Academic achievement in individuals with infantile nephropathic ...

Academic achievement in individuals with infantile nephropathic ...

American Journal of Medical Genetics (Neuropsychiatric Genetics) 74:157–161 (1997)Academic Achievement in Individuals WithInfantile Nephropathic CystinosisAngela O. Ballantyne, Kathleen M. Scarvie, and Doris A. Trauner*Departments of Neurosciences and Pediatrics, University of California, San Diego, School of Medicine,La Jolla, CaliforniaThe present study examined academic skillsin children and young adults with infantilenephropathic cystinosis. Cystinosis is a geneticmetabolic disorder in which the aminoacid cystine accumulates in various tissuesand organs, including the kidney, cornea,thyroid, and brain. Individuals with cystinosishave normal intelligence but subtle visualprocessing impairments. Subjects were19 children and young adults with cystinosisand 19 age-, sex-, and IQ-matched controls.All subjects had IQs within the normalrange. On a test of academic achievement,mean standard scores for cystinosis andcontrol subjects, respectively, were as follows:arithmetic 89.95 ± 13.77 vs. 102.16 ±9.62; spelling 90.68 ± 18.81 vs. 98.00 ± 10.96;reading 97.47 ± 15.59 vs. 98.58 ± 12.41. Multivariateanalysis of variance revealed a significantmain effect for Group (P = .009);there was no main effect for Sex, nor wasthere a Group x Sex interaction. Univariatefollow-up tests indicated that the cystinosisgroup performed significantly more poorlythan did controls on the arithmetic subtest(P = .001) and that there was a trend (P =.085) toward poorer performance by the cystinosisgroup on the spelling subtest. Regressionanalyses revealed no evidence of adevelopmental lag or deterioration of functionwith age. The visual processing deficitspreviously identified in these individualsmay underlie the academic difficulties observedhere. It is possible that both visualprocessing and academic difficulties mayreflect a common mechanism of selectivecortical damage by this genetic defect. Am.J. Med. Genet. 74:157–161, 1997.© 1997 Wiley-Liss, Inc.Contract grant sponsor: National Institutes of Health; Contractgrant number RO1 HD 23854; Contract grant sponsor: GeneralClinical Research Center; Contract grant number MO1 RR 00827.*Correspondence to: Doris A. Trauner, M.D., Division of PediatricNeurology, 0935, University of California, San Diego, LaJolla, CA 92093-0935. e-mail: dtrauner@ucsd.eduReceived 21 May 1996; Revised 26 August 1996© 1997 Wiley-Liss, Inc.KEY WORDS: cystinosis; WRAT-R; visualprocessing; autosomal recessive;neurogeneticsINTRODUCTIONCystinosis is an autosomal recessive metabolic disordercharacterized by defective transport of the aminoacid cystine out of lysosomes, and consequent cystinedeposition in various tissues and organs of the bodyincluding the kidney, cornea, and thyroid. There is alsoevidence of increased brain levels of cystine in childrenand adults with cystinosis [e.g., Ebbesen et al., 1976;Jonas et al., 1987; Levine and Paparo, 1982; Vogel etal., 1990]. Studies of the cognitive effects of cystinosissuggest specific visual processing deficits against abackground of normal intelligence [Nichols et al., 1990;Trauner et al., 1988, 1989; Wolff et al., 1989]. For example,individuals with cystinosis exhibit deficits ontasks involving complex visual processing and spatialrelations, but maintain intact skills in the areas of auditoryprocessing, auditory attention and memory, receptivelanguage, and basic visual perception [Trauneret al., 1989; Nichols et al., 1990]. There are severalpotential mechanisms by which these cognitive deficitscould occur. For example, early accumulation of cystinein the fetal brain could potentially alter brain development.Progressive accumulation of cystine in postnatallife might cause later alterations in cognitive or neurologicfunction. It is possible that both of these mechanismsmight be at work simultaneously.Personal communications from affected families indicatethat academic difficulties in individuals withcystinosis are a common concern, yet few studies haveaddressed this issue. Wolff et al. [1982] studied thepsychosocial and intellectual development of 12 Germanchildren with cystinosis. They found school performanceto be predominantly ‘‘average’’ or ‘‘normal’’according to school records and teachers’ impressions.No standardized measure was administered, however.Another study by Wolff et al. [1989] indicated that childrenwith cystinosis had ‘‘average’’ school performance,though no formal assessment of such was apparent.Ehrich et al. [1979] studied four children with cystinosis,all of whom had documented brain atrophy on CT.Despite their brain atrophy, the children’s school per-

158 Ballantyne et al.formance was ‘‘mainly average.’’ Williams et al. [1994]studied intellectual and academic function in familiesaffected by cystinosis and found that children with cystinosishad normal IQs, but that their IQs were significantlylower than those of their parents and siblings,suggesting an adverse effect of cystinosis on the nervoussystem. In addition, academic performance, particularlyin spelling, was poorer in children with cystinosisthan in their parents and siblings. The Williamset al. study, however, was specifically a family study(i.e., comparisons were made only among family members)and did not make comparisons to normal controlchildren or to normative standards.OBJECTIVEThe present study was undertaken to examine academicfunctioning, as assessed by the Wide RangeAchievement Test-Revised (WRAT-R) [Jastak andWilkinson, 1984], in individuals with cystinosis. TheWRAT-R assesses academic skills in the areas of arithmetic,spelling, and reading. The performance of thecystinosis subjects was compared to that of individually-matchedcontrol subjects, as well as to the normativestandards. In addition, the cystinosis subjects’ academicperformance at different ages was evaluated todetermine whether or not there were changes in performanceover time (e.g., improvement or decline). Achange over time could be indicative of either a developmentallag or a deterioration of cognitive function,whereas no change over time would suggest a staticdeficit.Normally developing controls were used as a contrastinggroup for several reasons. First, patients withcystinosis have previously been said to perform at normallevels in school, and they do not demonstrate severecognitive or intellectual deficiencies. Since theyare in age-appropriate classroom placements, the goalwas to determine whether subtle academic differencesmight be present despite the placement. Second, nomore suitable control group could be identified. For example,patients with other chronic medical conditionsare inappropriate controls because of 1) invasive treatmentsthat can affect the brain (e.g., radiation therapyfor leukemia), 2) secondary neurologic complications ofthe disease (e.g., chronic hypoxemia in cystic fibrosis),or 3) potential primary neurologic or cognitive effects ofthe underlying medical condition (e.g., Turner syndrome).In light of the anecdotal reports of academic difficulties,documented CNS involvement, and visual-spatialdifficulties in individuals with cystinosis, it was hypothesizedthat they would demonstrate difficulty in atleast some areas of academic achievement. In additionto further defining the neurocognitive effects of the disorder,the present study may have implications for remediationand ultimately for the academic success ofchildren with this disorder. In addition, such studiesmay provide a better understanding of the behavioralconsequences of genetic disorders.METHODSSubjectsNineteen subjects with a diagnosis of infantile nephropathiccystinosis (9 males, 10 females), and 19 controlsubjects (9 males, 10 females) participated in thestudy. Control subjects were individually matched tothe cystinosis subjects on the basis of age (±1 year forsubjects < 18 years, ±3 years for subjects 18 years),sex, and IQ (±10 points). Statistical analysis indicatedthat the groups did not differ on age (cystinosis group:mean age 8 years 10 months, range 5 years 1month to 25 years 4 months; control group: mean age 8 years 9 months, range 5 years 1 month to 26years 0 months) or IQ (cystinosis group: mean IQ 108 ± 10; control group: mean IQ 108 ± 9). All subjectshad IQs within the normal range (85) and werefree from uncorrected visual difficulties. The diagnosisof infantile nephropathic cystinosis was based on elevatedleukocyte cystine levels [Smith et al., 1987;Smolin et al., 1987] and clinical history. All of the cystinosissubjects had been treated with cysteamine orphosphocysteamine for varying lengths of time. Noneof the cystinosis subjects was experiencing renal failureat the time of testing and all were euthyroid. Allcontrol subjects had normal developmental and medicalhistories.Materials and ProceduresAll subjects were administered the WRAT-R, accordingto standardized procedure, as part of a larger studyexamining the neurocognitive effects of cystinosis. TheWRAT-R is comprised of the subtests of arithmetic(counting items, reading of numbers, simple word problems,solving printed arithmetic problems), spelling(copying of symbols, writing of name, writing words todictation), and reading (letter recognition, letter identification,word pronunciation). The WRAT-R manualprovides normative data for ages 5–0 through 74–11years and standard scores with a mean of 100 and astandard deviation of 15. Standard scores for the threesubtests were analyzed using multivariate analysis ofvariance (MANOVA), with the independent variablesof group and sex, and the dependent variables the threesubtest scores. Matched pairs t-tests were used for follow-upcomparisons. In addition, a regression analysisof each subtest score with age was performed to identifyany potential relationship between score and age inour cross-sectional study. The data were also examinedqualitatively in order to better characterize the cystinosisgroup’s performance.RESULTSThe arithmetic, spelling, and reading means andstandard deviations for the cystinosis and controlgroups are presented in Table I. MANOVA revealed asignificant main effect for Group (P .009). Follow-upcomparisons indicated that the cystinosis group performedsignificantly more poorly (P .001) than didthe control group on the arithmetic subtest and thatthere was a trend (P .085) toward poorer performanceby the cystinosis group on the spelling subtest.

Academic Achievement in Cystinosis 159TABLE I. Means and Standard Deviations Obtained by theCystinosis Group and the Control Group on Arithmetic,Spelling, and ReadingCystinosis Group(N 19)Control Group(N 19)Subtest M SD M SD PArithmetic 89.95 13.77 102.16 9.62 .001Spelling 90.68 18.81 98.00 10.96 .085Reading 97.47 15.59 98.58 12.41 .726The cystinosis group did not differ significantly fromthe control group on the reading subtest. TheMANOVA revealed no significant main effect for Sex,nor was there a Group x Sex interaction. The cystinosisand control subjects’ standard scores on each subtestare plotted in Figure 1. Regression analyses of age witharithmetic, spelling, and reading standard scores revealedno significant correlations in either the cystinosisor control group.In terms of the level of performance on each subtest,the cystinosis group scored at the juncture of the averageand low average ranges on both arithmetic (mean 89.95 ± 13.77) and spelling (mean 90.68 ± 18.81).They performed within the average range on reading(mean 97.47 ± 15.59). The control group performedwithin the average range on each subtest. Given thecystinosis group’s generally poorer and more variableperformance in comparison to controls (see Table I), thedata were also analyzed qualitatively on two dimensions:the first was the number of subjects falling at orbelow a standard score of 85 (16th percentile), indicatingan impaired performance. The second was thenumber of subjects scoring at or above a standard scoreof 100 (50th percentile), indicating an average toFig. 1. Standard scores for cystinosis (Cyst) and control (Ctrl) subjectson the Arithmetic, Spelling, and Reading subtests.above average performance. Table II presents the numberand percentage of cystinosis and control subjectsdemonstrating ‘‘impaired’’ and ‘‘50th percentile+’’ performanceon each of the three subtests. As can be seenin Table II, the number of cystinosis subjects falling inthe impaired range is considerably greater than thenumber of control subjects falling in the impairedrange, particularly on the subtests of arithmetic andspelling. Similarly, when considering the number ofscores at or above the 50th percentile, there are farfewer cystinosis than control subjects performing atthis level.Since the normative data for the WRAT-R are basedon age, whereas academic skills are largely related tograde level in school, it was important to determinewhether differences in performance were due to differencesin grade level between the two groups. Therefore,a comparison of grade level was performed for all butone of the cystinosis-control pairs (data for one pairwere unavailable). Eight cystinosis-control pairs werein the same grade, in six pairs the control was onegrade ahead of the cystinosis subject, and in four pairsthe cystinosis subject was one grade ahead of the controlsubject. Moreover, all subjects but two with cystinosiswere grade-appropriate for their age. In the caseof the two, one cystinosis subject was a year behind andone was a year advanced.DISCUSSIONThe results of this study indicate that, despite normalintelligence and age-appropriate grade level inschool, individuals with cystinosis may demonstrateacademic difficulties, particularly in arithmetic and toa lesser extent in spelling. The observed difference inacademic performance could not be attributed to anydifference in educational level between the two groups,since both groups had comparable grade levels. Furthermore,no trends were found between age and standardscore for cystinosis subjects on any of the subtests.Hence, in this cross-sectional sample, there was no evidenceof either a developmental lag or deterioration offunction with age. This might argue for the presence ofan early alteration in brain development that produceda static deficit.The observed academic differences may be related tothe underlying visual processing deficits previouslyidentified in these individuals. The visual deficits includedifficulty with spatial relationships, part–wholerelationships, some aspects of visual memory, mentalimagery, and mental rotation. Such difficulties may atleast partially explain the arithmetic and spelling performancesobserved here. Both of these academic skillsrequire multiple aspects of visual processing and visual–spatialintegration. Disturbances in these basic cognitiveabilities could interfere with normal acquisitionof, and proficiency in, certain academic abilities. Theobserved differences in the cystinosis group do not appearto be simply a problem of delayed learning of academicskills, since the standard scores of the older andyounger subjects were similar.It is possible that the differences in both visual processingand academic skills may reflect a common

160 Ballantyne et al.TABLE II. Number and Percentage of Cystinosis and Control Subjects Demonstrating ‘‘Impaired’’ and ‘‘50th Percentile +’’Performance on Arithmetic, Spelling, and ReadingImpaired 50th Percentile +Cystinosis Control Cystinosis ControlSubtestN % N % N % N %Arithmetic 8 42 1 5 5 26 12 63Spelling 7 37 2 11 8 42 11 58Reading 5 26 2 11 10 53 12 63mechanism of selective cortical damage by the metabolicdisorder. Although a cause for such selective damagehas not been identified to date, several hypotheticalmechanisms deserve consideration. The genetic defectinvolves a gene that normally encodes for atransport protein which allows cystine to cross the lysosomalmembrane [Gahl et al., 1982a,b]. Cystine isthus trapped within lysosomes. The resultant cystineaccumulation within neural tissue may cause functionalimpairments in cognitive performance in one oftwo ways: either by a structural alteration in braindevelopment in utero, or by progressive damage as aresult of continuing accumulation over time. Other potentialmechanisms that might be considered includeother, as yet undefined, membrane alterations associatedwith the genetic defect; or the gene for cystinosismay be contiguous to a gene that influences visual processingor a related cognitive skill.There is evidence to support a direct effect of cystineaccumulation. Cystine has been found to accumulate inthe kidneys in utero [Schneider et al., 1974], and it islikely that cystine accumulates in fetal neural tissue aswell. This might well produce a static functional deficitsuch as we observed in this study. There may be progressivecystine accumulation in the brain throughoutchildhood as well. However, if ongoing cystine accumulationwere responsible for differences in cognitivefunction, individuals with cystinosis might be expectedto have progressively poorer performance over time.The present study did not demonstrate such changeswith age, but the cross-sectional nature of the studymay have obscured a trend toward longitudinal decline.There is as yet no experimental evidence to substantiatethe validity of the other two hypotheticalmechanisms mentioned above.There are several caveats that must be taken intoconsideration in the interpretation of these findings.We cannot completely rule out the possibility that indirecteffects of the illness, such as poor school attendance,chronic malaise, medication effects, or othermedical factors, could have contributed to poorer performance.Parental reports were obtained on all of thesubjects. Most of the children in this study did not havean unusually large number of absences from schoolcompared with controls. Furthermore, there was no indicationfrom parental reports of chronic fatigue orother obvious medical or psychosocial causes of differentialacademic performance. At this time we are unableto determine whether the various treatments forthe underlying disease have any effect on academicperformance.The implications of this research extend beyond thegroup of individuals with cystinosis. Carriers of thegene also have elevated cystine levels [Adamson et al.,1989; Gahl, 1986; Gahl et al., 1982a] and may be at riskfor subtle cognitive differences. Preliminary studies ofcarriers demonstrate subtle cognitive [Trauner et al.,1995] and neurophysiologic [Sarfaty et al., 1992] differencescompared with controls. Further studies are requiredto address this issue.At the present time, there is little information regardingdifferential localization of cystine in the brain,nor are detailed neuro-anatomic studies available tohelp define structural features that might correlatewith functional differences. Further studies of structure–functionrelationships may help to elucidate theunderlying mechanisms by which cognitive changes occurin this genetic metabolic disorder.ACKNOWLEDGMENTSThis research was funded by a grant from the NationalInstitutes of Health (RO1 HD 23854) and by aGeneral Clinical Research Center Grant (MO1 RR00827). We thank Dr. Jerry Schneider for referring thepatients for the study. We are grateful to all of theindividuals who participated in the study.REFERENCESAdamson MD, Andersson HC, Gahl WA (1989): Cystinosis. Semin Nephrol9:147–161.Ebbesen F, Mygind KI, Holck F (1976): Infantile nephropathic cystinosis inDenmark. Dan Med Bull 23:216–222.Ehrich JHH, Wolff G, Stoeppler L, Heyer R, Offner G, Brodehl J (1979):Psychosocial intellectual development of children with infantile cystinosisand cerebral atrophy. Klin Padiat 191:483–492.Gahl WA (1986): Cystinosis coming of age. Adv Pediatr 33:95–126.Gahl WA, Bashan N, Tietze F, Bernardini I, Schulman JD (1982a): Cystinetransport is defective in isolated leukocyte lysosomes from patientswith cystinosis. Science 217:1263–1265.Gahl WA, Tietze F, Bashan N, Steinherz R, Schulman JD (1982b): Defectivecystine exodus from isolated lysosome-rich fractions of cystinoticleukocytes. J Biol Chem 257:9570–9575.Jastak S, Wilkinson GS (1984): ‘‘Wide Range Achievement Test-Revised.’’Wilmington, Delaware: Jastak Associates.Jonas AJ, Conley SB, Marshall R, Johnson RA, Marks M, Rosenberg H(1987): Nephropathic cystinosis with central nervous system involvement.Am J Med 83:966–970.Levine S, Paparo G (1982): Brain lesions in a case of cystinosis. Acta Neuropathol(Berl) 57:217–220.Nichols SL, Press GA, Schneider JA, Trauner DA (1990): Cortical atrophyand cognitive performance in infantile nephropathic cystinosis. 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Academic Achievement in Cystinosis 161VG, Spear GS, Jacobson C, Pellett OL, Becker FLA (1974): Prenataldiagnosis of cystinosis. N Engl J Med 290:878–882.Smith M, Furlong CE, Green AA, Schneider JA (1987): Cystine: Bindingprotein assay. Methods Enzymol 143:144–148.Smolin LA, Clark KF, Schneider JA (1987): An improved method for heterozygotedetection of cystinosis, using polymorphonuclear leukocytes.Am J Hum Genet 41:266–275.Trauner DA, Chase C, Scheller J, Katz B, Schneider JA (1988): Neurologicand cognitive deficits in children with cystinosis. J Pediatr 112:912–914.Trauner DA, Chase C, Ballantyne A, Tallal P, Schneider J (1989): Patternsof visual memory dysfunction in children with cystinosis. Ann Neurol26:436.Trauner DA, Williams BL, Ballantyne AO, Scarvie KM, Schneider J, ChaseC (1995): Cognitive deficits in heterozygous carriers of the cystinosisgene. Pediatr Res 37:154A.Vogel DG, Malekzadeh MH, Cornford ME, Schneider JA, Shields WD,Vinters HV (1990): Central nervous system involvement in nephropathiccystinosis. J Neuropathol Exp Neurol 49:591–599.Williams BLH, Schneider JA, Trauner DA (1994): Global intellectual deficitsin cystinosis. Am J Med Genet 49:83–87.Wolff G, Ehrich JH, Offner G, Brodehl J (1982): Psychosocial and intellectualdevelopment in twelve patients with infantile nephropathic cystinosis.Acta Paediatr Scand 71:1007–1011.Wolff G, Ehrich JHH, Offner G, Brodehl J (1989): Cognitive and scholasticfunctioning in patients with infantile nephropathic cystinosis. VIIICongress of the International Pediatric Nephrology Association. Abstract8.007.

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