the healthy control group, differences between the rates of the clinically significant scores were observed in the total problem behavior scale (P = 0.004), withdrawn (P = 0.03), somatic complaint (P = 0.019), anxious/depressed (P = 0.017), social problems (P <0.001), attention problems (P = 0.022), delinquent behavior (P = 0.015), aggressive behavior P = 0.028), internalizing (P = 0.008), and externalizing (P = 0.020). How­ever, there was no significant difference bet­ween the two groups in the thought problems (P >0.842).
Table 4: Mean and SD of the T scores of individuals clinically "at risk" (T score ≥ 67) on the CBCL scales for the study subjects.

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An MRI of the brain was performed on the 13 patients with NCTN, revealing atrophic brain changes, mainly cortical and to lesser extent central, in seven patients. In addition, other features such as skull diploe cavum sep­tum pellucidum and dysmyelination without atrophic changes were also seen.

   Discussion Top

This study focuses on the frequently over­looked neurocognitive and psychological assess­ment when dealing with cystinotic patients. Our results highlight the importance of early diagnosis, as it correlates with better esti­mated glomerular filtration rate (eGFR). The latter has also positively correlated with a higher IQ. Moreover, the longer the duration of the disease, the lower is the eGFR as well as the IQ. With regard to the aforementioned cor­relation established, to the best of our know­ledge, no study has found a correlation bet­ween IQ, disease severity, age at diagnosis, and age at evaluation, in patients with NCTN.

Contrary to our results, Spilkin et al have demonstrated that children with NCTN have a mean full IQ at the low end of the average range. Their overall cognitive functioning is comprised of average verbal abilities and low average non-verbal abilities. [9] Gustavo et al. have also reported that children with infantile NCTN have evidence of a visuospatial deficit on a background of normal intellectual and verbal skills. [10] This difference may be attri­buted to a lower socioeconomic status, lower schooling percentage, and interrupted cysteamine therapy, in our study patients.

Nevertheless, although our findings were dif­ferent from those in the earlier studies de­monstrating normal composite IQs on the Stanford-Binet Intelligence Scale scores, [5],[11] as well as average performance in the areas of language, [11] more recent studies have shown a significant alteration of performance (non-ver­bal) IQ. [12] Moreover, Gustavo et al also found a defect in the performance of their patients, very similar to ours. [10] Meanwhile, William et al demonstrated a significantly lower IQ in 15 patients compared to the controls, where the most affected item was spelling, [13] while Ballantyne et al reported that the performance of children with NCTN was significantly lower on tests of arithmetic and spelling than the controls. Also, the deficient performance of patients with NCTN compared to the controls was demonstrated on tasks involving spatial relations [5] and visuomotor skills. [14]

In the current study, both visuospatial and visual perceptual abilities of the patients were defective, with the first being significantly lower. Although this is consistent with the fin­dings of Gustavo et al, [10] Trauner et al reported that children with NCTN performed signi­ficantly more poorly on the visuospatial and visuomotor measures than the controls, where­as, the visual perceptual skills remained intact. [15],[16] Recently, Spilkin et al found that the visual learning and memory impairment in cystinosis may result from difficulty with pro­cessing visual information quickly. On increa­sing the exposure time for each visual stimulus (from 1-3 seconds), the patients were able to perform at the same level as controls. [17] In our series, the CBCL results demonstrated a significantly higher total behavioral problem score in patients than in controls, most particu­larly in social and attention problems. Items of the social problems scale were more com­monly reported in the NCTN patients than in the control group. [10]

The definite cause of the observed cognitive deficit is uncertain. Different explanations are hypothesized ranging from the direct effect of CTNS gene mutation on the developing brain in utero causing structural or functional altera­tion, or the accumulation of cystine progressively during infancy and childhood, [9],[16] and eventually, the effect of the emerging uremia on cognitive dysfunction. In this study, cogni­tive deficits were seen in NCTN cases with normal GFR and no evidence of severe meta­bolic dysfunction, making uremia unlikely to be an explanation for the observed deficits. If cumulative cystine deposition during child­hood is responsible for the cognitive diffe­rences observed in subjects with NCTN, it might be expected that young children, espe­cially those treated early with cysteamine would not demonstrate such cognitive profiles. Recent studies, including ours, support the first hypothesis. where the cognitive deficit would most likely be present early in life due to the effect of the mutated gene. [16],[17]

Brain MRI results demonstrated atrophic changes of variable degrees in seven patients. The atrophic brain changes were predomi­nantly cortical and to a lesser extent, central. Nichols et al found higher results where 91% of the pediatric patients had cortical atrophy. [8],[18] Our MRI findings did not correlate with the age at diagnosis or the start of cysteamine therapy. The same brain atrophic changes were found in a 12-year-old female, with a delayed diagnosis at six years of age, having mild mental retardation (IQ = 58) and also found in a 1.7-year-old male, having a below average IQ of 88, who was diagnosed early at six months of age and in whom cysteamine therapy was begun immediately after diagnosis. Although, no relation between the age at diagnosis, cysteamine initiation, and structural brain alteration was found, the num­ber of patients in the current study was too small and it needs further consolidation. MRI studies of children and adults with NCTN demonstrate, primarily, abnormalities of the white matter, [19],[20] while one limited retrospec­tive study showed a reversal of brain com­puted tomography scan abnormalities and resolution of the neurological symptoms in two out of the four patients treated with cysteamine over a period of some months to years. [20]

   Conclusion Top

The approach to the management of NCTN patients should encompass the metabolic, phy­sical, as well as the psychological derange­ments present in this systemic disease, through multidisciplinary management; this would help in formulating comprehensive plans for social and educational rehabilitation.

Conflict of interest: None

   References Top

Town M, Jean G, Cherqui S, et al. A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. Nat Genet 1998;18:319-24.  Back to cited text no. 1
Gahl WA, Thoene JG, Schneider JA. Cystinosis: A disorder of lysosomal membrane transport. In Scriver CR, Beaud, Sly WS, Valle D, eds. The metabolic & molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill; 2001. p. 5085-108.  Back to cited text no. 2
Gahl WA, Reed GF, Thoene JG, et al. Cysteamine therapy for children with nephropathic cystinosis. N Engl J Med 1987;316: 971-7.  Back to cited text no. 3
Trauner DA, Chase C, Ballantyne A, Tallal P, Schneider J. Patterns of visual memory dys­function in children with cystinosis. Ann Neurol 1989;26:436.  Back to cited text no. 4
Trauner DA, Chase C, Scheller J, Katz B, Schneider JA. Neurologic and cognitive defi­cits in children with cystinosis. J Pediatr 1988; 112:912-4.  Back to cited text no. 5
Ahmed and Meleka. Stanford Binet Test of Intelligence, 2nd ed. Cairo: Dar Al Nahda Al-Massreyah; 1968.  Back to cited text no. 6
Porteus SD. Porteus Maze Test. Fifty years application. New York: Psychological Corpo­ration; 1965.  Back to cited text no. 7
Achenbach TM. Manual for the Child Beha­vior Checklist 4-18. Burlington, VT: Depart­ment of Psychiatry, University of Vermont; 1991.  Back to cited text no. 8
Spilkin AM, Ballantyne AO, Babchuck LR, Trauner DA. Non-verbal deficits in young children with a genetic metabolic disorder: WPPSI-III performance in cystinosis. Am J Med Genet Part B Neuropsychiatr Genet 2007; 144B:444-7.  Back to cited text no. 9
Delgado G, Schatz A, Nichols S, Appelbaum M, Trauner D. Behavioral profiles of children with infantile nephropathic cystinosis. Dev Med Child Neurol 2005;47:403-7.  Back to cited text no. 10
Nichols SL, Press GA, Schneider JA, Trauner DA. Cortical atrophy and cognitive perfor­mance in infantile nephropathic cystinosis. Pediatr Neurol 1990;6:379-81.  Back to cited text no. 11
Ulmer FF, Landolt MA, Vinh H, et al. Intellectual and motor performance, quality of life and psychological adjustment in children with cystinosis. Pediatr Neurol 2009;7:1371-8.  Back to cited text no. 12
Williams BL, Schneider JA, Trauner DA. Global intellectual deficits in cystinosis. Am J Med Genet 1994;49:83-7.  Back to cited text no. 13
Scarvie KM, Ballantyne AO, Trauner DA. Visuomotor performance in children with infantile nephropathic cystinosis. Percept Mot Skills 1996;82:67-75.  Back to cited text no. 14
Ballantyne AO, Trauner DA. Neurobehavioral consequences of a genetic metabolic disorder: Visual processing deficits in infantile nephropathic cystinosis. Neuropsychiatry Neuropsychol Behav Neurol 2000;13:254-63.  Back to cited text no. 15
Trauner DA, Spilkin AM, Williams J, Babchuck L. Specific cognitive deficits in young chil­dren with cystinosis: Evidence for an early effect of the cystinosin gene on neural func­tion. J Pediatr 2007;151:192-6.  Back to cited text no. 16
Spilkin AM, Ballantynea AO, Traunera DA. Visual and verbal learning in a genetic meta­bolic disorder. Neuropsychologia 2009;47: 1883-92.  Back to cited text no. 17
Gipson DS, Duquette PJ, Icard PH, Hooper SR. The central nervous system in childhood chronic kidney disease. Pediatr Nephrol 2007; 22:1703-10.  Back to cited text no. 18
Hodge BL, Hesselink JR, Trauner DA. MRI study of white matter changes in cystinosis. Society Neurosci Abstr 1992;18:333.  Back to cited text no. 19
Broyer M, Taete MJ, Guest G, Berthaelaemae JP, Labrousse F, Poisson M. Clinical poly­morphism of cystinosis encephalopathy. Re­sults of treatment with cysteamine. J Inherit Metab Dis 1996;19:65-75.  Back to cited text no. 20

Correspondence Address:
Dr. Samuel Makar
Department of Pediatrics-Center of Pediatric Nephrology and Transplantation, Cairo University, Cairo
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DOI: 10.4103/1319-2442.144256

PMID: 25394439

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  [Table 1], [Table 2], [Table 3], [Table 4]


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